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  1. Computed tomography of amyloid plaques in a mouse model of Alzheimers disease using diffraction enhanced imaging

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    Connor, D.M.; Miller, L.; Benveniste, H.; Dilmanian, A.; Kritzer, M.; Zhong, Z.

    2009-03-19

    Our understanding of early development in Alzheimer's disease (AD) is clouded by the scale at which the disease progresses; amyloid beta (A{beta}) plaques, a hallmark feature of AD, are small ({approx} 50 {micro}m) and low contrast in diagnostic clinical imaging techniques. Diffraction enhanced imaging (DEI), a phase contrast x-ray imaging technique, has greater soft tissue contrast than conventional radiography and generates higher resolution images than magnetic resonance microimaging. Thus, in this proof of principle study, DEI in micro-CT mode was performed on the brains of AD-model mice to determine if DEI can visualize A{beta} plaques. Results revealed small nodules in the cortex and hippocampus of the brain. Histology confirmed that the features seen in the DEI images of the brain were A{beta} plaques. Several anatomical structures, including hippocampal subregions and white matter tracks, were also observed. Thus, DEI has strong promise in early diagnosis of AD, as well as general studies of the mouse brain.

  2. Selenomethionine reduces the deposition of beta-amyloid plaques by modulating β-secretase and enhancing selenoenzymatic activity in a mouse model of Alzheimer's disease.

    Science.gov (United States)

    Zhang, Zhong-Hao; Chen, Chen; Wu, Qiu-Yan; Zheng, Rui; Liu, Qiong; Ni, Jia-Zuan; Hoffmann, Peter R; Song, Guo-Li

    2016-08-01

    Alzheimer's disease (AD) is characterized by the production of large amounts of beta-amyloid (Aβ) and the accumulation of extracellular senile plaques, which have been considered to be potential targets in the treatment of AD. Selenium (Se) is a nutritionally essential trace element with known antioxidant potential and Se status has been shown to decrease with age and has a close relationship with cognitive competence in AD. Selenomethionine (Se-Met), a major reserve form of Se in organisms, has been shown in our previous study to ameliorate the decline in cognitive function, increase oxidation resistance, and reduce tau hyperphosphorylation in a triple transgenic mouse model of AD. However, it has not been reported whether Se-Met has any effects on Aβ pathology in AD mice. To study the effect of Se-Met on Aβ pathology and the function of selenoproteins/selenoenzymes in 3× Tg-AD mice, 3× Tg-AD mice at 8 months of age were treated with Se-Met for 3 months. Se-Met led to significantly reduced production and deposition of Aβ, down-regulation of β-secretase levels and enhanced activity of selenoenzymes as well as increased levels of Se in the hippocampus and cortex. Se-Met reduces amyloidogenic processing of amyloid precursor protein while modulating β-secretase and selenoenzymatic activity in AD mice. These results indicate that Se-Met might exert its therapeutic effect through multiple pathways in AD. PMID:27465436

  3. Amyloid plaque imaging in vivo: current achievement and future prospects

    Energy Technology Data Exchange (ETDEWEB)

    Nordberg, Agneta [Karolinska University Hospital Huddinge, Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Division of Alzheimer Neurobiology, Stockholm (Sweden); Karolinska University Hospital Huddinge, Department of Geriatric Medicine, Stockholm (Sweden)

    2008-03-15

    Alzheimer's disease (AD) is a very complex neurodegenerative disorder, the exact cause of which is still not known. The major histopathological features, amyloid plaques and neurofibrillary tangles, already described by Alois Alzheimer, have been the focus in research for decades. Despite a probable whole cascade of events in the brain leading to impairment of cognition, amyloid is still the target for diagnosis and treatment. The rapid development of molecular imaging techniques now allows imaging of amyloid plaques in vivo in Alzheimer patients by PET amyloid ligands such as Pittsburgh compound B (PIB). Studies so far have revealed high {sup 11}C-PIB retention in brain at prodromal stages of AD and a possibility to discriminate AD from other dementia disorders by {sup 11}C-PIB. Ongoing studies are focussing to understand the relationship between brain and CSF amyloid processes and cognitive processes. In vivo imaging of amyloid will be important for early diagnosis and evaluation of new anti-amyloid therapies in AD. (orig.)

  4. Amyloid Plaques in PSAPP Mice Bind Less Metal than Plaques in Human Alzheimer's Disease

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    Leskovjan, A.; Lanzirotti, A; Miller, L

    2009-01-01

    Amyloid beta (A{Beta}) is the primary component of Alzheimer's disease (AD) plaques, a key pathological feature of the disease. Metal ions of zinc (Zn), copper (Cu), iron (Fe), and calcium (Ca) are elevated in human amyloid plaques and are thought to be involved in neurodegeneration. Transgenic mouse models of AD also exhibit amyloid plaques, but fail to exhibit the high degree of neurodegeneration observed in humans. In this study, we imaged the Zn, Cu, Fe, and Ca ion distribution in the PSAPP transgenic mouse model representing end-stage AD (N = 6) using synchrotron X-ray fluorescence (XRF) microprobe. In order to account for differences in density in the plaques, the relative protein content was imaged with synchrotron Fourier transform infrared microspectroscopy (FTIRM) on the same samples. FTIRM results revealed a 61% increase in protein content in the plaques compared to the surrounding tissue. After normalizing to protein density, we found that the PSAPP plaques contained only a 29% increase in Zn and there was actually less Cu, Fe, and Ca in the plaque compared to the surrounding tissue. Since metal binding to A{beta} is thought to induce redox chemistry that is toxic to neurons, the reduced metal binding in PSAPP mice is consistent with the lack of neurodegeneration in these animals. These findings were in stark contrast to the high metal ion content observed in human AD plaques, further implicating the role of metal ions in human AD pathology.

  5. Augmented Senile Plaque Load in Aged Female β-Amyloid Precursor Protein-Transgenic Mice

    OpenAIRE

    Callahan, Michael J.; Lipinski, William J.; Bian, Feng; Durham, Robert A.; Pack, Amy; Walker, Lary C.

    2001-01-01

    Transgenic mice (Tg2576) overexpressing human β-amyloid precursor protein with the Swedish mutation (APP695SWE) develop Alzheimer’s disease-like amyloid β protein (Aβ) deposits by 8 to 10 months of age. These mice show elevated levels of Aβ40 and Aβ42, as well as an age-related increase in diffuse and compact senile plaques in the brain. Senile plaque load was quantitated in the hippocampus and neocortex of 8- to 19-month-old male and female Tg2576 mice. In all mice, plaque burden increased m...

  6. Optimal parameters for near infrared fluorescence imaging of amyloid plaques in Alzheimer's disease mouse models

    International Nuclear Information System (INIS)

    Amyloidplaques are an Alzheimer's disease biomarker which present unique challenges for near-infrared fluorescence tomography because of size (<50 μm diameter) and distribution. We used high-resolution simulations of fluorescence in a digital Alzheimer's disease mouse model to investigate the optimal fluorophore and imaging parameters for near-infrared fluorescence tomography of amyloid plaques. Fluorescence was simulated for amyloid-targeted probes with emission at 630 and 800 nm, plaque-to-background ratios from 1-1000, amyloid burden from 0-10%, and for transmission and reflection measurement geometries. Fluorophores with high plaque-to-background contrast ratios and 800 nm emission performed significantly better than current amyloid imaging probes. We tested idealized fluorophores in transmission and full-angle tomographic measurement schemes (900 source-detector pairs), with and without anatomical priors. Transmission reconstructions demonstrated strong linear correlation with increasing amyloid burden, but underestimated fluorescence yield and suffered from localization artifacts. Full-angle measurements did not improve upon the transmission reconstruction qualitatively or in semi-quantitative measures of accuracy; anatomical and initial-value priors did improve reconstruction localization and accuracy for both transmission and full-angle schemes. Region-based reconstructions, in which the unknowns were reduced to a few distinct anatomical regions, produced highly accurate yield estimates for cortex, hippocampus and brain regions, even with a reduced number of measurements (144 source-detector pairs).

  7. Characterization of in vivo MRI detectable thalamic amyloid plaques from APP/PS1 mice

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    Dhenain, M. [URA CEA CNRS 2210, I2BM, SHFJ, 4 Place du General Leclerc, 91401 Orsay Cedex (France); Dhenain, M.; El Tannir El Tayara, N.; Wu, T.D.; Volk, A.; Quintana, C. [U759 INSERM, Centre Universitaire, Laboratoire 112, 91405 Orsay Cedex (France); Dhenain, M.; El Tannir El Tayara, N.; Wu, T.D.; Volk, A.; Quintana, C. [Institut Curie, Centre Universitaire, Laboratoire 112, 91405 Orsay Cedex (France); Guegan, M.; Delatour, B. [Instituto de Microelectronica de Madrid-CSIC, 8, Isaac Newton, 28760 Tres Cantos, Madrid (Spain)

    2009-07-01

    Amyloid deposits are one of the hallmarks of Alzheimer's disease. Recent studies, in transgenic mice modeling Alzheimer's disease showed that, using in vivo, contrast agent-free, MRI, thalamic amyloid plaques are more easily detected than other plaques of the brain. Our study evaluated the characteristics of these thalamic plaques in a large population of APP/PS1, PS1 and C57BL/6 mice. Thalamic spots were detected in all mice but with different frequency and magnitude. Hence, the prevalence and size of the lesions were higher in APP/PS1 mice. However, even in APP/PS1 mice, thalamic spots did not occur in all the old animals. In APP/PS1 mice, spots detection was related to high iron and calcium load within amyloid plaques and thus reflects the ability of such plaque to capture large amounts of minerals. Interestingly, calcium and iron was also detected in extra-thalamic plaques but with a lower intensity. Hypointense lesions in the thalamus were not associated with the iron load in the tissue surrounding the plaques, nor with micro-hemorrhages, inflammation, or a neuro-degenerative context. (authors)

  8. In vivo detection of amyloid plaques by gadolinium-stained MRI can be used to demonstrate the efficacy of an anti-amyloid immunotherapy

    Directory of Open Access Journals (Sweden)

    Mathieu D. Santin

    2016-03-01

    Full Text Available Extracellular deposition of β amyloid plaques is an early event associated to Alzheimer's disease. Here we have used in vivo gadolinium-stained high resolution (29*29*117µm3 MRI to follow-up in a longitudinal way individual amyloid plaques in APP/PS1 mice and evaluate the efficacy of a new immunotherapy (SAR255952 directed against protofibrillar and fibrillary forms of Aβ. APP/PS1 mice were treated for 5 months between the age of 3.5 and 8.5 months. SAR255952 reduced amyloid load in 8.5-month-old animals, but not in 5.5-month animals compared to mice treated with a control antibody (DM4. Histological evaluation confirmed the reduction of amyloid load and revealed a lower density of amyloid plaques in 8.5-month SAR255952-treated animals. The longitudinal follow-up of individual amyloid plaques by MRI revealed that plaques that were visible at 5.5 months were still visible at 8.5 months in both SAR255952 and DM4-treated mice. This suggests that the amyloid load reduction induced by SAR255952 is related to a slowing down in the formation of new plaques rather than to the clearance of already formed plaques.

  9. Polarization properties of amyloid-beta plaques in Alzheimer's disease (Conference Presentation)

    Science.gov (United States)

    Baumann, Bernhard; Wöhrer, Adelheid; Ricken, Gerda; Pircher, Michael; Kovacs, Gabor G.; Hitzenberger, Christoph K.

    2016-03-01

    In histopathological practice, birefringence is used for the identification of amyloidosis in numerous tissues. Amyloid birefringence is caused by the parallel arrangement of fibrous protein aggregates. Since neurodegenerative processes in Alzheimer's disease (AD) are also linked to the formation of amyloid-beta (Aβ) plaques, optical methods sensitive to birefringence may act as non-invasive tools for Aβ identification. At last year's Photonics West, we demonstrated polarization-sensitive optical coherence tomography (PS-OCT) imaging of ex vivo cerebral tissue of advanced stage AD patients. PS-OCT provides volumetric, structural imaging based on both backscatter contrast and tissue polarization properties. In this presentation, we report on polarization-sensitive neuroimaging along with numerical simulations of three-dimensional Aβ plaques. High speed PS-OCT imaging was performed using a spectral domain approach based on polarization maintaining fiber optics. The sample beam was interfaced to a confocal scanning microscope arrangement. Formalin-fixed tissue samples as well as thin histological sections were imaged. For comparison to the PS-OCT results, ray propagation through plaques was modeled using Jones analysis and various illumination geometries and plaque sizes. Characteristic polarization patterns were found. The results of this study may not only help to understand PS-OCT imaging of neuritic Aβ plaques but may also have implications for polarization-sensitive imaging of other fibrillary structures.

  10. The Centiloid Project: Standardizing Quantitative Amyloid Plaque Estimation by PET

    Science.gov (United States)

    Klunk, William E.; Koeppe, Robert A.; Price, Julie C.; Benzinger, Tammie; Devous, Michael D.; Jagust, William; Johnson, Keith; Mathis, Chester A.; Minhas, Davneet; Pontecorvo, Michael J.; Rowe, Christopher C.; Skovronsky, Daniel; Mintun, Mark

    2014-01-01

    Although amyloid imaging with PiB-PET, and now with F-18-labelled tracers, has produced remarkably consistent qualitative findings across a large number of centers, there has been considerable variability in the exact numbers reported as quantitative outcome measures of tracer retention. In some cases this is as trivial as the choice of units, in some cases it is scanner dependent, and of course, different tracers yield different numbers. Our working group was formed to standardize quantitative amyloid imaging measures by scaling the outcome of each particular analysis method or tracer to a 0 to 100 scale, anchored by young controls (≤45 years) and typical Alzheimer’s disease patients. The units of this scale have been named “Centiloids.” Basically, we describe a “standard” method of analyzing PiB PET data and then a method for scaling any “non-standard” method of PiB PET analysis (or any other tracer) to the Centiloid scale. PMID:25443857

  11. Polyfluorinated bis-styrylbenzenes as amyloidplaque binding ligands.

    Science.gov (United States)

    Nabuurs, Rob J A; Kapoerchan, Varsha V; Metaxas, Athanasios; de Jongh, Sanne; de Backer, Maaike; Welling, Mick M; Jiskoot, Wim; Windhorst, Albert D; Overkleeft, Hermen S; van Buchem, Mark A; Overhand, Mark; van der Weerd, Louise

    2014-04-15

    Detection of cerebral β-amyloid (Aβ) by targeted contrast agents remains of great interest to aid the in vivo diagnosis of Alzheimer's disease (AD). Bis-styrylbenzenes have been previously reported as potential Aβ imaging agents. To further explore their potency as (19)F MRI contrast agents we synthetized several novel fluorinated bis-styrylbenzenes and studied their fluorescent properties and amyloid-β binding characteristics. The compounds showed a high affinity for Aβ plaques on murine and human brain sections. Interestingly, competitive binding experiments demonstrated that they bound to a different binding site than chrysamine G. Despite their high logP values, many bis-styrylbenzenes were able to enter the brain and label murine amyloid in vivo. Unfortunately initial post-mortem (19)F NMR studies showed that these compounds as yet do not warrant further MRI studies due to the reduction of the (19)F signal in the environment of the brain. PMID:24657049

  12. [18F]Fluoroazabenzoxazoles as potential amyloid plaque PET tracers: synthesis and in vivo evaluation in rhesus monkey

    International Nuclear Information System (INIS)

    Introduction: An 18F-labeled positron emission tomography (PET) tracer for amyloid plaque is desirable for early diagnosis of Alzheimer's disease, particularly to enable preventative treatment once effective therapeutics are available. Similarly, such a tracer would be useful as a biomarker for enrollment of patients in clinical trials for evaluation of antiamyloid therapeutics. Furthermore, changes in the level of plaque burden as quantified by an amyloid plaque PET tracer may provide valuable insights into the effectiveness of amyloid-targeted therapeutics. This work describes our approach to evaluate and select a candidate PET tracer for in vivo quantification of human amyloid plaque. Methods: Ligands were evaluated for their in vitro binding to human amyloid plaques, lipophilicity and predicted blood–brain barrier permeability. Candidates with favorable in vitro properties were radiolabeled with 18F and evaluated in vivo. Baseline PET scans in rhesus monkey were conducted to evaluate the regional distribution and kinetics of each tracer using tracer kinetic modeling methods. High binding potential in cerebral white matter and cortical grey matter was considered an unfavorable feature of the candidate tracers. Results: [18F]MK-3328 showed the most favorable combination of low in vivo binding potential in white matter and cortical grey matter in rhesus monkeys, low lipophilicity (Log D=2.91) and high affinity for human amyloid plaques (IC50=10.5±1.3 nM). Conclusions: [18F]MK-3328 was identified as a promising PET tracer for in vivo quantification of amyloid plaques, and further evaluation in humans is warranted.

  13. Nanoparticulate Radiolabelled Quinolines Detect Amyloid Plaques in Mouse Models of Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Celeste A. Roney

    2009-01-01

    Full Text Available Detecting aggregated amyloid peptides (Aβ plaques presents targets for developing biomarkers of Alzheimer's disease (AD. Polymeric n-butyl-2-cyanoacrylate (PBCA nanoparticles (NPs were encapsulated with radiolabelled amyloid affinity I125-clioquinol (CQ, 5-chloro-7-iodo-8-hydroxyquinoline as in vivo probes. I125-CQ-PBCA NPs crossed the BBB (2.3±0.9 ID/g (P<.05 in the WT mouse (N = 210, compared to I125-CQ (1.0±0.4 ID/g. I125-CQ-PBCA NP brain uptake increased in AD transgenic mice (APP/PS1 versus WT (N = 38; 2.54×105±5.31×104 DLU/mm2; versus 1.98×105±2.22×104 DLU/mm2 and in APP/PS1/Tau. Brain increases were in mice intracranially injected with aggregated Aβ42 peptide (N = 17; 7.19×105±1.25×105 DLU/mm2, versus WT (6.07×105±7.47×104 DLU/mm2. Storage phosphor imaging and histopathological staining of the plaques, Fe2+ and Cu2+, validated results. I125-CQ-PBCA NPs have specificity for Aβ in vitro and in vivo and are promising as in vivo SPECT (I123, or PET (I124 amyloid imaging agents.

  14. Optimal parameters for near infrared fluorescence imaging of amyloid plaques in Alzheimer's disease mouse models

    Energy Technology Data Exchange (ETDEWEB)

    Raymond, S B [Harvard-MIT Division of Health Sciences and Technology, 77 Mass Ave., E25-519, Cambridge, MA 02139 (United States); Kumar, A T N; Boas, D A [Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, 149 13th St Charlestown, MA 02129 (United States); Bacskai, B J [Alzheimer' s Research Unit, Department of Neurology, Massachusetts General Hospital, 114 16th St, Charlestown, MA 02129 (United States)], E-mail: bbacskai@partners.org

    2009-10-21

    Amyloid-{beta} plaques are an Alzheimer's disease biomarker which present unique challenges for near-infrared fluorescence tomography because of size (<50 {mu}m diameter) and distribution. We used high-resolution simulations of fluorescence in a digital Alzheimer's disease mouse model to investigate the optimal fluorophore and imaging parameters for near-infrared fluorescence tomography of amyloid plaques. Fluorescence was simulated for amyloid-targeted probes with emission at 630 and 800 nm, plaque-to-background ratios from 1-1000, amyloid burden from 0-10%, and for transmission and reflection measurement geometries. Fluorophores with high plaque-to-background contrast ratios and 800 nm emission performed significantly better than current amyloid imaging probes. We tested idealized fluorophores in transmission and full-angle tomographic measurement schemes (900 source-detector pairs), with and without anatomical priors. Transmission reconstructions demonstrated strong linear correlation with increasing amyloid burden, but underestimated fluorescence yield and suffered from localization artifacts. Full-angle measurements did not improve upon the transmission reconstruction qualitatively or in semi-quantitative measures of accuracy; anatomical and initial-value priors did improve reconstruction localization and accuracy for both transmission and full-angle schemes. Region-based reconstructions, in which the unknowns were reduced to a few distinct anatomical regions, produced highly accurate yield estimates for cortex, hippocampus and brain regions, even with a reduced number of measurements (144 source-detector pairs)

  15. In vivo detection of prion amyloid plaques using [11C]BF-227 PET

    International Nuclear Information System (INIS)

    In vivo detection of pathological prion protein (PrP) in the brain is potentially useful for the diagnosis of transmissible spongiform encephalopathies (TSEs). However, there are no non-invasive ante-mortem means for detection of pathological PrP deposition in the brain. The purpose of this study is to evaluate the amyloid imaging tracer BF-227 with positron emission tomography (PET) for the non-invasive detection of PrP amyloid in the brain. The binding ability of BF-227 to PrP amyloid was investigated using autoradiography and fluorescence microscopy. Five patients with TSEs, including three patients with Gerstmann-Straeussler-Scheinker disease (GSS) and two patients with sporadic Creutzfeldt-Jakob disease (CJD), underwent [11C]BF-227 PET scans. Results were compared with data from 10 normal controls and 17 patients with Alzheimer's disease (AD). The regional to pons standardized uptake value ratio was calculated as an index of BF-227 retention. Binding of BF-227 to PrP plaques was confirmed using brain samples from autopsy-confirmed GSS cases. In clinical PET study, significantly higher retention of BF-227 was detected in the cerebellum, thalamus and lateral temporal cortex of GSS patients compared to that in the corresponding tissues of normal controls. GSS patients also showed higher retention of BF-227 in the cerebellum, thalamus and medial temporal cortex compared to AD patients. In contrast, the two CJD patients showed no obvious retention of BF-227 in the brain. Although [11C]BF-227 is a non-specific imaging marker of cerebral amyloidosis, it is useful for in vivo detection of PrP plaques in the human brain in GSS, based on the regional distribution of the tracer. PET amyloid imaging might provide a means for both early diagnosis and non-invasive disease monitoring of certain forms of TSEs. (orig.)

  16. In vivo detection of prion amyloid plaques using [{sup 11}C]BF-227 PET

    Energy Technology Data Exchange (ETDEWEB)

    Okamura, Nobuyuki; Yanai, Kazuhiko [Tohoku University School of Medicine, Department of Pharmacology, Sendai (Japan); Shiga, Yusei; Itoyama, Yasuhito [Tohoku University School of Medicine, Department of Neurology, Sendai (Japan); Furumoto, Shozo [Tohoku University School of Medicine, Department of Pharmacology, Sendai (Japan); Tohoku University, Division of Radiopharmaceutical Chemistry, Cyclotron and Radioisotope Center, Sendai (Japan); Tashiro, Manabu [Tohoku University, Division of Cyclotron Nuclear Medicine, Cyclotron and Radioisotope Center, Sendai (Japan); Tsuboi, Yoshio [Fukuoka University School of Medicine, Department of Neurology, Fukuoka (Japan); Furukawa, Katsutoshi; Arai, Hiroyuki [Institute of Development, Aging, and Cancer, Tohoku University, Department of Geriatrics and Gerontology, Division of Brain Sciences, Sendai (Japan); Iwata, Ren [Tohoku University, Division of Radiopharmaceutical Chemistry, Cyclotron and Radioisotope Center, Sendai (Japan); Kudo, Yukitsuka [Tohoku University, Innovation of New Biomedical Engineering Center, Sendai (Japan); Doh-ura, Katsumi [Tohoku University School of Medicine, Department of Prion Research, 2-1 Seiryo-machi, Aoba-ku, Sendai (Japan)

    2010-05-15

    In vivo detection of pathological prion protein (PrP) in the brain is potentially useful for the diagnosis of transmissible spongiform encephalopathies (TSEs). However, there are no non-invasive ante-mortem means for detection of pathological PrP deposition in the brain. The purpose of this study is to evaluate the amyloid imaging tracer BF-227 with positron emission tomography (PET) for the non-invasive detection of PrP amyloid in the brain. The binding ability of BF-227 to PrP amyloid was investigated using autoradiography and fluorescence microscopy. Five patients with TSEs, including three patients with Gerstmann-Straeussler-Scheinker disease (GSS) and two patients with sporadic Creutzfeldt-Jakob disease (CJD), underwent [{sup 11}C]BF-227 PET scans. Results were compared with data from 10 normal controls and 17 patients with Alzheimer's disease (AD). The regional to pons standardized uptake value ratio was calculated as an index of BF-227 retention. Binding of BF-227 to PrP plaques was confirmed using brain samples from autopsy-confirmed GSS cases. In clinical PET study, significantly higher retention of BF-227 was detected in the cerebellum, thalamus and lateral temporal cortex of GSS patients compared to that in the corresponding tissues of normal controls. GSS patients also showed higher retention of BF-227 in the cerebellum, thalamus and medial temporal cortex compared to AD patients. In contrast, the two CJD patients showed no obvious retention of BF-227 in the brain. Although [{sup 11}C]BF-227 is a non-specific imaging marker of cerebral amyloidosis, it is useful for in vivo detection of PrP plaques in the human brain in GSS, based on the regional distribution of the tracer. PET amyloid imaging might provide a means for both early diagnosis and non-invasive disease monitoring of certain forms of TSEs. (orig.)

  17. Type II fuzzy systems for amyloid plaque segmentation in transgenic mouse brains for Alzheimer's disease quantification

    Science.gov (United States)

    Khademi, April; Hosseinzadeh, Danoush

    2014-03-01

    Alzheimer's disease (AD) is the most common form of dementia in the elderly characterized by extracellular deposition of amyloid plaques (AP). Using animal models, AP loads have been manually measured from histological specimens to understand disease etiology, as well as response to treatment. Due to the manual nature of these approaches, obtaining the AP load is labourious, subjective and error prone. Automated algorithms can be designed to alleviate these challenges by objectively segmenting AP. In this paper, we focus on the development of a novel algorithm for AP segmentation based on robust preprocessing and a Type II fuzzy system. Type II fuzzy systems are much more advantageous over the traditional Type I fuzzy systems, since ambiguity in the membership function may be modeled and exploited to generate excellent segmentation results. The ambiguity in the membership function is defined as an adaptively changing parameter that is tuned based on the local contrast characteristics of the image. Using transgenic mouse brains with AP ground truth, validation studies were carried out showing a high degree of overlap and low degree of oversegmentation (0.8233 and 0.0917, respectively). The results highlight that such a framework is able to handle plaques of various types (diffuse, punctate), plaques with varying Aβ concentrations as well as intensity variation caused by treatment effects or staining variability.

  18. Synthesis and evaluation of ethyleneoxylated and allyloxylated chalcone derivatives for imaging of amyloid β plaques by SPECT

    OpenAIRE

    Fuchigami, Takeshi; Yamashita, Yuki; Haratake, Mamoru; Ono, Masahiro; Yoshida, Sakura; Nakayama, Morio

    2014-01-01

    We report radioiodinated chalcone derivatives as new SPECT imaging probes for amyloid β (Aβ) plaques. The monoethyleneoxy derivative 2 and allyloxy derivative 8 showed a high affinity for Aβ(1-42) aggregates with Ki values of 24 and 4.5 nM, respectively. Fluorescent imaging demonstrated that 2 and 8 clearly stained thioflavin-S positive Aβ plaques in the brain sections of Tg2576 transgenic mice. In vitro autoradiography revealed that [125I]2 displayed no clear accumulation toward Aβ plaques i...

  19. RNA aptamer probes as optical imaging agents for the detection of amyloid plaques.

    Directory of Open Access Journals (Sweden)

    Christian T Farrar

    Full Text Available Optical imaging using multiphoton microscopy and whole body near infrared imaging has become a routine part of biomedical research. However, optical imaging methods rely on the availability of either small molecule reporters or genetically encoded fluorescent proteins, which are challenging and time consuming to develop. While directly labeled antibodies can also be used as imaging agents, antibodies are species specific, can typically not be tagged with multiple fluorescent reporters without interfering with target binding, and are bioactive, almost always eliciting a biological response and thereby influencing the process that is being studied. We examined the possibility of developing highly specific and sensitive optical imaging agents using aptamer technology. We developed a fluorescently tagged anti-Aβ RNA aptamer, β55, which binds amyloid plaques in both ex vivo human Alzheimer's disease brain tissue and in vivo APP/PS1 transgenic mice. Diffuse β55 positive halos, attributed to oligomeric Aβ, were observed surrounding the methoxy-XO4 positive plaque cores. Dot blots of synthetic Aβ aggregates provide further evidence that β55 binds both fibrillar and non-fibrillar Aβ. The high binding affinity, the ease of probe development, and the ability to incorporate multiple and multimodal imaging reporters suggest that RNA aptamers may have complementary and perhaps advantageous properties compared to conventional optical imaging probes and reporters.

  20. Synthesis and evaluation of 18F-fluoroethylated benzothiazole derivatives for in vivo imaging of amyloid plaques in Alzheimer's disease

    International Nuclear Information System (INIS)

    Amyloid aggregates play a major role in the development of Alzheimer's disease. Targeting these aggregates by PET probes enables non-invasively the detection and quantification of amyloid deposit distribution in human brains. Based on benzothiazole core structure a series of amyloid imaging agents were developed. Currently [11C]2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole (Pittsburgh Compound-B (PIB) is the most specific and widely used amyloid imaging ligand. But due to the short half life of 11C, longer lived 18F-labeled derivatives offer logistic advantages and higher contrast images. In this work, three different [18F]fluoroethoxy-substituted benzothiazole derivatives ([18F]2-(4'-(methylamino)phenyl)-6-(2-fluoroethoxy)benzothiazole, [18F]2-((2'-(2-fluoroethoxy)-4'-amino)phenyl)benzothiazole and [18F]2-(3'-((2-fluoroethoxy)-4'-amino)phenyl)benzothiazole) were synthesized via [18F]fluoroethylation. The latter two derivatives with fluoroethoxy-substitution on the aromatic amino group showed very low binding affinity for amyloid aggregates. In contrast [18F]2-(4'-(methylamino)phenyl)-6-(2-fluoroethoxy)benzothiazole with [18F]fluoroethoxy-substitution in 6-position showed excellent amyloid imaging properties with respect to lipophilicity, brain entry and brain clearance in normal SCID mice, amyloid plaque binding affinity and specificity.

  1. Synthesis of Oxorhenium(V) and Oxotechnetium(V) Complexes That Bind to AmyloidPlaques.

    Science.gov (United States)

    Hayne, David J; White, Jonathan M; McLean, Catriona A; Villemagne, Victor L; Barnham, Kevin J; Donnelly, Paul S

    2016-08-15

    Alzheimer's disease is characterized by the presence of amyloid plaques in the brain. The primary constituents of the plaques are aggregated forms of the amyloid-β (Aβ) peptide. With the goal of preparing technetium-99(m) complexes that bind to Aβ plaques with the potential to be diagnostic imaging agents for Alzheimer's disease, new tetradentate ligands capable of forming neutral and lipophilic complexes with oxotechentium(V) and oxorhenium(V) were prepared. Nonradioactive isotopes of technetium are not available so rhenium was used as a surrogate for exploratory chemistry. Two planar tetradentate N3O ligands were prepared that form charge-neutral complexes with oxorhenium(v) as well as a ligand featuring a styrylpyridyl functional group designed to bind to Aβ plaques. All three ligands formed complexes with oxorhenium(V), and each complex was characterized by NMR spectroscopy, mass spectrometry, and X-ray crystallography. The oxorhenium(V) complex with a styrylpyridyl functional group binds to Aβ plaques present in post-mortem human brain tissue. The chemistry was extrapolated to technetium-99(m) at the tracer level for two of the ligands. The resulting oxotechnetium(V) complexes were sufficiently lipophilic and charge-neutral to suggest that they have the potential to cross the blood-brain barrier but exhibited modest stability with respect to exchange with histidine. The chemistry presented here identifies a strategy to integrate styrylpyridyl functional groups into tetradentate ligands capable of forming complexes with [M═O](3+) cores (M = Re or Tc).

  2. Effect of catalpol on senile plaques and spatial learning and memory ability in amyloid-β protein precursor/presenilin 1 double transgenic mice

    Institute of Scientific and Technical Information of China (English)

    宋冲

    2013-01-01

    Objective To investigate whether catalpol affects senile plaque formation and spatial learning and memory ability in the amyloid-βprotein precursor/presenilin 1(APP/PS1)double transgenic mice.Methods

  3. Antibodies targeted to the brain with image-guided focused ultrasound reduces amyloid-beta plaque load in the TgCRND8 mouse model of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Jessica F Jordão

    Full Text Available Immunotherapy for Alzheimer's disease (AD relies on antibodies directed against toxic amyloid-beta peptide (Abeta, which circulate in the bloodstream and remove Abeta from the brain. In mouse models of AD, the administration of anti-Abeta antibodies directly into the brain, in comparison to the bloodstream, was shown to be more efficient at reducing Abeta plaque pathology. Therefore, delivering anti-Abeta antibodies to the brain of AD patients may also improve treatment efficiency. Transcranial focused ultrasound (FUS is known to transiently-enhance the permeability of the blood-brain barrier (BBB, allowing intravenously administered therapeutics to enter the brain. Our goal was to establish that anti-Abeta antibodies delivered to the brain using magnetic resonance imaging-guided FUS (MRIgFUS can reduce plaque pathology. To test this, TgCRND8 mice received intravenous injections of MRI and FUS contrast agents, as well as anti-Abeta antibody, BAM-10. MRIgFUS was then applied transcranially. Within minutes, the MRI contrast agent entered the brain, and BAM-10 was later found bound to Abeta plaques in targeted cortical areas. Four days post-treatment, Abeta pathology was significantly reduced in TgCRND8 mice. In conclusion, this is the first report to demonstrate that MRIgFUS delivery of anti-Abeta antibodies provides the combined advantages of using a low dose of antibody and rapidly reducing plaque pathology.

  4. A Novel liposomal nanoparticle for the imaging of amyloid plaque by MRI

    OpenAIRE

    Tanifum, Eric A; Ghaghada, Ketan; Vollert, Craig; Head, Elizabeth; Eriksen, Jason L.; Annapragada, Ananth

    2016-01-01

    Amyloid binding molecules with greater hydrophilicity than existing ligands were synthesized. The lead candidate ET6-21 bound amyloid fibrils, and amyloid deposits in dog brain and human brain tissue ex vivo. The ligand was used to prepare novel amyloid-targeted liposomal nanoparticles. The preparation was tested in the Tg2576 and TetO/APP mouse models of amyloid deposition. Gd chelates and Indocyanine green were included in the particles for visualization by MRI and near-infrared microscopy....

  5. Evaluation of the early enhancement of coronary atherosclerotic plaque by contrast-enhanced MR angiography

    International Nuclear Information System (INIS)

    Purpose: To evaluate the early enhancement of coronary atherosclerotic plaque using contrast-enhanced MR angiography (CE-MRA) and investigate the association between unstable angina pectoris (UAP) and early enhancement of the plaque. Methods: Forty-one patients presenting with angina pectoris and demonstrating single-vessel disease with non-calcified plaque and significant coronary stenosis (≥50%) on CTA were consecutively recruited for coronary CE-MRA. Contrast-to-noise ratio of the culprit plaque guided by CTA was measured on a cross-sectional multi-planar reconstruction image of the plaque on both pre- and post-CE-MRA. A 50% increasing of CNR was defined as plaque enhancement. The association between early enhancement of the plaques and UAP was analyzed. Results: Thirty-seven non-calcified plaques with significant coronary stenosis were detected in the 37 patients on MRA. 4 subjects were excluded because coronary atherosclerotic plaques were inadequate for identification on MRA. Of the 37 patients, 18 patients had UAP and other 19 patients presented stable angina pectoris (SAP). Of the 37 plaques on CE-MRA, 13 and 24 plaques presented early enhancement and no enhancement, respectively. Of the 13 early-enhanced plaques, 11 (85%) and 2 (15%) were found in the patients with UAP and SAP, respectively (p < 0.01). Of the 37 patients, 11 (61%) with UAP and 2 (11%) with SAP had early-enhanced plaques, respectively (p < 0.01). Conclusion: CE-MRA allows detection of early enhancement of coronary atherosclerotic plaque. The early enhancement is common in unstable angina and could be a sign of vulnerability.

  6. Affinity of nat/68Ga-Labelled Curcumin and Curcuminoid Complexes for β-Amyloid Plaques: Towards the Development of New Metal-Curcumin Based Radiotracers

    Science.gov (United States)

    Rubagotti, Sara; Croci, Stefania; Ferrari, Erika; Iori, Michele; Capponi, Pier C.; Lorenzini, Luca; Calzà, Laura; Versari, Annibale; Asti, Mattia

    2016-01-01

    Curcumin derivatives labelled with fluorine-18 or technetium-99m have recently shown their potential as diagnostic tools for Alzheimer’s disease. Nevertheless, no study by exploiting the labelling with gallium-68 has been performed so far, in spite of its suitable properties (positron emitter, generator produced radionuclide). Herein, an evaluation of the affinity for synthetic β-amyloid fibrils and for amyloid plaques of three nat/68Ga-labelled curcumin analogues, namely curcumin curcumin (CUR), bis-dehydroxy-curcumin (bDHC) and diacetyl-curcumin (DAC), was performed. Affinity and specificity were tested in vitro on amyloid synthetic fibrils by using gallium-68 labelled compounds. Post-mortem brain cryosections from Tg2576 mice were used for the ex vivo visualization of amyloid plaques. The affinity of 68Ga(CUR)2+, 68Ga(DAC)2+, and 68Ga(bDHC)2+ for synthetic β-amyloid fibrils was moderate and their uptake could be observed in vitro. On the other hand, amyloid plaques could not be visualized on brain sections of Tg2576 mice after injection, probably due to the low stability of the complexes in vivo and of a hampered passage through the blood–brain barrier. Like curcumin, all nat/68Ga-curcuminoid complexes maintain a high affinity for β-amyloid plaques. However, structural modifications are still needed to improve their applicability as radiotracers in vivo. PMID:27608011

  7. Affinity of (nat/68)Ga-Labelled Curcumin and Curcuminoid Complexes for β-Amyloid Plaques: Towards the Development of New Metal-Curcumin Based Radiotracers.

    Science.gov (United States)

    Rubagotti, Sara; Croci, Stefania; Ferrari, Erika; Iori, Michele; Capponi, Pier C; Lorenzini, Luca; Calzà, Laura; Versari, Annibale; Asti, Mattia

    2016-01-01

    Curcumin derivatives labelled with fluorine-18 or technetium-99m have recently shown their potential as diagnostic tools for Alzheimer's disease. Nevertheless, no study by exploiting the labelling with gallium-68 has been performed so far, in spite of its suitable properties (positron emitter, generator produced radionuclide). Herein, an evaluation of the affinity for synthetic β-amyloid fibrils and for amyloid plaques of three (nat/68)Ga-labelled curcumin analogues, namely curcumin curcumin (CUR), bis-dehydroxy-curcumin (bDHC) and diacetyl-curcumin (DAC), was performed. Affinity and specificity were tested in vitro on amyloid synthetic fibrils by using gallium-68 labelled compounds. Post-mortem brain cryosections from Tg2576 mice were used for the ex vivo visualization of amyloid plaques. The affinity of (68)Ga(CUR)₂⁺, (68)Ga(DAC)₂⁺, and (68)Ga(bDHC)₂⁺ for synthetic β-amyloid fibrils was moderate and their uptake could be observed in vitro. On the other hand, amyloid plaques could not be visualized on brain sections of Tg2576 mice after injection, probably due to the low stability of the complexes in vivo and of a hampered passage through the blood-brain barrier. Like curcumin, all (nat/68)Ga-curcuminoid complexes maintain a high affinity for β-amyloid plaques. However, structural modifications are still needed to improve their applicability as radiotracers in vivo. PMID:27608011

  8. Organotypic vibrosections from whole brain adult Alzheimer mice (overexpressing amyloid-precursor-protein with the Swedish-Dutch-Iowa mutations as a model to study clearance of beta-amyloid plaques

    Directory of Open Access Journals (Sweden)

    Christian eHumpel

    2015-04-01

    Full Text Available Alzheimer´s disease is a severe neurodegenerative disorder of the brain, pathologically characterized by extracellular beta-amyloid plaques, intraneuronal Tau inclusions, inflammation, reactive glial cells, vascular pathology and neuronal cell death. The degradation and clearance of beta-amyloid plaques is an interesting therapeutic approach, and the proteases neprilysin (NEP, insulysin and matrix metalloproteinases (MMP are of particular interest. The aim of this project was to establish and characterize a simple in vitro model to study the degrading effects of these proteases. Organoytpic brain vibrosections (120 µm thick were sectioned from adult (9 month old wildtype and transgenic mice (expressing amyloid precursor protein (APP harboring the Swedish K670N/M671L, Dutch E693Q, and Iowa D694N mutations; APP_SDI and cultured for 2 weeks. Plaques were stained by immunohistochemistry for beta-amyloid and Thioflavin S. Our data show that plaques were evident in 2 week old cultures from 9 month old transgenic mice. These plaques were surrounded by reactive GFAP+ astroglia and Iba1+ microglia. Incubation of fresh slices for 2 weeks with 1-0.1-0.01 µg/ml of NEP, insulysin, MMP-2 or MMP-9 showed that NEP, insulysin and MMP-9 markedly degradeded beta-amyloid plaques but only at the highest concentration. Our data provide for the first time a potent and powerful living brain vibrosection model containing a high number of plaques, which allows to rapidly and simply study the degradation and clearance of beta-amyloid plaques in vitro.

  9. Molecular cloning and characterization of a cDNA encoding the cerebrovascular and the neuritic plaque amyloid peptides

    Energy Technology Data Exchange (ETDEWEB)

    Robakis, N.K.; Ramakrishna, N.; Wolfe, G.; Wisniewski, H.M.

    1987-06-01

    Deposits of amyloid fibers are found in large numbers in the walls of blood vessels and in neuritic plaques in the brains of patients with Alzheimer disease and adults with Down syndrome. The authors used the amino acid sequence of the amyloid peptide to synthesize oligonucleotide probes specific for the gene encoding this peptide. When a human brain cDNA library was screened with this probe, a clone was found with a 1.7-kilobase insert that contains a long open reading frame coding for 412 amino acid residues including the 28 amino acids of the amyloid peptide. RNA gel blots revealed that a 3.3-kilobase mRNA species was present in the brains of individuals with Alzheimer disease, with Down syndrome, or with not apparent neurological disorders. Southern blots showed that homologous genes are present in the genomic DNA of humans, rabbits, sheep, hamsters, and mice, suggesting that this gene has been conserved through mammalian evolution. Localization of the corresponding genomic sequences on human chromosome 21 suggest a genetic relationship between Alzheimer disease and Down syndrome, and it may explain the early appearance of large numbers of neuritic plaques in adult Down syndrome patients.

  10. Presynaptic dystrophic neurites surrounding amyloid plaques are sites of microtubule disruption, BACE1 elevation, and increased Aβ generation in Alzheimer's disease.

    Science.gov (United States)

    Sadleir, Katherine R; Kandalepas, Patty C; Buggia-Prévot, Virginie; Nicholson, Daniel A; Thinakaran, Gopal; Vassar, Robert

    2016-08-01

    Alzheimer's disease (AD) is characterized by amyloid plaques composed of the β-amyloid (Aβ) peptide surrounded by swollen presynaptic dystrophic neurites consisting of dysfunctional axons and terminals that accumulate the β-site amyloid precursor protein (APP) cleaving enzyme (BACE1) required for Aβ generation. The cellular and molecular mechanisms that govern presynaptic dystrophic neurite formation are unclear, and elucidating these processes may lead to novel AD therapeutic strategies. Previous studies suggest Aβ may disrupt microtubules, which we hypothesize have a critical role in the development of presynaptic dystrophies. To investigate this further, here we have assessed the effects of Aβ, particularly neurotoxic Aβ42, on microtubules during the formation of presynaptic dystrophic neurites in vitro and in vivo. Live-cell imaging of primary neurons revealed that exposure to Aβ42 oligomers caused varicose and beaded neurites with extensive microtubule disruption, and inhibited anterograde and retrograde trafficking. In brain sections from AD patients and the 5XFAD transgenic mouse model of amyloid pathology, dystrophic neurite halos with BACE1 elevation around amyloid plaques exhibited aberrant tubulin accumulations or voids. At the ultrastructural level, peri-plaque dystrophies were strikingly devoid of microtubules and replete with multi-lamellar vesicles resembling autophagic intermediates. Proteins of the microtubule motors, kinesin and dynein, and other neuronal proteins were aberrantly localized in peri-plaque dystrophies. Inactive pro-cathepsin D also accumulated in peri-plaque dystrophies, indicating reduced lysosomal function. Most importantly, BACE1 accumulation in peri-plaque dystrophies caused increased BACE1 cleavage of APP and Aβ generation. Our study supports the hypothesis that Aβ induces microtubule disruption in presynaptic dystrophic neurites that surround plaques, thus impairing axonal transport and leading to accumulation of

  11. Radioiodinated benzimidazole derivatives as single photon emission computed tomography probes for imaging of {beta}-amyloid plaques in Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Cui Mengchao [Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan); Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875 (China); Ono, Masahiro, E-mail: ono@pharm.kyoto-u.ac.j [Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan); Kimura, Hiroyuki; Kawashima, Hidekazu [Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan); Liu Boli [Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875 (China); Saji, Hideo, E-mail: hsaji@pharm.kyoto-u.ac.j [Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan)

    2011-04-15

    Five iodinated 2-phenyl-1H-benzo[d]imidazole derivatives were synthesized and evaluated as potential probes for {beta}-amyloid (A{beta}) plaques. One of the compounds, 4-(6-iodo-1H-benzo[d]imidazol-2-yl)-N,N-dimethylaniline (12), showed excellent affinity for A{beta}{sub 1-42} aggregates (K{sub i}=9.8 nM). Autoradiography with sections of postmortem Alzheimer's disease (AD) brain revealed that a radioiodinated probe [{sup 125}I]12, labeled A{beta} plaques selectively with low nonspecific binding. Biodistribution experiments with normal mice injected intravenously with [{sup 125}I]12 showed high uptake [4.14 percent injected dose per gram (% ID/g) at 2 min] into and rapid clearance (0.15% ID/g at 60 min) from the brain, which may bring about a good signal-to-noise ratio and therefore achieve highly sensitive detection of A{beta} plaques. In addition, [{sup 125}I]12 labeled amyloid plaques in vivo in an AD transgenic model. The preliminary results strongly suggest that [{sup 125}I]12 bears characteristics suitable for detecting amyloid plaques in vivo. When labeled with {sup 123}I, it may be a useful SPECT imaging agent for A{beta} plaques in the brain of living AD patients.

  12. Vaccination with a non-human random sequence amyloid oligomer mimic results in improved cognitive function and reduced plaque deposition and micro hemorrhage in Tg2576 mice

    Directory of Open Access Journals (Sweden)

    Rasool Suhail

    2012-08-01

    Full Text Available Abstract Background It is well established that vaccination of humans and transgenic animals against fibrillar Aβ prevents amyloid accumulation in plaques and preserves cognitive function in transgenic mouse models. However, autoimmune side effects have halted the development of vaccines based on full length human Aβ. Further development of an effective vaccine depends on overcoming these side effects while maintaining an effective immune response. Results We have previously reported that the immune response to amyloid oligomers is largely directed against generic epitopes that are common to amyloid oligomers of many different proteins and independent of a specific amino acid sequence. Here we have examined whether we can exploit this generic immune response to develop a vaccine that targets amyloid oligomers using a non-human random sequence amyloid oligomer. In order to study the effect of vaccination against generic oligomer epitopes, a random sequence oligomer (3A was selected as it forms oligomers that react with the oligomer specific A11 antibody. Oligomer mimics from 3A peptide, Aβ, islet amyloid polypeptide (IAPP, and Aβ fibrils were used to vaccinate Tg2576 mice, which develop a progressive accumulation of plaques and cognitive impairment. Vaccination with the 3A random sequence antigen was just as effective as vaccination with the other antigens in improving cognitive function and reducing total plaque load (Aβ burden in the Tg2576 mouse brains, but was associated with a much lower incidence of micro hemorrhage than Aβ antigens. Conclusion These results shows that the amyloid Aβ sequence is not necessary to produce a protective immune response that specifically targets generic amyloid oligomers. Using a non-human, random sequence antigen may facilitate the development of a vaccine that avoids autoimmune side effects.

  13. A new molecular model for Congo Red-β amyloid interaction: implications for diagnosis and inhibition of brain plaque formation in Alzheimer's disease

    Science.gov (United States)

    Zhang, Kristine A.; Li, Yat

    2015-08-01

    Alzheimer's disease (AD), an age-related neurodegenerative disorder, is the seventh leading cause of death in the United States. One strong pathological indicator of AD is senile plaques, which are aggregates of fibrils formed from amyloid β (Aβ) peptides. Thus, detection and inhibition of Aβ aggregation are critical for the prevention and treatment of AD. Congo red (CR) is one of the most widely used dye molecules for probing as well as inhabiting Aβ aggregation. However, the nature of interaction between CR and Aβ is not well understood. In this research, we systematically studied the interaction between CR and Aβ using a combination of optical techniques, including electronic absorption, fluorescence, Raman scattering, and circular dichroism, to provide detailed information with molecular specificity and high sensitivity. Compared to CR alone, interaction of the dye with Aβ results in a new absorption peak near 540 nm and significantly enhanced photoluminescence as well as Raman signal. Our results led us to propose a new model suggesting that CR exists primarily in a micellar form, resembling H-aggregates, in water and dissociates into monomers upon interaction with Aβ. This model has significant implications for the development of new strategies to detect and inhibit brain plaques for treatment of neurological diseases like AD.

  14. Acetylcholinesterase, a senile plaque component, affects the fibrillogenesis of amyloid-beta-peptides.

    Science.gov (United States)

    Alvarez, A; Bronfman, F; Pérez, C A; Vicente, M; Garrido, J; Inestrosa, N C

    1995-12-01

    Acetylcholinesterase (AChE) colocalizes with amyloid-beta peptide (A beta) deposits present in the brain of Alzheimer's patients. Recent studies showed that A beta 1-40 can adopt two different conformational states in solution (an amyloidogenic conformer, A beta ac, and a non-amyloidogenic conformer, A beta nac) which have distinct abilities to form amyloid fibrils. We report here that AChE binds A beta nac and accelerates amyloid formation by the same peptide. No such effect was observed with A beta ac, the amyloidogenic conformer, suggesting that AChE acts as a 'pathological chaperone' inducing a conformational transition from A beta nac into A beta ac in vitro.

  15. Diminished perisomatic GABAergic terminals on cortical neurons adjacent to amyloid plaques

    Directory of Open Access Journals (Sweden)

    Virginia Garcia-Marin

    2009-11-01

    Full Text Available One of the main pathological hallmarks of Alzheimer’s disease (AD is the accumulation of plaques in the cerebral cortex, which may appear either in the neuropil or in direct association with neuronal somata. Since different axonal systems innervate the dendritic (mostly glutamatergic and perisomatic (mostly GABAergic regions of neurons, the accumulation of plaques in the neuropil or associated with the soma might produce different alterations to synaptic circuits. We have used a variety of conventional light, confocal and electron microscopy techniques to study their relationship with neuronal somata in the cerebral cortex from AD patients and APP/PS1 transgenic mice. The main finding was that the membrane surfaces of neurons (mainly pyramidal cells in contact with plaques lack GABAergic perisomatic synapses. Since these perisomatic synapses are thought to exert a strong influence on the output of pyramidal cells, their loss may lead to the hyperactivity of the neurons in contact with plaques. These results suggest that plaques modify circuits in a more selective manner than previously thought.

  16. Contrast-enhanced ultrasound imaging of the vasa vasorum of carotid artery plaque

    Institute of Scientific and Technical Information of China (English)

    Ze-Zhou; Song; Yan-Ming; Zhang

    2015-01-01

    The vasa vasorum of carotid artery plaque is a novel marker of accurately evaluating the vulnerability of carotid artery plaque, which was associated with symptomatic cerebrovascular and cardiovascular disease. The presence of ultrasound contrast agents in carotid artery plaque represents the presence of the vasa vasorum in carotid artery plaque because the ultrasoundcontrast agents are strict intravascular tracers. Therefore, contrast-enhanced ultrasound(CEUS) is a novel and safe imaging modality for evaluating the vasa vasorum in carotid artery plaque. However, there are some issues that needs to be assessed to embody fully the clinical utility of the vasa vasorum in carotid artery plaque with CEUS.

  17. Impairment of in vivo calcium signaling in amyloid plaque-associated microglia.

    Science.gov (United States)

    Brawek, Bianca; Schwendele, Bernd; Riester, Karin; Kohsaka, Shinichi; Lerdkrai, Chommanad; Liang, Yajie; Garaschuk, Olga

    2014-04-01

    Neuroinflammation is a hallmark of Alzheimer's disease (AD) both in man and in multiple mouse models, and epidemiological studies link the use of anti-inflammatory drugs with a reduced risk of developing the disease. AD-related neuroinflammation is largely mediated by microglia, the main immune cells of the central nervous system. In vitro, executive functions of microglia are regulated by intracellular Ca(2+) signals, but little is known about microglial Ca(2+) signaling in vivo. Here we analyze in vivo properties of these cells in two mouse models of AD. In both strains plaque-associated microglia had hypertrophic/amoeboid morphology and were strongly positive for markers of activation such as CD11b and CD68. Activated microglia failed to respond reliably to extracellular release of adenosine triphosphate (ATP, mimicking tissue damage) and showed an increased incidence of spontaneous intracellular Ca(2+) transients. These Ca(2+) transients required activation of ATP receptors and Ca(2+) release from the intracellular Ca(2+) stores, and were not induced by neuronal or astrocytic hyperactivity. Neuronal silencing, however, selectively increased the frequency of Ca(2+) transients in plaque-associated microglia. Thus, our in vivo data reveal substantial dysfunction of plaque-associated microglia and identify a novel Ca(2+) signal possibly triggering a Ca(2+)-dependent release of toxic species in the plaque vicinity.

  18. Synthesis and evaluation of {sup 18}F-fluoroethylated benzothiazole derivatives for in vivo imaging of amyloid plaques in Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Neumaier, B. [Department of Nuclear Medicine, University of Ulm, Ulm (Germany); Max Planck Institute for Neurological Research, Klaus-Joachim-Zuelch Laboratories of the Max Planck Society and the Faculty of Medicine of the University of Cologne, Cologne (Germany)], E-mail: bernd.neumaier@nf.mpg.de; Deisenhofer, S. [Department of Nuclear Medicine, University of Ulm, Ulm (Germany); Sommer, C. [Department of Neuropathology, University of Mainz (Germany); Solbach, C.; Reske, S.N. [Department of Nuclear Medicine, University of Ulm, Ulm (Germany); Mottaghy, F. [Department of Nuclear Medicine, University of Ulm, Ulm (Germany); Department of Nuclear Medicine, RWTH Aachen, Aachen (Germany)

    2010-06-15

    Amyloid aggregates play a major role in the development of Alzheimer's disease. Targeting these aggregates by PET probes enables non-invasively the detection and quantification of amyloid deposit distribution in human brains. Based on benzothiazole core structure a series of amyloid imaging agents were developed. Currently [{sup 11}C]2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole (Pittsburgh Compound-B (PIB) is the most specific and widely used amyloid imaging ligand. But due to the short half life of {sup 11}C, longer lived {sup 18}F-labeled derivatives offer logistic advantages and higher contrast images. In this work, three different [{sup 18}F]fluoroethoxy-substituted benzothiazole derivatives ([{sup 18}F]2-(4'-(methylamino)phenyl)-6-(2-fluoroethoxy)benzothiazole, [{sup 18}F]2-((2'-(2-fluoroethoxy)-4'-amino)phenyl)benzothiazole and [{sup 18}F]2-(3'-((2-fluoroethoxy)-4'-amino)phenyl)benzothiazole) were synthesized via [{sup 18}F]fluoroethylation. The latter two derivatives with fluoroethoxy-substitution on the aromatic amino group showed very low binding affinity for amyloid aggregates. In contrast [{sup 18}F]2-(4'-(methylamino)phenyl)-6-(2-fluoroethoxy)benzothiazole with [{sup 18}F]fluoroethoxy-substitution in 6-position showed excellent amyloid imaging properties with respect to lipophilicity, brain entry and brain clearance in normal SCID mice, amyloid plaque binding affinity and specificity.

  19. Striking reduction of amyloid plaque burden in an Alzheimer's mouse model after chronic administration of carmustine

    OpenAIRE

    Hayes, Crystal D.; Dey, Debleena; Palavicini, Juan Pablo; Wang, Hongjie; Patkar, Kshitij A; Minond, Dimitriy; Nefzi, Adel; Lakshmana, Madepalli K.

    2013-01-01

    Background Currently available therapies for Alzheimer's disease (AD) do not treat the underlying cause of AD. Anecdotal observations in nursing homes from multiple studies strongly suggest an inverse relationship between cancer and AD. Therefore, we reasoned that oncology drugs may be effective against AD. Methods We screened a library of all the FDA-approved oncology drugs and identified bis-chloroethylnitrosourea (BCNU or carmustine) as an effective amyloid beta (Aβ) reducing compound. To ...

  20. Minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE-1 in a transgenic model of Alzheimer's disease-like amyloid pathology

    Directory of Open Access Journals (Sweden)

    Ferretti Maria

    2012-04-01

    Full Text Available Abstract Background A growing body of evidence indicates that inflammation is one of the earliest neuropathological events in Alzheimer's disease. Accordingly, we have recently shown the occurrence of an early, pro-inflammatory reaction in the hippocampus of young, three-month-old transgenic McGill-Thy1-APP mice in the absence of amyloid plaques but associated with intracellular accumulation of amyloid beta petide oligomers. The role of such a pro-inflammatory process in the progression of the pathology remained to be elucidated. Methods and results To clarify this we administered minocycline, a tetracyclic derivative with anti-inflammatory and neuroprotective properties, to young, pre-plaque McGill-Thy1-APP mice for one month. The treatment ended at the age of three months, when the mice were still devoid of plaques. Minocycline treatment corrected the up-regulation of inducible nitric oxide synthase and cyclooxygenase-2 observed in young transgenic placebo mice. Furthermore, the down-regulation of inflammatory markers correlated with a reduction in amyloid precursor protein levels and amyloid precursor protein-related products. Beta-site amyloid precursor protein cleaving enzyme 1 activity and levels were found to be up-regulated in transgenic placebo mice, while minocycline treatment restored these levels to normality. The anti-inflammatory and beta-secretase 1 effects could be partly explained by the inhibition of the nuclear factor kappa B pathway. Conclusions Our study suggests that the pharmacological modulation of neuroinflammation might represent a promising approach for preventing or delaying the development of Alzheimer's disease neuropathology at its initial, pre-clinical stages. The results open new vistas to the interplay between inflammation and amyloid pathology.

  1. Green-fluorescent protein+ Astrocytes Attach to beta-Amyloid Plaques in an Alzheimer Mouse Model and GFPare Sensitive for Clasmatodendrosis

    Directory of Open Access Journals (Sweden)

    Christian eHumpel

    2016-04-01

    Full Text Available Alzheimer’s disease (AD is pathologically characterized by beta-amyloid (Aβ plaques and Tau pathology. It is well-established that Aβ plaques are surrounded by reactive astrocytes, highly expressing glial fibrillary acidic protein (GFAP. In order to study the cellular interaction of reactive astrocytes with Aβ plaques, we crossbred mice overexpressing amyloid precursor protein (APP with the Swedish-Dutch-Iowa mutations (APP-SweDI with mice expressing green fluorescent protein (GFP under the GFAP-promotor. Three-dimensional confocal microscopy revealed a tight association and intense sprouting of astrocytic fine branched processes towards Aβ plaques in 12 month old mice. In order to study phagocytosis, 110 µm thick brain slices from 12 month old crossbred mice were cultured overnight, however, we found that the GFP fluorescence faded away, distal processes degenerated and a complete loss of astrocytic morphology was seen (clasmatodendrosis. In summary, our data show that GFP+ reactive astrocytes make intense contact with Aβ plaques but these cells are highly vulnerable for degeneration.

  2. Image Analysis for Contrast Enhanced Ultrasound Carotid Plaque Imaging

    NARCIS (Netherlands)

    Z. Akkus (Zeynettin)

    2014-01-01

    markdownabstract__Abstract__ Intraplaque neovascularization (IPN) has been presented as an important biomarker for progressive atherosclerotic disease and plaque vulnerability in several pathological studies. Therefore, quantification of IPN may allow early prediction of plaque at risk of rupture a

  3. Plaque deposition dependent decrease in 5-HT2A serotonin receptor in AbetaPPswe/PS1dE9 amyloid overexpressing mice

    DEFF Research Database (Denmark)

    Holm, Peter; Ettrup, Anders; Klein, Anders B;

    2010-01-01

    -HT2A receptor regulation in double transgenic AbetaPPswe/PS1dE9 mice which display excess production of Abeta and age-dependent increase in amyloid plaques. Three different age-groups, 4-month-old, 8- month-old, and 11-month-old were included in the study. [3H]-MDL100907, [3H]-escitalopram, and [11C...

  4. Liberation of copper from amyloid plaques: making a risk factor useful for Alzheimer's disease treatment.

    Science.gov (United States)

    Geng, Jie; Li, Meng; Wu, Li; Ren, Jinsong; Qu, Xiaogang

    2012-11-01

    Alzheimer's disease (AD) is a complex multifactorial syndrome. Metal chelator and Aβ inhibitor are showing promise against AD. In this report, three small hybrid compounds (1, 2, and 3) have been designed and synthesized utilizing salicylaldehyde (SA) based Schiff bases as the chelators and benzothiazole (BT) as the recognition moiety for AD treatment. These conjugates can capture Cu(2+) from Aβ and become dimers upon Cu(2+) coordination and show high efficiency for both Cu(2+) elimination and Aβ assembly inhibition. Besides, the complexes have superoxide dismutase (SOD) activity and significant antioxidant capacity and are capable of decreasing intracellular reactive oxygen species (ROS) and increasing cell viability. All these results indicate that the multifunctional metal complexes which have Aβ specific recognition moiety and metal ion chelating elements show the potential for AD treatment. Therefore, our work will provide new insights into exploration of more potent amyloid inhibitors.

  5. Relationship between Enhanced Intensity of Contrast Enhanced Ultrasound and Microvessel Density of Aortic Atherosclerostic Plaque in Rabbit Model

    OpenAIRE

    Xiangdong You; Pintong Huang; Chao Zhang; Minghui Wang; Ying Zhang; Yurong Hong; Shumei Wei; Chunmei Liu; Zhaoxia Pu; Jianmin Zhang; Shuyuan Chen

    2014-01-01

    The aim of this study was to evaluate the relationship between enhanced intensity of contrast enhanced ultrasound and microvessel density of aortic atherosclerotic plaque in rabbit model. The abdominal aortas of thirty-six male New Zealand rabbits were damaged by balloon expansion and the animals were then fed a high fat diet for 12 weeks. Twenty-seven plaques on the near aortic wall were detected using conventional ultrasound examination. The maximum thickness of each plaque was recorded. CE...

  6. Forebrain microglia from wild-type but not adult 5xFAD mice prevent amyloidplaque formation in organotypic hippocampal slice cultures.

    Science.gov (United States)

    Hellwig, Sabine; Masuch, Annette; Nestel, Sigrun; Katzmarski, Natalie; Meyer-Luehmann, Melanie; Biber, Knut

    2015-01-01

    The role of microglia in amyloid-β (Aβ) deposition is controversial. In the present study, an organotypic hippocampal slice culture (OHSC) system with an in vivo-like microglial-neuronal environment was used to investigate the potential contribution of microglia to Aβ plaque formation. We found that microglia ingested Aβ, thereby preventing plaque formation in OHSCs. Conversely, Aβ deposits formed rapidly in microglia-free wild-type slices. The capacity to prevent Aβ plaque formation was absent in forebrain microglia from young adult but not juvenile 5xFamilial Alzheimer's disease (FAD) mice. Since no loss of Aβ clearance capacity was observed in both wild-type and cerebellar microglia from 5xFAD animals, the high Aβ1-42 burden in the forebrain of 5xFAD animals likely underlies the exhaustion of microglial Aβ clearance capacity. These data may therefore explain why Aβ plaque formation has never been described in wild-type mice, and point to a beneficial role of microglia in AD pathology. We also describe a new method to study Aβ plaque formation in a cell culture setting.

  7. The anti-inflammatory glycoprotein, CD200, restores neurogenesis and enhances amyloid phagocytosis in a mouse model of Alzheimer's disease.

    Science.gov (United States)

    Varnum, Megan M; Kiyota, Tomomi; Ingraham, Kaitlin L; Ikezu, Seiko; Ikezu, Tsuneya

    2015-11-01

    Cluster of Differentiation-200 (CD200) is an anti-inflammatory glycoprotein expressed in neurons, T cells, and B cells, and its receptor is expressed on glia. Both Alzheimer's disease patients and mouse models display age-related or amyloid-β peptide (Aβ)-induced reductions in CD200. The goal of this study was to determine if neuronal CD200 expression restores hippocampal neurogenesis and reduces Aβ in the amyloid precursor protein mouse model. Amyloid precursor protein and wild-type mice were injected at 6 months of age with an adeno-associated virus expressing CD200 into the hippocampus and sacrificed at 12 months. CD200 expression restored neural progenitor cell proliferation and differentiation in the subgranular and granular cell layers of the dentate gyrus and reduced diffuse but not thioflavin-S(+) plaques in the hippocampus. In vitro studies demonstrated that CD200-stimulated microglia increased neural differentiation of neural stem cells and enhanced axon elongation and dendrite number. CD200 also enhanced Aβ uptake by microglia. These data indicate that CD200 is capable of enhancing microglia-mediated Aβ clearance and neural differentiation and has potential as a therapeutic for Alzheimer's disease.

  8. Bacterial Amyloid and DNA are Important Constituents of Senile Plaques: Further Evidence of the Spirochetal and Biofilm Nature of Senile Plaques

    Science.gov (United States)

    Miklossy, Judith

    2016-01-01

    It has long been known that spirochetes form clumps or micro colonies in vitro and in vivo. Cortical spirochetal colonies in syphilitic dementia were considered as reproductive centers for spirochetes. Historic and recent data demonstrate that senile plaques in Alzheimer’s disease (AD) are made up by spirochetes. Spirochetes, are able to form biofilm in vitro. Senile plaques are also reported to contain elements of biofilm constituents. We expected that AβPP and Aβ (the main components of senile plaques) also occur in pure spirochetal biofilms, and bacterial DNA (an important component of biofilm) is also present in senile plaques. Histochemical, immunohistochemical, and in situ hybridization techniques and the TUNEL assay were used to answer these questions. The results obtained demonstrate that Aβ and DNA, including spirochete-specific DNA, are key components of both pure spirochetal biofilms and senile plaques in AD and confirm the biofilm nature of senile plaques. These results validate validate previous observations that AβPP and/or an AβPP-like amyloidogenic protein are an integral part of spirochetes, and indicate that bacterial and host derived Aβ are both constituents of senile plaques. DNA fragmentation in senile plaques further confirms their bacterial nature and provides biochemical evidence for spirochetal cell death. Spirochetes evade host defenses, locate intracellularly, form more resistant atypical forms and notably biofilms, which contribute to sustain chronic infection and inflammation and explain the slowly progressive course of dementia in AD. To consider co-infecting microorganisms is equally important, as multi-species biofilms result in a higher resistance to treatments and a more severe dementia. PMID:27314530

  9. Accumulation of amyloid-like Aβ1–42 in AEL (autophagy–endosomal–lysosomal vesicles: potential implications for plaque biogenesis

    Directory of Open Access Journals (Sweden)

    Daijun Ling

    2014-03-01

    Full Text Available Abnormal accumulation of Aβ (amyloid β within AEL (autophagy–endosomal–lysosomal vesicles is a prominent neuropathological feature of AD (Alzheimer's disease, but the mechanism of accumulation within vesicles is not clear. We express secretory forms of human Aβ1–40 or Aβ1–42 in Drosophila neurons and observe preferential localization of Aβ1–42 within AEL vesicles. In young animals, Aβ1–42 appears to associate with plasma membrane, whereas Aβ1–40 does not, suggesting that recycling endocytosis may underlie its routing to AEL vesicles. Aβ1–40, in contrast, appears to partially localize in extracellular spaces in whole brain and is preferentially secreted by cultured neurons. As animals become older, AEL vesicles become dysfunctional, enlarge and their turnover appears delayed. Genetic inhibition of AEL function results in decreased Aβ1–42 accumulation. In samples from older animals, Aβ1–42 is broadly distributed within neurons, but only the Aβ1–42 within dysfunctional AEL vesicles appears to be in an amyloid-like state. Moreover, the Aβ1–42-containing AEL vesicles share properties with AD-like extracellular plaques. They appear to be able to relocate to extracellular spaces either as a consequence of age-dependent neurodegeneration or a non-neurodegenerative separation from host neurons by plasma membrane infolding. We propose that dysfunctional AEL vesicles may thus be the source of amyloid-like plaque accumulation in Aβ1–42-expressing Drosophila with potential relevance for AD.

  10. Novel ¹⁸F-labeled benzoxazole derivatives as potential positron emission tomography probes for imaging of cerebral β-amyloid plaques in Alzheimer's disease.

    Science.gov (United States)

    Cui, Mengchao; Ono, Masahiro; Kimura, Hiroyuki; Ueda, Masashi; Nakamoto, Yuji; Togashi, Kaori; Okamoto, Yoko; Ihara, Masafumi; Takahashi, Ryosuke; Liu, Boli; Saji, Hideo

    2012-11-01

    Two radiofluoro-pegylated phenylbenzoxazole derivatives, 4-(5-(2-(2-(2-[(18)F]fluoroethoxy)ethoxy)ethoxy)benzo[d]oxazol-2-yl)-N-methylaniline ([(18)F]24) and 4-(5-(2-(2-(2-[(18)F]fluoroethoxy)ethoxy)ethoxy)benzo[d]oxazol-2-yl)-N,N-dimethylaniline ([(18)F]32), were synthesized and evaluated as probes for imaging cerebral β-amyloid (Aβ) plaques in living brain tissue by PET. [(18)F]24 and [(18)F]32 displayed high affinity for Aβ(1-42) aggregates (K(i) = 9.3 and 3.9 nM, respectively). In vitro autoradiography with sections of post-mortem AD brain and transgenic mouse brain confirmed the affinity of these tracers. Initial high uptake into and rapid washout from the brain in normal mice were observed. [(18)F]24 also displayed excellent binding to Aβ plaques in ex vivo autoradiographic experiments with Tg2576 mice. Furthermore, small-animal PET studies demonstrated significant differences in the clearance profile after the administration of [(18)F]24 between Tg2576 and wild-type mice. The results suggest [(18)F]24 to be a useful PET agent for detecting Aβ plaques in the living human brain.

  11. Epigenetic age of the pre-frontal cortex is associated with neuritic plaques, amyloid load, and Alzheimer's disease related cognitive functioning.

    Science.gov (United States)

    Levine, Morgan E; Lu, Ake T; Bennett, David A; Horvath, Steve

    2015-12-01

    There is an urgent need to develop molecular biomarkers of brain age in order to advance our understanding of age related neurodegeneration. Recently, we developed a highly accurate epigenetic biomarker of tissue age (known as epigenetic clock) which is based on DNA methylation levels. Here we use n=700 dorsolateral prefrontal cortex (DLPFC) samples from Caucasian subjects of the Religious Order Study and the Rush Memory and Aging Project to examine the association between epigenetic age and Alzheimer's disease (AD) related cognitive decline, and AD related neuropathological markers. Epigenetic age acceleration of DLPFC is correlated with several neuropathological measurements including diffuse plaques (r=0.12, p=0.0015), neuritic plaques (r=0.11, p=0.0036), and amyloid load (r=0.091, p=0.016). Further, it is associated with a decline in global cognitive functioning (β=-0.500, p=0.009), episodic memory (β=-0.411, p=0.009) and working memory (β=-0.405, p=0.011) among individuals with AD. The neuropathological markers may mediate the association between epigenetic age and cognitive decline. Genetic complex trait analysis (GCTA) revealed that epigenetic age acceleration is heritable (h2=0.41) and has significant genetic correlations with diffuse plaques (r=0.24, p=0.010) and possibly working memory (r=-0.35, p=0.065). Overall, these results suggest that the epigenetic clock may lend itself as a molecular biomarker of brain age. PMID:26684672

  12. An overview on therapeutics attenuating amyloid β level in Alzheimer's disease: targeting neurotransmission, inflammation, oxidative stress and enhanced cholesterol levels.

    Science.gov (United States)

    Zhou, Xiaoling; Li, Yifei; Shi, Xiaozhe; Ma, Chun

    2016-01-01

    Alzheimer's disease (AD) is the most common underlying cause of dementia, and novel drugs for its treatment are needed. Of the different theories explaining the development and progression of AD, "amyloid hypothesis" is the most supported by experimental data. This hypothesis states that the cleavage of amyloid precursor protein (APP) leads to the formation of amyloid beta (Aβ) peptides that congregate with formation and deposition of Aβ plaques in the frontal cortex and hippocampus. Risk factors including neurotransmitter modulation, chronic inflammation, metal-induced oxidative stress and elevated cholesterol levels are key contributors to the disease progress. Current therapeutic strategies abating AD progression are primarily based on anti-acetylcholinesterase (AChE) inhibitors as cognitive enhancers. The AChE inhibitor, donepezil, is proven to strengthen cognitive functions and appears effective in treating moderate to severe AD patients. N-Methyl-D-aspartate receptor antagonist, memantine, is also useful, and its combination with donepezil demonstrated a strong stabilizing effect in clinical studies on AD. Nonsteroidal anti-inflammatory drugs delayed the onset and progression of AD and attenuated cognitive dysfunction. Based upon epidemiological evidence and animal studies, antioxidants emerged as potential AD preventive agents; however, clinical trials revealed inconsistencies. Pharmacokinetic and pharmacodynamic profiling demonstrated pleiotropic functions of the hypolipidemic class of drugs, statins, potentially contributing towards the prevention of AD. In addition, targeting the APP processing pathways, stimulating neuroprotective signaling mechanisms, using the amyloid anti-aggregants and Aβ immunotherapy surfaced as well-tested strategies in reducing the AD-like pathology. Overall, this review covers mechanism of inducing the Aβ formation, key risk factors and major therapeutics prevalent in the AD treatment nowadays. It also delineates the need

  13. New quantification methods for carotid intra-plaque neovascularization using contrast-enhanced ultrasound.

    Science.gov (United States)

    Akkus, Zeynettin; Hoogi, Assaf; Renaud, Guillaume; van den Oord, Stijn C H; Ten Kate, Gerrit L; Schinkel, Arend F L; Adam, Dan; de Jong, Nico; van der Steen, Antonius F W; Bosch, Johan G

    2014-01-01

    As carotid intra-plaque neovascularization (IPN) is linked to progressive atherosclerotic disease and plaque vulnerability, its accurate quantification might allow early detection of plaque vulnerability. We therefore developed several new quantitative methods for analyzing IPN perfusion and structure. From our analyses, we derived six quantitative parameters-IPN surface area (IPNSA), IPN surface ratio (IPNSR), plaque mean intensity, plaque-to-lumen enhancement ratio, mean plaque contrast percentage and number of micro-vessels (MVN)-and compared these with visual grading of IPN by two independent physicians. A total of 45 carotid arteries with symptomatic stenosis in 23 patients were analyzed. IPNSA (correlation r = 0.719), IPNSR (r = 0.538) and MVN (r = 0.484) were found to be significantly correlated with visual scoring (p < 0.01). IPNSA was the best match to visual scoring. These results indicate that IPNSA, IPNSR and MVN may have the potential to replace qualitative visual scoring and to measure the degree of carotid IPN. PMID:24161799

  14. GMP-compliant automated synthesis of [{sup 18}F]AV-45 (Florbetapir F 18) for imaging {beta}-amyloid plaques in human brain

    Energy Technology Data Exchange (ETDEWEB)

    Yao, C.-H. [Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital, Taiwan (China); Lin, K.-J. [Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital, Taiwan (China); Department of Medical Imaging and Radiological Sciences, Chang Gung University, 259 Wen-Hua 1st Road, Kweishan, Taoyuan 333, Taiwan (China); Weng, C.-C. [Department of Medical Imaging and Radiological Sciences, Chang Gung University, 259 Wen-Hua 1st Road, Kweishan, Taoyuan 333, Taiwan (China); Hsiao, I.-T. [Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital, Taiwan (China); Department of Medical Imaging and Radiological Sciences, Chang Gung University, 259 Wen-Hua 1st Road, Kweishan, Taoyuan 333, Taiwan (China); Ting, Y.-S. [Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital, Taiwan (China); Yen, T.-C. [Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital, Taiwan (China); Department of Medical Imaging and Radiological Sciences, Chang Gung University, 259 Wen-Hua 1st Road, Kweishan, Taoyuan 333, Taiwan (China); Jan, T.-R. [Department and Graduate Institute of Veterinary Medicine, National Taiwan University, Taipei, Taiwan (China); Skovronsky, Daniel [Avid Radiopharmaceuticals, Inc., Philadelphia, PA 19104 (United States); Kung, M.-P. [Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital, Taiwan (China); Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104 (United States); Wey, S.-P., E-mail: spwey@mail.cgu.edu.t [Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital, Taiwan (China); Department of Medical Imaging and Radiological Sciences, Chang Gung University, 259 Wen-Hua 1st Road, Kweishan, Taoyuan 333, Taiwan (China)

    2010-12-15

    We report herein the Good Manufacturing Practice (GMP)-compliant automated synthesis of {sup 18}F-labeled styrylpyridine, AV-45 (Florbetapir), a novel tracer for positron emission tomography (PET) imaging of {beta}-amyloid (A{beta}) plaques in the brain of Alzheimer's disease patients. [{sup 18}F]AV-45 was prepared in 105 min using a tosylate precursor with Sumitomo modules for radiosynthesis under GMP-compliant conditions. The overall yield was 25.4{+-}7.7% with a final radiochemical purity of 95.3{+-}2.2% (n=19). The specific activity of [{sup 18}F]AV-45 reached as high as 470{+-}135 TBq/mmol (n=19). The present studies show that [{sup 18}F]AV-45 can be manufactured under GMP-compliant conditions and could be widely available for routine clinical use.

  15. Relationship between enhanced intensity of contrast enhanced ultrasound and microvessel density of aortic atherosclerostic plaque in rabbit model.

    Directory of Open Access Journals (Sweden)

    Xiangdong You

    Full Text Available The aim of this study was to evaluate the relationship between enhanced intensity of contrast enhanced ultrasound and microvessel density of aortic atherosclerotic plaque in rabbit model. The abdominal aortas of thirty-six male New Zealand rabbits were damaged by balloon expansion and the animals were then fed a high fat diet for 12 weeks. Twenty-seven plaques on the near aortic wall were detected using conventional ultrasound examination. The maximum thickness of each plaque was recorded. CEUS was performed on these 27 plaques and the time-intensity curves (TICs were analyzed offline. Using the quantitative ACQ software, features such as the arrival time (AT, time to peak (TTP, baseline intensity (BI, peak intensity (PI and enhanced intensity (EI (EI = PI-BI were assessed. Inter- and intra-observer agreement of EI were assessed using the Bland-Altman test. After CEUS examination, the rabbits were sacrificed for pathological examination and CD34 monoclonal antibody immunohistochemical detection. Microvessel density (MVD was counted under the microscope. The relationship between indexes of CEUS and the level of MVD was analyzed. There was a good positive linear correlation between EI and MVD (γ = 0. 854, P<0. 001, the intraclass correlations for inter- and intra-observer agreement for EI were 0.73 and 0.82 respectively, suggesting that EI may be act as a useful index for plaque risk stratification in animal models.

  16. The effects of enhanced zinc on spatial memory and plaque formation in transgenic mice

    Science.gov (United States)

    Linkous, D.H.; Adlard, P.A.; Wanschura, P.B.; Conko, K.M.; Flinn, J.M.

    2009-01-01

    There is considerable evidence suggesting that metals play a central role in the pathogenesis of Alzheimer's disease. Reports suggest that elevated dietary metals may both precipitate and potentiate an Alzheimer's disease phenotype. Despite this, there remain few studies that have examined the behavioral consequences of elevated dietary metals in wild type and Alzheimer's disease animals. To further investigate this in the current study, two separate transgenic models of AD (Tg2576 and TgCRND8), together with wild type littermates were administered 10 ppm (0.153 mM) Zn. Tg2576 animals were maintained on a zinc-enriched diet both pre- and postnatally until 11 months of age, while TgCRND8 animals were treated for five months following weaning. Behavioral testing, consisting of "Atlantis" and "moving" platform versions of the Morris water maze, were conducted at the end of the study, and tissues were collected for immunohistochemical analysis of amyloid-β burden. Our data demonstrate that the provision of a zinc-enriched diet potentiated Alzheimer-like spatial memory impairments in the transgenic animals and was associated with reduced hippocampal amyloidplaque deposits. Zinc-related behavioral deficits were also demonstrated in wild type mice, which were sometimes as great as those present in the transgenic animals. However, zinc-related cognitive impairments in transgenic mice were greater than the summation of zinc effects in the wild type mice and the transgene effects.

  17. Astrocytosis precedes amyloid plaque deposition in Alzheimer APPswe transgenic mouse brain: a correlative positron emission tomography and in vitro imaging study

    International Nuclear Information System (INIS)

    Pathological studies suggest that neuroinflammation is exacerbated by increased beta-amyloid (Aβ) levels in the brain early in Alzheimer's disease (AD). The time course and relationships between astrocytosis and Aβ deposition were examined using multitracer in vivo positron emission tomography (PET) imaging in an AD transgenic mouse model, followed by postmortem autoradiography and immunohistochemistry analysis. PET imaging with the amyloid plaque tracer 11C-AZD2184 and the astroglial tracer 11C-deuterium-L-deprenyl (11C-DED) was carried out in APPswe mice aged 6, 8-15 and 18-24 months (4-6 animals/group) and in wild-type (wt) mice aged 8-15 and 18-24 months (3-6 animals/group). Tracer uptake was quantified by region of interest analysis using PMOD software and a 3-D digital mouse brain atlas. Postmortem brain tissues from the same APPswe and wt mice in all age groups were analysed for Aβ deposition and astrocytosis by in vitro autoradiography using 3H-AZD2184, 3H-Pittsburgh compound B (PIB) and 3H-L-deprenyl and immunostaining performed with antibodies for Aβ42 and glial fibrillary acidic protein (GFAP) in sagittal brain sections. 11C-AZD2184 PET retention in the cerebral cortices of APPswe mice was significantly higher at 18-24 months than in age-matched wt mice. Cortical and hippocampal 11C-DED PET binding was significantly higher at 6 months than at 8-15 months or 18-24 months in APPswe mice, and it was also higher than at 8-15 months in wt mice. In vitro autoradiography 3H-AZD2184 and 3H-PIB binding confirmed the in vivo findings with 11C-AZD2184 and demonstrated age-dependent increases in Aβ deposition in APPswe cortex and hippocampus. There were no significant differences between APPswe and wt mice in 3H-L-deprenyl autoradiography binding across age groups. Immunohistochemical quantification demonstrated more Aβ42 deposits in the cortex and hippocampus and more GFAP+ reactive astrocytes in the hippocampus at 18-24 months than at 6 months in APPswe

  18. Astrocytosis precedes amyloid plaque deposition in Alzheimer APPswe transgenic mouse brain: a correlative positron emission tomography and in vitro imaging study

    Energy Technology Data Exchange (ETDEWEB)

    Rodriguez-Vieitez, Elena; Ni, Ruiqing; Voytenko, Larysa; Marutle, Amelia [Karolinska Institutet, Division of Translational Alzheimer Neurobiology, Centre for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Stockholm (Sweden); Gulyas, Balazs; Halldin, Christer [Karolinska Institutet, Centre for Psychiatric Research, Department of Clinical Neuroscience, Stockholm (Sweden); Nanyang Technological University, NTU - Imperial College, Lee Kong Chian School of Medicine, Singapore (Singapore); Toth, Miklos; Haeggkvist, Jenny [Karolinska Institutet, Centre for Psychiatric Research, Department of Clinical Neuroscience, Stockholm (Sweden); Nordberg, Agneta [Karolinska Institutet, Division of Translational Alzheimer Neurobiology, Centre for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Stockholm (Sweden); Karolinska University Hospital Huddinge, Department of Geriatric Medicine, Stockholm (Sweden)

    2015-04-17

    Pathological studies suggest that neuroinflammation is exacerbated by increased beta-amyloid (Aβ) levels in the brain early in Alzheimer's disease (AD). The time course and relationships between astrocytosis and Aβ deposition were examined using multitracer in vivo positron emission tomography (PET) imaging in an AD transgenic mouse model, followed by postmortem autoradiography and immunohistochemistry analysis. PET imaging with the amyloid plaque tracer {sup 11}C-AZD2184 and the astroglial tracer {sup 11}C-deuterium-L-deprenyl ({sup 11}C-DED) was carried out in APPswe mice aged 6, 8-15 and 18-24 months (4-6 animals/group) and in wild-type (wt) mice aged 8-15 and 18-24 months (3-6 animals/group). Tracer uptake was quantified by region of interest analysis using PMOD software and a 3-D digital mouse brain atlas. Postmortem brain tissues from the same APPswe and wt mice in all age groups were analysed for Aβ deposition and astrocytosis by in vitro autoradiography using {sup 3}H-AZD2184, {sup 3}H-Pittsburgh compound B (PIB) and {sup 3}H-L-deprenyl and immunostaining performed with antibodies for Aβ{sub 42} and glial fibrillary acidic protein (GFAP) in sagittal brain sections. {sup 11}C-AZD2184 PET retention in the cerebral cortices of APPswe mice was significantly higher at 18-24 months than in age-matched wt mice. Cortical and hippocampal {sup 11}C-DED PET binding was significantly higher at 6 months than at 8-15 months or 18-24 months in APPswe mice, and it was also higher than at 8-15 months in wt mice. In vitro autoradiography {sup 3}H-AZD2184 and {sup 3}H-PIB binding confirmed the in vivo findings with {sup 11}C-AZD2184 and demonstrated age-dependent increases in Aβ deposition in APPswe cortex and hippocampus. There were no significant differences between APPswe and wt mice in {sup 3}H-L-deprenyl autoradiography binding across age groups. Immunohistochemical quantification demonstrated more Aβ{sub 42} deposits in the cortex and hippocampus and more

  19. Effects of Hypertension and Anti-Hypertensive Treatment on Amyloid-β (Aβ) Plaque Load and Aβ-Synthesizing and Aβ-Degrading Enzymes in Frontal Cortex.

    Science.gov (United States)

    Ashby, Emma L; Miners, James S; Kehoe, Patrick G; Love, Seth

    2016-01-01

    Epidemiological data associate hypertension with a predisposition to Alzheimer's disease (AD), and a number of postmortem and in vivo studies also demonstrate that hypertension increases amyloid-β (Aβ) pathology. In contrast, anti-hypertensive medications reportedly improve cognition and decrease the risk of AD, while certain classes of anti-hypertensive drugs are associated with decreased AD-related pathology. We investigated the effects of hypertension and anti-hypertensive treatment on Aβ plaque load in postmortem frontal cortex in AD. Aβ load was significantly increased in hypertensive (n = 20) relative to normotensive cases (n = 62) and was also significantly higher in treated (n = 9) than untreated hypertensives (n = 11). We then looked into mechanisms by which hypertension and treatment might increase Aβ load, focusing on Aβ-synthesizing enzymes, β- and γ-secretase, and Aβ-degrading enzymes, angiotensin-converting enzyme (ACE), insulin-degrading enzyme (IDE) and neprilysin. ACE and IDE protein levels were significantly lower in hypertensive (n = 21) than normotensive cases (n = 64), perhaps translating to decreased Aβ catabolism in hypertensives. ACE level was significantly higher in treated (n = 9) than untreated hypertensives (n = 12), possibly reflecting feedback upregulation of the renin-angiotensin system. Prospective studies in larger cohorts stratified according to anti-hypertensive drug class are needed to confirm these initial findings and to elucidate the interactions between hypertension, anti-hypertensive treatments, and Aβ metabolism. PMID:26836178

  20. Zileuton improves memory deficits, amyloid and tau pathology in a mouse model of Alzheimer's disease with plaques and tangles.

    Directory of Open Access Journals (Sweden)

    Jin Chu

    Full Text Available The 5-lipoxygenase (5LO enzyme is widely distributed within the central nervous system. Previous works showed that this protein is up-regulated in Alzheimer's disease (AD, and plays an active role in the development of brain amyloidosis in the APP transgenic mice. In the present paper, we studied the effect of its pharmacological inhibition on the entire AD-like phenotype of a mouse model with plaques and tangles, the 3 × Tg mice. Compared with mice receiving placebo, the group treated with zileuton, a specific 5LO inhibitor, manifested a significant improvement of their memory impairments. The same animals had a significant reduction in Aβ levels and deposition, which was secondary to a down-regulation of the γ-secretase pathway. Additionally, while total tau levels were unchanged for both groups, zileuton-treated mice had a significant reduction in its phosphorylation state and insoluble forms, secondary to a decreased activation of the cdk5 kinase. These data establish a functional role for 5LO in the pathogenesis of the full spectrum of the AD-like phenotype and represent the successful completion of the initial step for the preclinical development of 5LO inhibitors as viable therapeutic agents for AD.

  1. Prion seeding activities of mouse scrapie strains with divergent PrPSc protease sensitivities and amyloid plaque content using RT-QuIC and eQuIC.

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    Sarah Vascellari

    Full Text Available Different transmissible spongiform encephalopathy (TSE-associated forms of prion protein (e.g. PrP(Sc can vary markedly in ultrastructure and biochemical characteristics, but each is propagated in the host. PrP(Sc propagation involves conversion from its normal isoform, PrP(C, by a seeded or templated polymerization mechanism. Such a mechanism is also the basis of the RT-QuIC and eQuIC prion assays which use recombinant PrP (rPrP(Sen as a substrate. These ultrasensitive detection assays have been developed for TSE prions of several host species and sample tissues, but not for murine models which are central to TSE pathogenesis research. Here we have adapted RT-QuIC and eQuIC to various murine prions and evaluated how seeding activity depends on glycophosphatidylinositol (GPI anchoring and the abundance of amyloid plaques and protease-resistant PrP(Sc (PrP(Res. Scrapie brain dilutions up to 10(-8 and 10(-13 were detected by RT-QuIC and eQuIC, respectively. Comparisons of scrapie-affected wild-type mice and transgenic mice expressing GPI anchorless PrP showed that, although similar concentrations of seeding activity accumulated in brain, the heavily amyloid-laden anchorless mouse tissue seeded more rapid reactions. Next we compared seeding activities in the brains of mice with similar infectivity titers, but widely divergent PrP(Res levels. For this purpose we compared the 263K and 139A scrapie strains in transgenic mice expressing P101L PrP(C. Although the brains of 263K-affected mice had little immunoblot-detectable PrP(Res, RT-QuIC indicated that seeding activity was comparable to that associated with a high-PrP(Res strain, 139A. Thus, in this comparison, RT-QuIC seeding activity correlated more closely with infectivity than with PrP(Res levels. We also found that eQuIC, which incorporates a PrP(Sc immunoprecipitation step, detected seeding activity in plasma from wild-type and anchorless PrP transgenic mice inoculated with 22L, 79A and/or RML

  2. Folic acid deficiency enhances abeta accumulation in APP/PS1 mice brain and decreases amyloid-associated miRNAs expression.

    Science.gov (United States)

    Liu, Huan; Tian, Tian; Qin, Shanchun; Li, Wen; Zhang, Xumei; Wang, Xuan; Gao, Yuxia; Huang, Guowei

    2015-12-01

    Recent efforts have revealed the microRNA (miRNA) pathways in the pathogenesis of Alzheimer's disease (AD). Epidemiological studies have revealed an association between folic acid deficiency and AD risk. However, the effects of folic acid deficiency on miRNA expression in AD animals have not been observed. We aimed to find if folic acid deficiency may enhance amyloid-β (Aβ) peptide deposition and regulate amyloid-associated miRNAs and their target genes expression in APP/PS1 mice. APP/PS1 mice and N2a cells were treated with folic acid-deficient diet or medium. Cognitive function of mice was assessed using the Morris water maze. miRNA profile was tested by polymerase chain reaction (PCR) array. Different expressional miRNAs were validated by real-time PCR. The deposition of Aβ plaques was evaluated by immunohistochemistry and enzyme-linked immunosorbent assay. APP and BACE1 proteins in mice brain and N2a cells were determined by Western blot. Folic acid deficiency aggravated amyloid pathology in AD mice. The AD+FD group showed shorter time spent in the target zone during the probe test. Analysis of miRNAs predicted to target these genes revealed several miRNA candidates that were differentially modulated by folic acid deficiency. In APP/PS1 mice brains and N2a cells with folic acid-deficient treatment, miR-106a-5p, miR-200b-3p and miR-339-5p were down-regulated, and their target genes APP and BACE1 were up-regulated. In conclusion, folic acid deficiency can enhance Aβ accumulation in APP/PS1 mice brain and decrease amyloid-associated miRNAs expression.

  3. Identifying Vulnerable Atherosclerotic Plaque in Rabbits Using DMSA-USPIO Enhanced Magnetic Resonance Imaging to Investigate the Effect of Atorvastatin.

    Directory of Open Access Journals (Sweden)

    Chunmei Qi

    Full Text Available Rupture of an atherosclerotic plaque is the primary cause of acute cardiovascular and cerebrovascular syndromes. Early and non-invasive detection of vulnerable atherosclerotic plaques (VP would be significant in preventing some aspects of these syndromes. As a new contrast agent, dimercaptosuccinic acid (DMSA modified ultra-small super paramagnetic iron oxide (USPIO was synthesized and used to identify VP and rupture plaque by magnetic resonance imaging (MRI.Atherosclerosis was induced in male New Zealand White rabbits by feeding a high cholesterol diet (n = 30. Group A with atherosclerosis plaque (n = 10 were controls. VP was established in groups B (n = 10 and C (n = 10 using balloon-induced endothelial injury of the abdominal aorta. Adenovirus-carrying p53 genes were injected into the aortic segments rich in plaques after 8 weeks. Group C was treated with atorvastatin for 8 weeks. Sixteen weeks later, all rabbits underwent pharmacological triggering, and imaging were taken daily for 5 d after DMSA-USPIO infusion. At the first day and before being killed, serum MMP-9, sCD40L, and other lipid indicators were measured.DMSA-USPIO particles accumulated in VP and rupture plaques. Rupture plaques appeared as areas of hyper-intensity on DMSA-USPIO enhanced MRI, especially T2*-weighted sequences, with a signal strength peaking at 96 h. The group given atorvastatin showed few DMSA-USPIO particles and had lower levels of serum indicators. MMP-9 and sCD40L levels in group B were significantly higher than in the other 2 groups (P <0.05.After successfully establishing a VP model in rabbits, DMSA-USPIO was used to enhance MRI for clear identification of plaque inflammation and rupture. Rupture plaques were detectable in this way probably due to an activating inflammatory process. Atorvastatin reduced the inflammatory response and stabilizing VP possibly by decreasing MMP-9 and sCD40L levels.

  4. A study of plaque vascularization and inflammation using quantitative contrast-enhanced US and PET/CT

    International Nuclear Information System (INIS)

    Background: Contrast-enhanced ultrasound (CEUS) is an in vivo methodology to quantify carotid plaque vascularization. Increased metabolism in plaques, measured as FDG uptake in PET/CT examination, has been associated with markers of inflammation in histological samples. In this study, we tested the association between FDG uptake and vascularization measured by CEUS to assess whether CEUS can be used as an in vivo marker of plaque vulnerability. Methods: After informed consent, subjects aged >60 years with carotid plaque height exceeding 2.5 mm were recruited. CEUS was performed and analyzed using earlier described protocol and software, Contrast Quantification Program, which calculates the fraction of the plaque being contrast positive (CQP value). PET/CT examination was performed within 3 months of CEUS (median time 7 days). PET/CT images were acquired 90 min after FDG injection (2.7 MBq/kg). FDG uptake was measured as tissue background index (TBI), calculated using Spearman's rho as mean standard uptake value (SUV) of the plaque divided by mean SUV in the jugular vein (mean of 7 measuring points). Local ethics committee approved the study. Results: We recruited 13 subjects (5 women) with a mean age of 71 years, 6 had a history of stroke or TIA, 1 had a history of ipsilateral stroke. CQP values showed a significant, positive correlation with TBI of carotid plaques, r = 0.67, p < 0.02. Conclusions: Plaque vascularization measured by CEUS correlates positively with FDG uptake measured by PET/CT in humans. This indicates an association between vascularization and inflammation and/or hypoxia, supporting the use of CEUS as a non-invasive method to detect plaque vulnerability

  5. A study of plaque vascularization and inflammation using quantitative contrast-enhanced US and PET/CT

    Energy Technology Data Exchange (ETDEWEB)

    Hjelmgren, Ola, E-mail: ola.hjelmgren@wlab.gu.se [Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Department of Molecular and Clinical Medicine, Clinical Physiology, Gothenburg (Sweden); Sahlgrenska University Hospital, Department of Clinical Physiology, Gothenburg (Sweden); Johansson, Lars, E-mail: lars.johansson@radiol.uu.se [Uppsala University, Department of Radiology, Uppsala (Sweden); Prahl, Ulrica, E-mail: ulrica-prahl-gullberg@wlab.gu.se [Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Department of Molecular and Clinical Medicine, Clinical Physiology, Gothenburg (Sweden); Schmidt, Caroline, E-mail: caroline.schmidt@wlab.gu.se [Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Department of Molecular and Clinical Medicine, Clinical Physiology, Gothenburg (Sweden); Fredén-Lindqvist, Johan, E-mail: johan.freden-lindqvist@vgregion.se [Sahlgrenska University Hospital, Department of Clinical Physiology, Gothenburg (Sweden); Bergström, Göran M.L., E-mail: goran.bergstrom@hjl.gu.se [Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Department of Molecular and Clinical Medicine, Clinical Physiology, Gothenburg (Sweden); Sahlgrenska University Hospital, Department of Clinical Physiology, Gothenburg (Sweden)

    2014-07-15

    Background: Contrast-enhanced ultrasound (CEUS) is an in vivo methodology to quantify carotid plaque vascularization. Increased metabolism in plaques, measured as FDG uptake in PET/CT examination, has been associated with markers of inflammation in histological samples. In this study, we tested the association between FDG uptake and vascularization measured by CEUS to assess whether CEUS can be used as an in vivo marker of plaque vulnerability. Methods: After informed consent, subjects aged >60 years with carotid plaque height exceeding 2.5 mm were recruited. CEUS was performed and analyzed using earlier described protocol and software, Contrast Quantification Program, which calculates the fraction of the plaque being contrast positive (CQP value). PET/CT examination was performed within 3 months of CEUS (median time 7 days). PET/CT images were acquired 90 min after FDG injection (2.7 MBq/kg). FDG uptake was measured as tissue background index (TBI), calculated using Spearman's rho as mean standard uptake value (SUV) of the plaque divided by mean SUV in the jugular vein (mean of 7 measuring points). Local ethics committee approved the study. Results: We recruited 13 subjects (5 women) with a mean age of 71 years, 6 had a history of stroke or TIA, 1 had a history of ipsilateral stroke. CQP values showed a significant, positive correlation with TBI of carotid plaques, r = 0.67, p < 0.02. Conclusions: Plaque vascularization measured by CEUS correlates positively with FDG uptake measured by PET/CT in humans. This indicates an association between vascularization and inflammation and/or hypoxia, supporting the use of CEUS as a non-invasive method to detect plaque vulnerability.

  6. {beta} - amyloid imaging probes

    Energy Technology Data Exchange (ETDEWEB)

    Jeong, Jae Min [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2007-04-15

    Imaging distribution of {beta} - amyloid plaques in Alzheimer's disease is very important for early and accurate diagnosis. Early trial of the {beta} -amyloid plaques includes using radiolabeled peptides which can be only applied for peripheral {beta} - amyloid plaques due to limited penetration through the blood brain barrier (BBB). Congo red or Chrysamine G derivatives were labeled with Tc-99m for imaging {beta} - amyloid plaques of Alzheimer patient's brain without success due to problem with BBB penetration. Thioflavin T derivatives gave breakthrough for {beta} - amyloid imaging in vivo, and a benzothiazole derivative [C-11]6-OH-BTA-1 brought a great success. Many other benzothiazole, benzoxazole, benzofuran, imidazopyridine, and styrylbenzene derivatives have been labeled with F-18 and I-123 to improve the imaging quality. However, [C-11]6-OH-BTA-1 still remains as the best. However, short half-life of C-11 is a limitation of wide distribution of this agent. So, it is still required to develop an Tc-99m, F-18 or I-123 labeled agent for {beta} - amyloid imaging agent.

  7. Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer's Disease.

    Science.gov (United States)

    Hansen, Henrik H; Fabricius, Katrine; Barkholt, Pernille; Kongsbak-Wismann, Pernille; Schlumberger, Chantal; Jelsing, Jacob; Terwel, Dick; Termont, Annelies; Pyke, Charles; Knudsen, Lotte Bjerre; Vrang, Niels

    2016-01-01

    One of the major histopathological hallmarks of Alzheimer's disease (AD) is cerebral deposits of extracellular β-amyloid peptides. Preclinical studies have pointed to glucagon-like peptide 1 (GLP-1) receptors as a potential novel target in the treatment of AD. GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD. Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP) and presenilin-1 (PS1) are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds. In this study, effects of long-term liraglutide treatment were therefore determined in two double APP/PS1 transgenic mouse models of Alzheimer's disease carrying different clinical APP/PS1 mutations, i.e. the 'London' (hAPPLon/PS1A246E) and 'Swedish' mutation variant (hAPPSwe/PS1ΔE9) of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPPLon/PS1A246E mice for 3 months (100 or 500 ng/kg/day, s.c.), or 7 month-old hAPPSwe/PS1ΔE9 mice for 5 months (500 ng/kg/day, s.c.). In both models, regional plaque load was quantified throughout the brain using stereological methods. Vehicle-dosed hAPPSwe/PS1ΔE9 mice exhibited considerably higher cerebral plaque load than hAPPLon/PS1A246E control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice. In conclusion, long-term liraglutide treatment exhibited no effect on cerebral plaque load in two transgenic mouse models of low- and high-grade amyloidosis, which suggests differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD. PMID:27421117

  8. Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1 Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer's Disease.

    Directory of Open Access Journals (Sweden)

    Henrik H Hansen

    Full Text Available One of the major histopathological hallmarks of Alzheimer's disease (AD is cerebral deposits of extracellular β-amyloid peptides. Preclinical studies have pointed to glucagon-like peptide 1 (GLP-1 receptors as a potential novel target in the treatment of AD. GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD. Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP and presenilin-1 (PS1 are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds. In this study, effects of long-term liraglutide treatment were therefore determined in two double APP/PS1 transgenic mouse models of Alzheimer's disease carrying different clinical APP/PS1 mutations, i.e. the 'London' (hAPPLon/PS1A246E and 'Swedish' mutation variant (hAPPSwe/PS1ΔE9 of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPPLon/PS1A246E mice for 3 months (100 or 500 ng/kg/day, s.c., or 7 month-old hAPPSwe/PS1ΔE9 mice for 5 months (500 ng/kg/day, s.c.. In both models, regional plaque load was quantified throughout the brain using stereological methods. Vehicle-dosed hAPPSwe/PS1ΔE9 mice exhibited considerably higher cerebral plaque load than hAPPLon/PS1A246E control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice. In conclusion, long-term liraglutide treatment exhibited no effect on cerebral plaque load in two transgenic mouse models of low- and high-grade amyloidosis, which suggests differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD.

  9. Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer’s Disease

    Science.gov (United States)

    Barkholt, Pernille; Kongsbak-Wismann, Pernille; Schlumberger, Chantal; Jelsing, Jacob; Terwel, Dick; Termont, Annelies; Pyke, Charles; Knudsen, Lotte Bjerre; Vrang, Niels

    2016-01-01

    One of the major histopathological hallmarks of Alzheimer’s disease (AD) is cerebral deposits of extracellular β-amyloid peptides. Preclinical studies have pointed to glucagon-like peptide 1 (GLP-1) receptors as a potential novel target in the treatment of AD. GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD. Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP) and presenilin-1 (PS1) are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds. In this study, effects of long-term liraglutide treatment were therefore determined in two double APP/PS1 transgenic mouse models of Alzheimer’s disease carrying different clinical APP/PS1 mutations, i.e. the ‘London’ (hAPPLon/PS1A246E) and ‘Swedish’ mutation variant (hAPPSwe/PS1ΔE9) of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPPLon/PS1A246E mice for 3 months (100 or 500 ng/kg/day, s.c.), or 7 month-old hAPPSwe/PS1ΔE9 mice for 5 months (500 ng/kg/day, s.c.). In both models, regional plaque load was quantified throughout the brain using stereological methods. Vehicle-dosed hAPPSwe/PS1ΔE9 mice exhibited considerably higher cerebral plaque load than hAPPLon/PS1A246E control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice. In conclusion, long-term liraglutide treatment exhibited no effect on cerebral plaque load in two transgenic mouse models of low- and high-grade amyloidosis, which suggests differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD. PMID:27421117

  10. Temporal dependence of in vivo USPIO-enhanced MRI signal changes in human carotid atheromatous plaques

    Energy Technology Data Exchange (ETDEWEB)

    Tang, T.Y.; Sadat, U. [Cambridge University Hospitals NHS Foundation Trust, University Department of Radiology, Cambridge (United Kingdom); Cambridge University Hospitals NHS Foundation Trust, Cambridge Vascular Unit, Cambridge (United Kingdom); Patterson, A.J.; Graves, M.J.; Howarth, S.P.S.; U-King-Im, J.M.; Li, Z.Y.; Young, V.E.; Gillard, J.H. [Cambridge University Hospitals NHS Foundation Trust, University Department of Radiology, Cambridge (United Kingdom); Miller, S.R. [GlaxoSmithKline, Biostatistics and Data Sciences, Harlow (United Kingdom); Walsh, S.R.; Boyle, J.R.; Gaunt, M.E. [Cambridge University Hospitals NHS Foundation Trust, Cambridge Vascular Unit, Cambridge (United Kingdom)

    2009-07-15

    Ultrasmall superparamagnetic iron oxide (USPIO)-enhanced MRI has been shown to be a useful modality to image activated macrophages in vivo, which are principally responsible for plaque inflammation. This study determined the optimum imaging time-window to detect maximal signal change post-USPIO infusion using T{sub 1}-weighted (T{sub 1}w), T{sub 2}*-weighted (T{sub 2}*w) and quantitative T{sub 2}* (qT{sub 2}*) imaging. Six patients with an asymptomatic carotid stenosis underwent high resolution T{sub 1}w, T{sub 2}*w and qT{sub 2}* MR imaging of their carotid arteries at 1.5 T. Imaging was performed before and at 24, 36, 48, 72 and 96 h after USPIO (Sinerem trademark, Guerbet, France) infusion. Each slice showing atherosclerotic plaque was manually segmented into quadrants and signal changes in each quadrant were fitted to an exponential power function to model the optimum time for post-infusion imaging. The power function determining the mean time to convergence for all patients was 46, 41 and 39 h for the T{sub 1}w, T{sub 2}*w and qT{sub 2}* sequences, respectively. When modelling each patient individually, 90% of the maximum signal intensity change was observed at 36 h for three, four and six patients on T{sub 1}w, T{sub 2}*w and qT{sub 2}*, respectively. The rates of signal change decrease after this period but signal change was still evident up to 96 h. This study showed that a suitable imaging window for T{sub 1}w, T{sub 2}*w and qT{sub 2}* signal changes post-USPIO infusion was between 36 and 48 h. Logistically, this would be convenient in bringing patients back for one post-contrast MRI, but validation is required in a larger cohort of patients. (orig.)

  11. The role of contrast-enhanced ultrasound (CEUS) in visualizing atherosclerotic carotid plaque vulnerability: Which injection protocol? Which scanning technique?

    Energy Technology Data Exchange (ETDEWEB)

    Iezzi, Roberto, E-mail: roberto.iezzi@rm.unicatt.it [Department of Bioimaging and Radiological Sciences, Institute of Radiology, “A. Gemelli” Hospital—Catholic University, L.go A Gemelli 8, 00168 Rome (Italy); Petrone, Gianluigi [Institute of Pathology, “A. Gemelli” Hospital—Catholic University, L.go A Gemelli 8, 00168, Rome (Italy); Ferrante, Angela [Department of Vascular Surgery, “A. Gemelli” Hospital—Catholic University, L.go A Gemelli 8, 00168 Rome (Italy); Lauriola, Libero [Institute of Pathology, “A. Gemelli” Hospital—Catholic University, L.go A Gemelli 8, 00168, Rome (Italy); Vincenzoni, Claudio [Department of Vascular Surgery, “A. Gemelli” Hospital—Catholic University, L.go A Gemelli 8, 00168 Rome (Italy); Torre, Michele Fabio la [Department of Bioimaging and Radiological Sciences, Institute of Radiology, “A. Gemelli” Hospital—Catholic University, L.go A Gemelli 8, 00168 Rome (Italy); Snider, Francesco [Department of Vascular Surgery, “A. Gemelli” Hospital—Catholic University, L.go A Gemelli 8, 00168 Rome (Italy); Rindi, Guido [Institute of Pathology, “A. Gemelli” Hospital—Catholic University, L.go A Gemelli 8, 00168, Rome (Italy); Bonomo, Lorenzo [Department of Bioimaging and Radiological Sciences, Institute of Radiology, “A. Gemelli” Hospital—Catholic University, L.go A Gemelli 8, 00168 Rome (Italy)

    2015-05-15

    Highlights: • CEUS is a safe and efficacious technique for the identification and characterization of carotid plaque. • CEUS represents a diagnostic tool for the management of patients with carotid plaque, particularly in asymptomatic patients. • Improved diagnostic performance is achieved with the injection of 4 mL bolus of contrast-medium. • Improved diagnostic performance is achieved with the use of Dynamic Imaging rather than late-phase imaging. - Abstract: Purpose: To correlate the degree of plaque vulnerability as determined by contrast-enhanced ultrasound (CEUS) with histological findings. Secondary objectives were to optimize the CEUS acquisition technique and image evaluation methods. Materials and methods: Fifty consecutive patients, either symptomatic and asymptomatic referring to our department in order to perform carotid endarterectomy (TEA), were enrolled. Each patient provided informed consent before undergoing CEUS. Ultrasound examination was performed using high-frequency (8–14 MHz) linear probe and a non-linear pulse inversion technique (mechanical index: 0.09–1.3). A double contrast media injection (Sonovue, 2 mL and 4 mL; Bracco, Italy) was performed. Two videotapes were recorded for every injection: early “dynamic” phase and late “flash” phase, performed with 6 high mechanical index impulses. Movies were quantitatively and qualitatively evaluated. Qualitative and quantitative evaluation were statistically compared to immunohistological diagnosis of vulnerable plaque, considered as gold standard. Results: Qualitative CEUS evaluation obtained high statistical results when compared to immunohistological results, with values of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy of 94%, 68%, 87%, 85% and 86%, respectively, which became higher if considering only asymptomatic patient, with a NPV of 91%. Nevertheless, quantitative software evaluation proved less

  12. Correction of lumen contrast-enhancement influence on non-calcified coronary atherosclerotic plaque quantification on CT.

    Science.gov (United States)

    Kristanto, Wisnumurti; Tuncay, Volkan; Vliegenthart, Rozemarijn; van Ooijen, Peter M A; Oudkerk, Matthijs

    2015-02-01

    Lumen contrast-enhancement influences non-calcified atherosclerotic plaque Hounsfield-unit (HU) values in computed tomography (CT). This study aimed to construct and validate an algorithm to correct for this influence. Three coronary vessel phantoms with 1, 2, and 4 mm circular hollow lumina; with normal and plaque-infested walls were scanned simultaneously in oil using a dual-source CT scanner. Scanning was repeated as the lumina were alternately filled with water and four contrast solutions (100-400 HU, at 100 HU intervals). Images were reconstructed at 0.4 mm x-y pixel size. Pixel-by-pixel comparisons of contrast-enhanced and non-contrast-enhanced images confirmed exponential declining patterns in lumen contrast-enhancement influence on wall HU-values from the lumen border (y = Ae(-λx) + c). The median difference of the inside and outside 2-pixel radius part of the contrast-enhanced coronary phantom wall to the reference (non-contrast-enhanced images) was 45 and 2 HU, respectively. Based on the lumen contrast-enhancement influence patterns, a generalized correction algorithm was formulated. Application of the generalized correction algorithm to the inside 2-pixel radius part of the wall reduced the median difference to the reference to 4 HU. In conclusion, lumen contrast-enhancement influence on the vessel wall can be defined by an exponential approximation, allowing correction of the CT density of the vessel wall closest to the lumen. With this correction, a more accurate determination of vessel wall composition can be made. PMID:25326412

  13. alpha-Synuclein enhances secretion and toxicity of amyloid beta peptides in PC12 cells

    NARCIS (Netherlands)

    Kazmierczak, Anna; Strosznajder, Joanna B.; Adamczyk, Agata

    2008-01-01

    alpha-Synuclein is the fundamental component of Lewy bodies which occur in the brain of 60% of sporadic and familial Alzheimer's disease patients. Moreover, a proteolytic fragment of alpha-synuclein, the so-called non-amyloid component of Alzheimer's disease amyloid, was found to be an integral part

  14. Mesenchymal stem cells enhance autophagy and increase β-amyloid clearance in Alzheimer disease models.

    Science.gov (United States)

    Shin, Jin Young; Park, Hyun Jung; Kim, Ha Na; Oh, Se Hee; Bae, Jae-Sung; Ha, Hee-Jin; Lee, Phil Hyu

    2014-01-01

    Current evidence suggests a central role for autophagy in Alzheimer disease (AD), and dysfunction in the autophagic system may lead to amyloid-β (Aβ) accumulation. Using in vitro and in vivo AD models, the present study investigated whether mesenchymal stem cells (MSCs) could enhance autophagy and thus exert a neuroprotective effect through modulation of Aβ clearance In Aβ-treated neuronal cells, MSCs increased cellular viability and enhanced LC3-II expression compared with cells treated with Aβ only. Immunofluorescence revealed that MSC coculture in Aβ-treated neuronal cells increased the number of LC3-II-positive autophagosomes that were colocalized with a lysosomal marker. Ultrastructural analysis revealed that most autophagic vacuoles (AVs) in Aβ-treated cells were not fused with lysosomes, whereas a large portion of autophagosomes were conjoined with lysosomes in MSCs cocultured with Aβ-treated neuronal cells. Furthermore, MSC coculture markedly increased Aβ immunoreactivity colocalized within lysosomes and decreased intracellular Aβ levels compared with Aβ-treated cells. In Aβ-treated animals, MSC administration significantly increased autophagosome induction, final maturation of late AVs, and fusion with lysosomes. Moreover, MSC administration significantly reduced the level of Aβ in the hippocampus, which was elevated in Aβ-treated mice, concomitant with increased survival of hippocampal neurons. Finally, MSC coculture upregulated BECN1/Beclin 1 expression in AD models. These results suggest that MSCs significantly enhance autolysosome formation and clearance of Aβ in AD models, which may lead to increased neuronal survival against Aβ toxicity. Modulation of the autophagy pathway to repair the damaged AD brain using MSCs would have a significant impact on future strategies for AD treatment.

  15. Three-dimensional reconstruction and analysis of structure characteristics on senile plaques of Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    YE Wei; LIU Jianwu; ZHOU Jiangning; HU Xiangyou; TANG Xiaowei

    2005-01-01

    Alzheimer's disease is a progressive neuro- degenerative disorder characterized by the presence of senile plaques primarily composed of amyloid ( in brain. Abnormal secretion and aggregation of amyloid ( are the key events in pathogenesis of Alzheimer's disease. Reduction of amyloid ( production and inhibition of amyloid ( aggregation to form senile plaques are hopeful strategies for the treatment and prevention of Alzheimer's disease. In the present study, the silver and immunohistochemical staining methods were applied to discover senile plaques in the hippocampus of Alzheimer's disease patients, and then images were processed and three-dimensionally reconstructed by Matlab and AVS software. The structure characteristics of senile plaques were measured through correlation function calculation and fractal dimension by a computer-aided method. Diffuse plaque had no amyloid center, but classic plaque presented compact central core structure; two types of plaques were both of porous structure, but the sizes of their pores were significantly different. Furthermore, there was difference in fractal dimension value between the diffuse plaque and classic plaque in the two staining methods. The comparison of structure characteristics between two types of plaques indicated that they developed independently. Establishment of the methods for reconstructing the three-dimen- sional structure of senile plaque and analyzing their structure characteristics is helpful for further study on the aggregation mechanism of senile plaque.

  16. A cytotoxic amyloid oligomer self-triggered and NIR- enhanced amyloidosis therapeutic system

    Institute of Scientific and Technical Information of China (English)

    Can Xu[1,2; Peng Shi[1,2; Meng Li[1,2; Jinsong Ren[1; xiaogang Qu[1

    2015-01-01

    We report a new strategy for improving the efficiency of non-specific amyloidosis therapeutic drugs by coating amyloid-responsive lipid bilayers. The approach had drawn inspiration from amyloid oligomer-mediated cell membrane disruption in the pathogenesis of amyloidosis. A graphene-mesoporous silica hybrid (GMS)-supported lipid bilayer (GMS-Lip) system was used as a drug carrier, Drugs were well confined inside the nanocarrier until encountering amyloid oligomers, which could pierce the lipid bilayer coat and cause drug release. To ensure release efficiency, use of a near-infrared (NIR) laser was also introduced to facilitate drug release, taking advantage of the photothermal effect of GMS and thermal sensitivity of lipid bilayers. To facilitate tracking, fluorescent dyes were co-loaded with drugs within GMS-Lip and the NIR laser was used once the oligomer-triggered release had been signaled. Because of the spatially and temporally controllable property of light, the NIR-assisted release could be easily and selectively activated locally by tracking the fluorescence signal. Our design is based on arnyloidosis pathogenesis, the cytotoxic amyloid oligomer self-triggered release via cell membrane disruption, for the controlled release of drug molecules. The results may shed light on the development of pathogenesis- inspired drug delivery systems,

  17. Hyperhomocysteinemia Increases β-Amyloid by Enhancing Expression of γ-Secretase and Phosphorylation of Amyloid Precursor Protein in Rat Brain

    OpenAIRE

    Zhang, Chang-E; Wei, Wei; Liu, Ying-Hua; Peng, Jun-Hua; Tian, Qing; Liu, Gong-Ping; ZHANG, YAO; Wang, Jian-Zhi

    2009-01-01

    Hyperhomocysteinemia and β-amyloid (Aβ) overproduction are critical etiological and pathological factors in Alzheimer disease, respectively; however, the intrinsic link between them is still missing. Here, we found that Aβ levels increased and amyloid precursor protein (APP) levels simultaneously decreased in hyperhomocysteinemic rats after a 2-week induction by vena caudalis injection of homocysteine. Concurrently, both the mRNA and protein levels of presenilin-1, a component of γ-secretase,...

  18. Progranulin protects against amyloid β deposition and toxicity in Alzheimer's disease mouse models.

    Science.gov (United States)

    Minami, S Sakura; Min, Sang-Won; Krabbe, Grietje; Wang, Chao; Zhou, Yungui; Asgarov, Rustam; Li, Yaqiao; Martens, Lauren H; Elia, Lisa P; Ward, Michael E; Mucke, Lennart; Farese, Robert V; Gan, Li

    2014-10-01

    Haploinsufficiency of the progranulin (PGRN) gene (GRN) causes familial frontotemporal lobar degeneration (FTLD) and modulates an innate immune response in humans and in mouse models. GRN polymorphism may be linked to late-onset Alzheimer's disease (AD). However, the role of PGRN in AD pathogenesis is unknown. Here we show that PGRN inhibits amyloid β (Aβ) deposition. Selectively reducing microglial expression of PGRN in AD mouse models impaired phagocytosis, increased plaque load threefold and exacerbated cognitive deficits. Lentivirus-mediated PGRN overexpression lowered plaque load in AD mice with aggressive amyloid plaque pathology. Aβ plaque load correlated negatively with levels of hippocampal PGRN, showing the dose-dependent inhibitory effects of PGRN on plaque deposition. PGRN also protected against Aβ toxicity. Lentivirus-mediated PGRN overexpression prevented spatial memory deficits and hippocampal neuronal loss in AD mice. The protective effects of PGRN against Aβ deposition and toxicity have important therapeutic implications. We propose enhancing PGRN as a potential treatment for PGRN-deficient FTLD and AD.

  19. Small-animal PET imaging of amyloid-beta plaques with [11C]PiB and its multi-modal validation in an APP/PS1 mouse model of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    André Manook

    Full Text Available In vivo imaging and quantification of amyloidplaque (Aβ burden in small-animal models of Alzheimer's disease (AD is a valuable tool for translational research such as developing specific imaging markers and monitoring new therapy approaches. Methodological constraints such as image resolution of positron emission tomography (PET and lack of suitable AD models have limited the feasibility of PET in mice. In this study, we evaluated a feasible protocol for PET imaging of Aβ in mouse brain with [(11C]PiB and specific activities commonly used in human studies. In vivo mouse brain MRI for anatomical reference was acquired with a clinical 1.5 T system. A recently characterized APP/PS1 mouse was employed to measure Aβ at different disease stages in homozygous and hemizygous animals. We performed multi-modal cross-validations for the PET results with ex vivo and in vitro methodologies, including regional brain biodistribution, multi-label digital autoradiography, protein quantification with ELISA, fluorescence microscopy, semi-automated histological quantification and radioligand binding assays. Specific [(11C]PiB uptake in individual brain regions with Aβ deposition was demonstrated and validated in all animals of the study cohort including homozygous AD animals as young as nine months. Corresponding to the extent of Aβ pathology, old homozygous AD animals (21 months showed the highest uptake followed by old hemizygous (23 months and young homozygous mice (9 months. In all AD age groups the cerebellum was shown to be suitable as an intracerebral reference region. PET results were cross-validated and consistent with all applied ex vivo and in vitro methodologies. The results confirm that the experimental setup for non-invasive [(11C]PiB imaging of Aβ in the APP/PS1 mice provides a feasible, reproducible and robust protocol for small-animal Aβ imaging. It allows longitudinal imaging studies with follow-up periods of approximately one and a

  20. Tetrahydrohyperforin Inhibits the Proteolytic Processing of Amyloid Precursor Protein and Enhances Its Degradation by Atg5-Dependent Autophagy.

    Directory of Open Access Journals (Sweden)

    Viviana A Cavieres

    Full Text Available Alzheimer's disease (AD is a neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ peptide. We have previously shown that the compound tetrahydrohyperforin (IDN5706 prevents accumulation of Aβ species in an in vivo model of AD, however the mechanism that explains this reduction is not well understood. We show herein that IDN5706 decreases the levels of ER degradation enhancer, mannosidase alpha-like 1 (EDEM1, a key chaperone related to endoplasmic-reticulum-associated degradation (ERAD. Moreover, we observed that low levels of EDEM1 correlated with a strong activation of autophagy, suggesting a crosstalk between these two pathways. We observed that IDN5706 perturbs the glycosylation and proteolytic processing of the amyloid precursor protein (APP, resulting in the accumulation of immature APP (iAPP in the endoplasmic reticulum. To investigate the contribution of autophagy, we tested the effect of IDN5706 in Atg5-depleted cells. We found that depletion of Atg5 enhanced the accumulation of iAPP in response to IDN5706 by slowing down its degradation. Our findings reveal that IDN5706 promotes degradation of iAPP via the activation of Atg5-dependent autophagy, shedding light on the mechanism that may contribute to the reduction of Aβ production in vivo.

  1. Tetrahydrohyperforin Inhibits the Proteolytic Processing of Amyloid Precursor Protein and Enhances Its Degradation by Atg5-Dependent Autophagy

    Science.gov (United States)

    Muñoz, Vanessa C.; Yefi, Claudia P.; Bustamante, Hianara A.; Barraza, Rafael R.; Tapia-Rojas, Cheril; Otth, Carola; Barrera, María José; González, Carlos; Mardones, Gonzalo A.; Inestrosa, Nibaldo C.; Burgos, Patricia V.

    2015-01-01

    Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) peptide. We have previously shown that the compound tetrahydrohyperforin (IDN5706) prevents accumulation of Aβ species in an in vivo model of AD, however the mechanism that explains this reduction is not well understood. We show herein that IDN5706 decreases the levels of ER degradation enhancer, mannosidase alpha-like 1 (EDEM1), a key chaperone related to endoplasmic-reticulum-associated degradation (ERAD). Moreover, we observed that low levels of EDEM1 correlated with a strong activation of autophagy, suggesting a crosstalk between these two pathways. We observed that IDN5706 perturbs the glycosylation and proteolytic processing of the amyloid precursor protein (APP), resulting in the accumulation of immature APP (iAPP) in the endoplasmic reticulum. To investigate the contribution of autophagy, we tested the effect of IDN5706 in Atg5-depleted cells. We found that depletion of Atg5 enhanced the accumulation of iAPP in response to IDN5706 by slowing down its degradation. Our findings reveal that IDN5706 promotes degradation of iAPP via the activation of Atg5-dependent autophagy, shedding light on the mechanism that may contribute to the reduction of Aβ production in vivo. PMID:26308941

  2. Sulfur (S)-induced enhancement of iron plaque formation in the rhizosphere reduces arsenic accumulation in rice (Oryza sativa L.) seedlings

    Energy Technology Data Exchange (ETDEWEB)

    Hu Zhengyi [State Key Laboratory of Soil and Sustainable Agriculture, Institute of Soil Science, Chinese Academy of Sciences, No. 71, East Beijing Road, Nanjing 210008 (China)]. E-mail: zhyhu@issas.ac.cn; Zhu Yongguan [Research Center for Eco-environmental Science, Chinese Academy of Sciences, Beijing 10085 (China); Li Min [State Key Laboratory of Soil and Sustainable Agriculture, Institute of Soil Science, Chinese Academy of Sciences, No. 71, East Beijing Road, Nanjing 210008 (China); Anhui Agriculture University, Hefei 230036 (China); Zhang Ligan [Anhui Agriculture University, Hefei 230036 (China); Cao Zhihong [State Key Laboratory of Soil and Sustainable Agriculture, Institute of Soil Science, Chinese Academy of Sciences, No. 71, East Beijing Road, Nanjing 210008 (China); Smith, F. Andrew [Soil and Land Systems, School of Earth and Environmental Sciences, University of Adelaide, SA5005 (Australia)

    2007-05-15

    The effects of two sulfur (S) sources (SO{sub 4} {sup 2-}, S{sup 0}), and three rates of S application (0, 30, 120 mg S/kg) on the formation of iron plaque in the rhizosphere, and on the root surface of rice, and As (arsenic) uptake into rice (Oryza sativa L.) were studied in a combined soil-sand culture experiment. Significant differences in As uptake into rice between +S and -S treatments were observed in relation to S sources, and rates of S application. Concentrations of As in rice shoots decreased with increasing rates of S application. The mechanism could be ascribed to sulfur, induced the formation of iron plaque, since concentrations of Fe in iron plaque on quartz sands in the rhizosphere, and on the root surface of rice increased with increasing rates of S application. The results suggest that sulfur fertilization may be important for the development approaches to reducing As accumulation in rice. - Sulfur-induced enhancement of iron plaque formation on the root surface of rice.

  3. Sulfur (S)-induced enhancement of iron plaque formation in the rhizosphere reduces arsenic accumulation in rice (Oryza sativa L.) seedlings

    International Nuclear Information System (INIS)

    The effects of two sulfur (S) sources (SO42-, S0), and three rates of S application (0, 30, 120 mg S/kg) on the formation of iron plaque in the rhizosphere, and on the root surface of rice, and As (arsenic) uptake into rice (Oryza sativa L.) were studied in a combined soil-sand culture experiment. Significant differences in As uptake into rice between +S and -S treatments were observed in relation to S sources, and rates of S application. Concentrations of As in rice shoots decreased with increasing rates of S application. The mechanism could be ascribed to sulfur, induced the formation of iron plaque, since concentrations of Fe in iron plaque on quartz sands in the rhizosphere, and on the root surface of rice increased with increasing rates of S application. The results suggest that sulfur fertilization may be important for the development approaches to reducing As accumulation in rice. - Sulfur-induced enhancement of iron plaque formation on the root surface of rice

  4. Targeting amyloid-degrading enzymes as therapeutic strategies in neurodegeneration.

    Science.gov (United States)

    Turner, Anthony J; Fisk, Lilia; Nalivaeva, Natalia N

    2004-12-01

    The levels of amyloid beta-peptides (Abeta) in the brain represent a dynamic equilibrium state as a result of their biosynthesis from the amyloid precursor protein (APP) by beta- and gamma-secretases, their degradation by a team of amyloid-degrading enzymes, their subsequent oligomerization, and deposition into senile plaques. While most therapeutic attention has focused on developing inhibitors of secretases to prevent Abeta formation, enhancing the rate of Abeta degradation represents an alternative and viable strategy. Current evidence both in vivo and in vitro suggests that there are three major players in amyloid turnover: neprilysin, endothelin converting enzyme(s), and insulin-degrading enzyme, all of which are zinc metallopeptidases. Other proteases have also been implicated in amyloid metabolism, including angiotensin-converting enzyme, and plasmin but for these the evidence is less compelling. Neprilysin and endothelin converting enzyme(s) are homologous membrane proteins of the M13 peptidase family, which normally play roles in the biosynthesis and/or metabolism of regulatory peptides. Insulin-degrading enzyme is structurally and mechanistically distinct. The regional, cellular, and subcellular localizations of these enzymes differ, providing an efficient and diverse mechanism for protecting the brain against the normal accumulation of toxic Abeta peptides. Reduction in expression levels of some of these proteases following insults (e.g., hypoxia and ischemia) or aging might predispose to the development of Alzheimer's disease. Conversely, enhancement of their levels by gene delivery or pharmacological means could be neuroprotective. Even a relatively small enhancement of Abeta metabolism could slow the inexorable progression of the disease. The relative merits of targeting these enzymes for the treatment of Alzheimer's disease will be reviewed and possible side-effects of enhancing their activity evaluated.

  5. Synthetic peptide homologous to β protein from Alzheimer's disease forms amyloid-like fibrils in vitro

    International Nuclear Information System (INIS)

    Progressive amyloid deposition in senile plaques and cortical blood vessels may play a central role in the pathogenesis of Alzheimer's disease. The authors have used x-ray diffraction and electron microscopy to study the molecular organization and morphology of macromolecular assemblies formed by three synthetic peptides homologous to β protein of brain amyloid: β-(1-28), residues 1-28 of the β protein; [Ala1-β-(1-28), β-(1-28) with alanine substituted for lysine at position 16; and β-(18-28), residues 18-28 of the β protein. β-(1-28) readily formed fibrils in vitro that were similar in ultrastructure to the in vivo amyloid and aggregated into large bundles resembling those of senile plaque cores. X-ray patterns from partially dried, oriented pellets showed a cross-β-conformation. [Ala16]β-(1-28) formed β-pleated sheet assemblies that were dissimilar to in vivo fibrils. The width of the 10-A spacing indicated stacks of about six sheets. Thus, substitution of the uncharged alanine for the positively charged lysine in the β-strand region enhances the packing of the sheets and dramatically alters the type of macromolecular aggregate formed. Β-(18-28) formed assemblies that had even a greater number of stacked sheets. The findings on these homologous synthetic assemblies help to define the specific sequence that is required to form Alzheimer's-type amyloid fibrils, thus providing an in vitro model of age-related cerebral amyloidogenesis

  6. Reactive oxidative species enhance amyloid toxicity in APP/PS1 mouse neurons

    Institute of Scientific and Technical Information of China (English)

    Bin Yang; Xiaqin Sun; Hilal Lashuel; Yan Zhang

    2012-01-01

    [Objective] To investigate whether intracellular amyloid β (iAβ) induces toxicity in wild type (WT) and APP/PS1 mice,a mouse model of Alzheimer's disease.[Methods] Different forms of Aβ aggregates were microinjected into cultured WT or APP/PS1 mouse hippocampal neurons.TUNEL staining was performed to examine neuronal cell death.Reactive oxidative species (ROS) were measured by MitoSOXTM Red mitochondrial superoxide indicator.[Results]Crude,monomer and protofibril Aβ induced more toxicity in APP/PS1 neurons than in WT neurons.ROS are involved in mediating the vulnerability of APP/PS1 neurons to iAβ toxicity.[[Conclusion

  7. Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation

    Directory of Open Access Journals (Sweden)

    Oh Ki

    2008-08-01

    Full Text Available Abstract Background Alzheimer's disease (AD is characterized by extensive loss of neurons in the brain of AD patients. Intracellular accumulation of beta-amyloid peptide (Aβ has also shown to occur in AD. Neuro-inflammation has been known to play a role in the pathogenesis of AD. Methods In this study, we investigated neuro-inflammation and amyloidogenesis and memory impairment following the systemic inflammation generated by lipopolysaccharide (LPS using immunohistochemistry, ELISA, behavioral tests and Western blotting. Results Intraperitoneal injection of LPS, (250 μg/kg induced memory impairment determined by passive avoidance and water maze tests in mice. Repeated injection of LPS (250 μg/kg, 3 or 7 times resulted in an accumulation of Aβ1–42 in the hippocampus and cerebralcortex of mice brains through increased β- and γ-secretase activities accompanied with the increased expression of amyloid precursor protein (APP, 99-residue carboxy-terminal fragment of APP (C99 and generation of Aβ1–42 as well as activation of astrocytes in vivo. 3 weeks of pretreatment of sulindac sulfide (3.75 and 7.5 mg/kg, orally, an anti-inflammatory agent, suppressed the LPS-induced amyloidogenesis, memory dysfunction as well as neuronal cell death in vivo. Sulindac sulfide (12.5–50 μM also suppressed LPS (1 μg/ml-induced amyloidogenesis in cultured neurons and astrocytes in vitro. Conclusion This study suggests that neuro-inflammatory reaction could contribute to AD pathology, and anti-inflammatory agent could be useful for the prevention of AD.

  8. Amyloid-beta Positron Emission Tomography Imaging Probes : A Critical Review

    NARCIS (Netherlands)

    Kepe, Vladimir; Moghbel, Mateen C.; Langstrom, Bengt; Zaidi, Habib; Vinters, Harry V.; Huang, Sung-Cheng; Satyamurthy, Nagichettiar; Doudet, Doris; Mishani, Eyal; Cohen, Robert M.; Hoilund-Carlsen, Poul F.; Alavi, Abass; Barrio, Jorge R.

    2013-01-01

    The rapidly rising prevalence and cost of Alzheimer's disease in recent decades has made the imaging of amyloid-beta deposits the focus of intense research. Several amyloid imaging probes with purported specificity for amyloid-beta plaques are currently at various stages of FDA approval. However, a

  9. Ultrasound Tissue Characterization of Vulnerable Atherosclerotic Plaque

    Directory of Open Access Journals (Sweden)

    Eugenio Picano

    2015-05-01

    Full Text Available A thrombotic occlusion of the vessel fed by ruptured coronary atherosclerotic plaque may result in unstable angina, myocardial infarction or death, whereas embolization from a plaque in carotid arteries may result in transient ischemic attack or stroke. The atherosclerotic plaque prone to such clinical events is termed high-risk or vulnerable plaque, and its identification in humans before it becomes symptomatic has been elusive to date. Ultrasonic tissue characterization of the atherosclerotic plaque is possible with different techniques—such as vascular, transesophageal, and intravascular ultrasound—on a variety of arterial segments, including carotid, aorta, and coronary districts. The image analysis can be based on visual, video-densitometric or radiofrequency methods and identifies three distinct textural patterns: hypo-echoic (corresponding to lipid- and hemorrhage-rich plaque, iso- or moderately hyper-echoic (fibrotic or fibro-fatty plaque, and markedly hyperechoic with shadowing (calcific plaque. Hypoechoic or dishomogeneous plaques, with spotty microcalcification and large plaque burden, with plaque neovascularization and surface irregularities by contrast-enhanced ultrasound, are more prone to clinical complications than hyperechoic, extensively calcified, homogeneous plaques with limited plaque burden, smooth luminal plaque surface and absence of neovascularization. Plaque ultrasound morphology is important, along with plaque geometry, in determining the atherosclerotic prognostic burden in the individual patient. New quantitative methods beyond backscatter (to include speed of sound, attenuation, strain, temperature, and high order statistics are under development to evaluate vascular tissues. Although not yet ready for widespread clinical use, tissue characterization is listed by the American Society of Echocardiography roadmap to 2020 as one of the most promising fields of application in cardiovascular ultrasound imaging

  10. Amyloid β Enhances Typical Rodent Behavior While It Impairs Contextual Memory Consolidation

    Directory of Open Access Journals (Sweden)

    Karla Salgado-Puga

    2015-01-01

    Full Text Available Alzheimer’s disease (AD is associated with an early hippocampal dysfunction, which is likely induced by an increase in soluble amyloid beta peptide (Aβ. This hippocampal failure contributes to the initial memory deficits observed both in patients and in AD animal models and possibly to the deterioration in activities of daily living (ADL. One typical rodent behavior that has been proposed as a hippocampus-dependent assessment model of ADL in mice and rats is burrowing. Despite the fact that AD transgenic mice show some evidence of reduced burrowing, it has not been yet determined whether or not Aβ can affect this typical rodent behavior and whether this alteration correlates with the well-known Aβ-induced memory impairment. Thus, the purpose of this study was to test whether or not Aβ affects burrowing while inducing hippocampus-dependent memory impairment. Surprisingly, our results show that intrahippocampal application of Aβ increases burrowing while inducing memory impairment. We consider that this Aβ-induced increase in burrowing might be associated with a mild anxiety state, which was revealed by increased freezing behavior in the open field, and conclude that Aβ-induced hippocampal dysfunction is reflected in the impairment of ADL and memory, through mechanisms yet to be determined.

  11. Amyloid β Peptide Enhances RANKL-Induced Osteoclast Activation through NF-κB, ERK, and Calcium Oscillation Signaling

    Directory of Open Access Journals (Sweden)

    Shangfu Li

    2016-10-01

    Full Text Available Osteoporosis and Alzheimer’s disease (AD are common chronic degenerative disorders which are strongly associated with advanced age. We have previously demonstrated that amyloid beta peptide (Aβ, one of the pathological hallmarks of AD, accumulated abnormally in osteoporotic bone specimens in addition to having an activation effect on osteoclast (Bone 2014,61:164-75. However, the underlying molecular mechanisms remain unclear. Activation of NF-κB, extracellular signal-regulated kinase (ERK phosphorylates, and calcium oscillation signaling pathways by receptor activator NF-κB ligand (RANKL plays a pivotal role in osteoclast activation. Targeting this signaling to modulate osteoclast function has been a promising strategy for osteoclast-related diseases. In this study, we investigated the effects of Aβ on RANKL-induced osteoclast signaling pathways in vitro. In mouse bone marrow monocytes (BMMs, Aβ exerted no effect on RANKL-induced osteoclastogenesis but promoted osteoclastic bone resorption. In molecular levels, Aβ enhanced NF-κB activity and IκB-α degradation, activated ERK phosphorylation and stimulated calcium oscillation, thus leading to upregulation of NFAT-c1 expression during osteoclast activation. Taken together, our data demonstrate that Aβ enhances RANKL-induced osteoclast activation through IκB-α degradation, ERK phosphorylation, and calcium oscillation signaling pathways and that Aβ may be a promising agent in the treatment of osteoclast-related disease such as osteoporosis.

  12. Prevalence of amyloid PET positivity in dementia syndromes

    DEFF Research Database (Denmark)

    Ossenkoppele, Rik; Jansen, Willemijn J; Rabinovici, Gil D;

    2015-01-01

    IMPORTANCE: Amyloid-β positron emission tomography (PET) imaging allows in vivo detection of fibrillar plaques, a core neuropathological feature of Alzheimer disease (AD). Its diagnostic utility is still unclear because amyloid plaques also occur in patients with non-AD dementia. OBJECTIVE: To use...... years; noncarriers [n = 77], 7% [95% CI, 3%-18%] at 60 years to 29% [95% CI, 17%-43%] at 80 years. CONCLUSIONS AND RELEVANCE: Among participants with dementia, the prevalence of amyloid positivity was associated with clinical diagnosis, age, and APOE genotype. These findings indicate the potential...

  13. Glial fibrillary acidic protein isoform expression in plaque related astrogliosis in Alzheimer's disease

    NARCIS (Netherlands)

    Kamphuis, W.; Middeldorp, Jinte; Kooijman, Lieneke; Sluijs, Jacqueline A; Kooi, Evert-Jan; Moeton, Martina; Freriks, Michel; Mizee, Mark R; Hol, Elly M

    2014-01-01

    In Alzheimer's disease (AD), amyloid plaques are surrounded by reactive astrocytes with an increased expression of intermediate filaments including glial fibrillary acidic protein (GFAP). Different GFAP isoforms have been identified that are differentially expressed by specific subpopulations of ast

  14. Transmissible amyloid.

    Science.gov (United States)

    Tjernberg, L O; Rising, A; Johansson, J; Jaudzems, K; Westermark, P

    2016-08-01

    There are around 30 human diseases associated with protein misfolding and amyloid formation, each one caused by a certain protein or peptide. Many of these diseases are lethal and together they pose an enormous burden to society. The prion protein has attracted particular interest as being shown to be the pathogenic agent in transmissible diseases such as kuru, Creutzfeldt-Jakob disease and bovine spongiform encephalopathy. Whether similar transmission could occur also in other amyloidoses such as Alzheimer's disease, Parkinson's disease and serum amyloid A amyloidosis is a matter of intense research and debate. Furthermore, it has been suggested that novel biomaterials such as artificial spider silk are potentially amyloidogenic. Here, we provide a brief introduction to amyloid, prions and other proteins involved in amyloid disease and review recent evidence for their potential transmission. We discuss the similarities and differences between amyloid and silk, as well as the potential hazards associated with protein-based biomaterials. PMID:27002185

  15. Ceria Doped Zinc Oxide Nanoflowers Enhanced Luminol-Based Electrochemiluminescence Immunosensor for Amyloid-β Detection.

    Science.gov (United States)

    Wang, Jing-Xi; Zhuo, Ying; Zhou, Ying; Wang, Hai-Jun; Yuan, Ruo; Chai, Ya-Qin

    2016-05-25

    In this work, ceria doped ZnO nanomaterials with flower-structure (Ce:ZONFs) were prepared to construct a luminol-based electrochemiluminescence (ECL) immunosensor for amyloid-β protein (Aβ) detection. Herein, carboxyl groups (-COOH) covered Ce:ZONFs were synthesized by a green method with lysine as reductant. After that, Ce:ZONFs-based ECL nanocomposite was prepared by combining the luminophore of luminol and Ce:ZONFs via amidation and physical absorption. Luminol modified on Ce:ZONFs surface could generate a strong ECL signal under the assistance of reactive oxygen species (ROSs) (such as OH(•) and O2(•-)), which were produced by a catalytic reaction between Ce:ZONFs and H2O2. It was worth noticing that a quick Ce(4+) ↔ Ce(3+) reaction in this doped material could increase the rate of electron transfer to realize the signal amplification. Subsequently, the luminol functionalized Ce:ZONFs (Ce:ZONFs-Lum) were covered by secondary antibody (Ab2) and glucose oxidase (GOD), respectively, to construct a novel Ab2 bioconjugate (Ab2-GOD@Ce:ZONFs-Lum). The wire-structured silver-cysteine complex (AgCys NWs) with a large number of -COOH, which was synthesized by AgNO3 and l-cysteine, was used as substrate of the immunosensor to capture the primary antibody (Ab1). Under the optimal conditions, this proposed ECL immunosensor had exhibited high sensitivity for Aβ detection with a wide linear range from 80 fg/mL to 100 ng/mL and an ultralow detection limit of 52 fg/mL. Meanwhile, this biosensor had good specificity for Aβ, indicating that the provided strategy had a promising potential in the detection of Aβ. PMID:27145690

  16. Oleocanthal Enhances Amyloid-β Clearance from the Brains of TgSwDI Mice and in Vitro across a Human Blood-Brain Barrier Model

    OpenAIRE

    Qosa, Hisham; Yazan S. Batarseh; Mohyeldin, Mohamed M.; Khalid A. El Sayed; Keller, Jeffrey N.; Kaddoumi, Amal

    2015-01-01

    Numerous clinical and preclinical studies have suggested several health promoting effects for the dietary consumption of extra-virgin olive oil (EVOO) that could protect and decrease the risk of developing Alzheimer’s disease (AD). Moreover, recent studies have linked this protective effect to oleocanthal, a phenolic secoiridoid component of EVOO. This protective effect of oleocanthal against AD has been related to its ability to prevent amyloid-β (Aβ) and tau aggregation in vitro, and enhanc...

  17. Radiolabeled probes for imaging Alzheimer's plaques

    Energy Technology Data Exchange (ETDEWEB)

    Kulkarni, P.V. [Departments of Radiology and Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9058 (United States)]. E-mail: padmakar.kulkarni@utsouthwestern.edu; Arora, V. [Departments of Radiology and Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9058 (United States); Roney, A.C. [Departments of Radiology and Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9058 (United States); White, C. [Departments of Radiology and Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9058 (United States); Bennett, M. [Departments of Radiology and Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9058 (United States); Antich, P.P. [Departments of Radiology and Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9058 (United States); Bonte, F.J. [Departments of Radiology and Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9058 (United States)

    2005-12-15

    Alzheimer's disease (AD) is a debilitating disease characterized by the presence of extra-cellular plaques and intra-cellular neurofibrillary tangles (NFTs) in the brain. The major protein component of these plaques is beta amyloid peptide (A{beta}), a 40-42 amino acid peptide cleaved from amyloid precursor protein (APP) by {beta}-secretase and a putative {gamma}-secretase. We radioiodinated quinoline derivatives (clioquinol and oxine) and evaluated them as potential amyloid imaging agents based on their ability to cross the blood brain barrier (BBB) and on their selectivity to metal binding sites on amyloid plaques. The uptake of theses tracers in the brains of normal swiss-webster mice was rapid and so was the clearance. Selectivity was demonstrated by higher binding to AD brain homogenates compared to normal brain. Autoradiographic studies demonstrated the localization of the tracers in the plaque regions of the AD brain sections as well as in liver tissue with amyloidosis. Further optimization and evaluations would likely lead to development of these molecules as AD plaque imaging agents.

  18. Valproic acid inhibits Aβ production, neuritic plaque formation, and behavioral deficits in Alzheimer's disease mouse models

    OpenAIRE

    Qing, Hong; He, Guiqiong; Ly, Philip T. T.; Fox, Christopher J; Staufenbiel, Matthias; Cai, Fang; Zhang, Zhuohua; Wei, Shengcai; Sun, Xiulian; Chen, Chia-Hsiung; Zhou, Weihui; Wang, Ke; Song, Weihong

    2008-01-01

    Neuritic plaques in the brains are one of the pathological hallmarks of Alzheimer's disease (AD). Amyloid β-protein (Aβ), the central component of neuritic plaques, is derived from β-amyloid precursor protein (APP) after β- and γ-secretase cleavage. The molecular mechanism underlying the pathogenesis of AD is not yet well defined, and there has been no effective treatment for AD. Valproic acid (VPA) is one of the most widely used anticonvulsant and mood-stabilizing agents for treating epileps...

  19. Polymorphism of amyloid fibrils formed by a peptide from the yeast prion protein Sup35: AFM and Tip-Enhanced Raman Scattering studies.

    Science.gov (United States)

    Krasnoslobodtsev, Alexey V; Deckert-Gaudig, Tanja; Zhang, Yuliang; Deckert, Volker; Lyubchenko, Yuri L

    2016-06-01

    Aggregation of prion proteins is the cause of various prion related diseases. The infectious form of prions, amyloid aggregates, exist as multiple strains. The strains are thought to represent structurally different prion protein molecules packed into amyloid aggregates, but the knowledge on the structure of different types of aggregates is limited. Here we report on the use of AFM (Atomic Force Microscopy) and TERS (Tip-Enhanced Raman Scattering) to study morphological heterogeneity and access underlying conformational features of individual amyloid aggregates. Using AFM we identified the morphology of amyloid fibrils formed by the peptide (CGNNQQNY) from the yeast prion protein Sup35 that is critically involved in the aggregation of the full protein. TERS results demonstrate that morphologically different amyloid fibrils are composed of a distinct set of conformations. Fibrils formed at pH 5.6 are composed of a mixture of peptide conformations (β-sheets, random coil and α-helix) while fibrils formed in pH~2 solution primarily have β-sheets. Additionally, peak positions in the amide III region of the TERS spectra suggested that peptides have parallel arrangement of β-sheets for pH~2 fibrils and antiparallel arrangement for fibrils formed at pH 5.6. We also developed a methodology for detailed analysis of the peptide secondary structure by correlating intensity changes of Raman bands in different regions of TERS spectra. Such correlation established that structural composition of peptides is highly localized with large contribution of unordered secondary structures on a fibrillar surface. PMID:27060278

  20. Amyloid imaging in Alzheimer's disease: a literature review.

    Science.gov (United States)

    Saidlitz, P; Voisin, T; Vellas, B; Payoux, P; Gabelle, A; Formaglio, M; Delrieu, J

    2014-07-01

    Therapies targeting amyloid-β peptide currently represent approximately 50% of drugs now being developed for Alzheimer's disease. Some, including active and passive anti-Aβ immunotherapy, directly target the amyloid plaques. The new amyloid tracers are increasingly being included in the proposed updated diagnostic criteria, and may allow earlier diagnosis. Those targeting amyloid-β peptide allow identification of amyloid plaques in vivo. We need to gain insight into all aspects of their application. As florbetapir (Amyvid™) and flutemetamol (Vizamyl™) have received marketing authorization, clinicians require deeper knowledge to be rationally used in diagnosis. In this paper, we review both completed and ongoing observational, longitudinal and interventional studies of these tracers, our main objective being to show the performance of the four most commonly used tracers and their validation. PMID:25226113

  1. Oleocanthal enhances amyloid-β clearance from the brains of TgSwDI mice and in vitro across a human blood-brain barrier model.

    Science.gov (United States)

    Qosa, Hisham; Batarseh, Yazan S; Mohyeldin, Mohamed M; El Sayed, Khalid A; Keller, Jeffrey N; Kaddoumi, Amal

    2015-11-18

    Numerous clinical and preclinical studies have suggested several health promoting effects for the dietary consumption of extra-virgin olive oil (EVOO) that could protect and decrease the risk of developing Alzheimer's disease (AD). Moreover, recent studies have linked this protective effect to oleocanthal, a phenolic secoiridoid component of EVOO. This protective effect of oleocanthal against AD has been related to its ability to prevent amyloid-β (Aβ) and tau aggregation in vitro, and enhance Aβ clearance from the brains of wild type mice in vivo; however, its effect in a mouse model of AD is not known. In the current study, we investigated the effect of oleocanthal on pathological hallmarks of AD in TgSwDI, an animal model of AD. Mice treatment for 4 weeks with oleocanthal significantly decreased amyloid load in the hippocampal parenchyma and microvessels. This reduction was associated with enhanced cerebral clearance of Aβ across the blood-brain barrier (BBB). Further mechanistic studies demonstrated oleocanthal to increase the expression of important amyloid clearance proteins at the BBB including P-glycoprotein and LRP1, and to activate the ApoE-dependent amyloid clearance pathway in the mice brains. The anti-inflammatory effect of oleocanthal in the brains of these mice was also obvious where it was able to reduce astrocytes activation and IL-1β levels. Finally, we could recapitulate the observed protective effect of oleocanthal in an in vitro human-based model, which could argue against species difference in response to oleocanthal. In conclusion, findings from in vivo and in vitro studies provide further support for the protective effect of oleocanthal against the progression of AD. PMID:26348065

  2. Soluble aggregates of the amyloid-β peptide are trapped by serum albumin to enhance amyloid-β activation of endothelial cells

    Directory of Open Access Journals (Sweden)

    Gonzalez-Velasquez Francisco J

    2009-04-01

    Full Text Available Abstract Background Self-assembly of the amyloid-β peptide (Aβ has been implicated in the pathogenesis of Alzheimer's disease (AD. As a result, synthetic molecules capable of inhibiting Aβ self-assembly could serve as therapeutic agents and endogenous molecules that modulate Aβ self-assembly may influence disease progression. However, increasing evidence implicating a principal pathogenic role for small soluble Aβ aggregates warns that inhibition at intermediate stages of Aβ self-assembly may prove detrimental. Here, we explore the inhibition of Aβ1–40 self-assembly by serum albumin, the most abundant plasma protein, and the influence of this inhibition on Aβ1–40 activation of endothelial cells for monocyte adhesion. Results It is demonstrated that serum albumin is capable of inhibiting in a dose-dependent manner both the formation of Aβ1–40 aggregates from monomeric peptide and the ongoing growth of Aβ1–40 fibrils. Inhibition of fibrillar Aβ1–40 aggregate growth is observed at substoichiometric concentrations, suggesting that serum albumin recognizes aggregated forms of the peptide to prevent monomer addition. Inhibition of Aβ1–40 monomer aggregation is observed down to stoichiometric ratios with partial inhibition leading to an increase in the population of small soluble aggregates. Such partial inhibition of Aβ1–40 aggregation leads to an increase in the ability of resulting aggregates to activate endothelial cells for adhesion of monocytes. In contrast, Aβ1–40 activation of endothelial cells for monocyte adhesion is reduced when more complete inhibition is observed. Conclusion These results demonstrate that inhibitors of Aβ self-assembly have the potential to trap small soluble aggregates resulting in an elevation rather than a reduction of cellular responses. These findings provide further support that small soluble aggregates possess high levels of physiological activity and underscore the importance of

  3. NO-flurbiprofen reduces amyloid-beta, is neuroprotective in cell culture, and enhances cognition in response to cholinergic blockade.

    Science.gov (United States)

    Abdul-Hay, Samer O; Luo, Jia; Ashghodom, Rezene T; Thatcher, Gregory R J

    2009-11-01

    The non-steroidal anti-inflammatory drug flurbiprofen is a selective amyloid lowering agent which has been studied clinically in Alzheimer's disease. HCT-1026 is an ester prodrug of flurbiprofen incorporating a nitrate carrier moiety that in vivo provides NO bioactivity and an improved safety profile. In vitro, HCT-1026 retained the cyclooxygenase inhibitory and non-steroidal anti-inflammatory drug activity of flurbiprofen, but at concentrations at which levels of amyloid-beta 1-42 amino acid were lowered by flurbiprofen, amyloid-beta 1-42 amino acid levels were elevated 200% by HCT-1026. Conversely, at lower concentrations, HCT-1026 behaved as a selective amyloid lowering agent with greater potency than flurbiprofen. The difference in concentration-responses between flurbiprofen and HCT-1026 in vitro suggests different cellular targets; and in no case did a combination of nitrate drug with flurbiprofen provide similar actions. In vivo, HCT-1026 was observed to reverse cognitive deficits induced by scopolamine in two behavioral assays; activity that was also shown by a classical nitrate drug, but not by flurbiprofen. The ability to restore aversive memory and spatial working and reference memory after cholinergic blockade has been demonstrated by other agents that stimulate NO/cGMP signaling. These observations add positively to the preclinical profile of HCT-1026 and NO chimeras in Alzheimer's disease.

  4. Preparation of Amyloid Immuno-Nanoparticles as Potential MRI Contrast Agents for Alzheimer's Disease Diagnosis.

    Science.gov (United States)

    Yin, Zhenyu; Yul, Tingting; Xu, Yun

    2015-09-01

    Alzheimer's disease (AD) is the most common form of dementia which is caused by accumulation in the brain of plaques made up of amyloid beta-peptide (Abeta). Research on nanosized systems indicated that nanoparticles (NPs) could pass across the blood-brain barrier (BBB) and improve the visibility of internal body structures in magnetic resonance imaging (MRI), which made it possible to aid the early diagnosis of AD. In this research study we synthesized magnetite nanoparticles by high-temperature solution-phase reaction, transferred into water based on a ligand exchange process and coated with meso-2,3-dimercaptosuccinic (DMSA). Subsequently, the anti-amyloid Abeta immunomagnetic nanoparticles (IMNPs) were prepared by grafting anti-amyloid antibodies on the surface of the DMSA-coated magnetic nanoparticles (MNPs). The enzyme linked immunosorbent assay (ELISA) method was introduced to evaluate the IMNPs activity and conjugation amount of antibodies. The biocompatibility of the IMNPs was tested by colony-forming assay. The results showed that the anti-amyloid Abeta IMNPs were biocompatible and biologically active, as well as effective in enhancing MRI solution, indicating that the IMNPs could be used as potential MRI contrast agents and targeted carriers for AD early diagnosis and therapy. PMID:26716196

  5. Neuroinflammation in Lyme neuroborreliosis affects amyloid metabolism

    Directory of Open Access Journals (Sweden)

    Anckarsäter Henrik

    2010-06-01

    Full Text Available Abstract Background The metabolism of amyloid precursor protein (APP and β-amyloid (Aβ is widely studied in Alzheimer's disease, where Aβ deposition and plaque development are essential components of the pathogenesis. However, the physiological role of amyloid in the adult nervous system remains largely unknown. We have previously found altered cerebral amyloid metabolism in other neuroinflammatory conditions. To further elucidate this, we investigated amyloid metabolism in patients with Lyme neuroborreliosis (LNB. Methods The first part of the study was a cross-sectional cohort study in 61 patients with acute facial palsy (19 with LNB and 42 with idiopathic facial paresis, Bell's palsy and 22 healthy controls. CSF was analysed for the β-amyloid peptides Aβ38, Aβ40 and Aβ42, and the amyloid precursor protein (APP isoforms α-sAPP and β-sAPP. CSF total-tau (T-tau, phosphorylated tau (P-tau and neurofilament protein (NFL were measured to monitor neural cell damage. The second part of the study was a prospective cohort-study in 26 LNB patients undergoing consecutive lumbar punctures before and after antibiotic treatment to study time-dependent dynamics of the biomarkers. Results In the cross-sectional study, LNB patients had lower levels of CSF α-sAPP, β-sAPP and P-tau, and higher levels of CSF NFL than healthy controls and patients with Bell's palsy. In the prospective study, LNB patients had low levels of CSF α-sAPP, β-sAPP and P-tau at baseline, which all increased towards normal at follow-up. Conclusions Amyloid metabolism is altered in LNB. CSF levels of α-sAPP, β-sAPP and P-tau are decreased in acute infection and increase after treatment. In combination with earlier findings in multiple sclerosis, cerebral SLE and HIV with cerebral engagement, this points to an influence of neuroinflammation on amyloid metabolism.

  6. Amyloid formation: functional friend or fearful foe?

    Science.gov (United States)

    Bergman, P; Roan, N R; Römling, U; Bevins, C L; Münch, J

    2016-08-01

    Amyloid formation has been most studied in the context of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, as well as in amyloidosis. However, it is becoming increasingly clear that amyloid is also present in the healthy setting; for example nontoxic amyloid formation is important for melanin synthesis and in innate immunity. Furthermore, bacteria have mechanisms to produce functional amyloid structures with important roles in bacterial physiology and interaction with host cells. Here, we will discuss some novel aspects of fibril-forming proteins in humans and bacteria. First, the amyloid-forming properties of the antimicrobial peptide human defensin 6 (HD6) will be considered. Intriguingly, unlike other antimicrobial peptides, HD6 does not kill bacteria. However, recent data show that HD6 can form amyloid structures at the gut mucosa with strong affinity for bacterial surfaces. These so-called nanonets block bacterial invasion by entangling the bacteria in net-like structures. Next, the role of functional amyloid fibrils in human semen will be discussed. These fibrils were discovered through their property to enhance HIV infection but they may also have other yet unknown functions. Finally, the role of amyloid formation in bacteria will be reviewed. The recent finding that bacteria can make amyloid in a controlled fashion without toxic effects is of particular interest and may have implications for human disease. The role of amyloid in health and disease is beginning to be unravelled, and here, we will review some of the most recent findings in this exciting area. PMID:27151743

  7. Influence of hydrophobic Teflon particles on the structure of amyloid beta-peptide

    NARCIS (Netherlands)

    Giacomelli, CE; Norde, W

    2003-01-01

    The amyloid beta-protein (Abeta) constitutes the major peptide component of the amyloid plaque deposits of Alzheimer's disease in humans. The Abeta changes from a nonpathogenic to a pathogenic conformation resulting in self-aggregation and deposition of the peptide. It has been established that dena

  8. A peptide study of the relationship between the collagen triple-helix and amyloid

    OpenAIRE

    Parmar, Avanish S.; Nunes, Ana Monica; Baum, Jean; Brodsky, Barbara

    2012-01-01

    Type XXV collagen, or Collagen-Like Amyloidogenic Component (CLAC), is a component of amyloid plaques, and recent studies suggest this collagen affects amyloid fibril elongation and has a genetic association with Alzheimer’s disease. The relationship between the collagen triple helix and amyloid fibrils was investigated by studying peptide models, including a very stable triple helical peptide (Pro-Hyp-Gly)10; an amyloidogenic peptide GNNQQNY; and a hybrid peptide where the GNNQQNY sequence w...

  9. Adolescent exposure to MDMA induces dopaminergic toxicity in substantia nigra and potentiates the amyloid plaque deposition in the striatum of APPswe/PS1dE9 mice.

    Science.gov (United States)

    Abad, Sonia; Ramon, Carla; Pubill, David; Camarasa, Jorge; Camins, Antonio; Escubedo, Elena

    2016-09-01

    MDMA is one of the most used drugs by adolescents and its consumption has been associated with many psychobiological problems, among them psychomotor problems. Moreover, some authors described that early exposure to MDMA may render the dopaminergic neurons more vulnerable to the effects of future neurotoxic insults. Alzheimer disease (AD) is the main cause of dementia in the elderly and a percentage of the patients have predisposition to suffer nigrostriatal alterations, developing extrapyramidal signs. Nigrostriatal dysfunction in the brain of aged APPswe/PS1dE9 (APP/PS1), a mouse model of familiar AD (FAD), has also been described. The aim of the present study was to investigate the consequences of adolescent exposure to MDMA in APP/PS1 mice, on nigrostriatal function on early adulthood. We used a MDMA schedule simulating weekend binge abuse of this substance. Our MDMA schedule produced a genotype-independent decrease in dopaminergic neurons in the substantia nigra that remained at least 3months. Shortly after the injury, wild-type animals showed a decrease in the locomotor activity and apparent DA depletion in striatum, however in the APP/PS1 mice neither the locomotor activity nor the DA levels were modified, but a reduction in dopamine transporter (DAT) expression and a higher levels of oxidative stress were observed. We found that these disturbances are age-related characteristics that this APP/PS1 mice develops spontaneously much later. Therefore, MDMA administration seems to anticipate the striatal dopaminergic dysfunction in this FAD model. The most important outcome lies in a potentiation, by MDMA, of the amyloid beta deposition in the striatum. PMID:27344237

  10. Arctigenin effectively ameliorates memory impairment in Alzheimer's disease model mice targeting both β-amyloid production and clearance.

    Science.gov (United States)

    Zhu, Zhiyuan; Yan, Jianming; Jiang, Wei; Yao, Xin-gang; Chen, Jing; Chen, Lili; Li, Chenjing; Hu, Lihong; Jiang, Hualiang; Shen, Xu

    2013-08-01

    Alzheimer's disease (AD) chiefly characterizes a progressively neurodegenerative disorder of the brain, and eventually leads to irreversible loss of intellectual abilities. The β-amyloid (Aβ)-induced neurodegeneration is believed to be the main pathological mechanism of AD, and Aβ production inhibition or its clearance promotion is one of the promising therapeutic strategies for anti-AD research. Here, we report that the natural product arctigenin from Arctium lappa (L.) can both inhibit Aβ production by suppressing β-site amyloid precursor protein cleavage enzyme 1 expression and promote Aβ clearance by enhancing autophagy through AKT/mTOR signaling inhibition and AMPK/Raptor pathway activation as investigated in cells and APP/PS1 transgenic AD model mice. Moreover, the results showing that treatment of arctigenin in mice highly decreased Aβ formation and senile plaques and efficiently ameliorated AD mouse memory impairment strongly highlight the potential of arctigenin in anti-AD drug discovery. PMID:23926267

  11. NO-flurbiprofen reduces amyloid β, is neuroprotective in cell culture, and enhances cognition in response to cholinergic blockade

    OpenAIRE

    Abdul-Hay, Samer O.; Luo, Jia; Ashghodom, Rezene T.; Thatcher, Gregory R. J.

    2009-01-01

    The nonsteroidal anti-inflamatory drug (NSAID) flurbiprofen is a selective amyloid lowering agent (SALA) which has been studied clinically in Alzheimer’s disease. HCT-1026 is an ester prodrug of flurbiprofen incorporating a nitrate carrier moiety that in vivo provides NO bioactivity and an improved safety profile. In vitro, HCT-1026 retained the COX inhibitory and NSAID activity of flurbiprofen, but at concentrations at which levels of Aβ1–42 were lowered by flurbiprofen, Aβ1–42 levels were e...

  12. Compressive deformation of ultralong amyloid fibrils

    Science.gov (United States)

    Paparcone, Raffaella; Cranford, Steven; Buehler, Markus J.

    2010-12-01

    Involved in various neurodegenerative diseases, amyloid fibrils and plaques feature a hierarchical structure, ranging from the atomistic to the micrometer scale. At the atomistic level, a dense and organized hydrogen bond network is resembled in a beta-sheet rich secondary structure, which drives a remarkable stiffness in the range of 10-20GPa, larger than many other biological nanofibrils, a result confirmed by both experiment and theory. However, the understanding of how these exceptional mechanical properties transfer from the atomistic to the nanoscale remains unknown. Here we report a multiscale analysis that, from the atomistic-level structure of a single fibril, extends to the mesoscale level, reaching size scales of hundreds of nanometers. We use parameters directly derived from full atomistic simulations of A β (1-40) amyloid fibrils to parameterize a mesoscopic coarse-grained model, which is used to reproduce the elastic properties of amyloid fibrils. We then apply our mesoscopic model in an analysis of the buckling behavior of amyloid fibrils with different lengths and report a comparison with predictions from continuum beam theory. An important implication of our results is a severe reduction of the effective modulus due to buckling, an effect that could be important to interpret experimental results of ultra-long amyloid fibrils. Our model represents a powerful tool to mechanically characterize molecular structures on the order of hundreds of nanometers to micrometers on the basis of the underlying atomistic behavior. The work provides insight into structural and mechanical properties of amyloid fibrils and may enable further analysis of larger-scale assemblies such as amyloidogenic bundles or plaques as found in disease states.

  13. Mechanisms of beta-amyloid neurotoxicity : Perspectives of pharmacotherapy

    NARCIS (Netherlands)

    Harkany, T; Abraham, [No Value; Konya, C; Nyakas, C; Zarandi, M; Penke, B; Luiten, PGM

    2000-01-01

    One of the characteristic neuropathological hallmarks of Alzheimer's disease (AD) is the extracellular accumulation of beta -amyloid peptides (A beta) in neuritic plaques, Experimental data indicate that different molecular forms of A beta affect a wide array of neuronal and glial functions and ther

  14. 常压高氧对淀粉样蛋白前体/早老素1双重转基因小鼠脑内老年斑及β-淀粉样蛋白的影响%The effect of normobaric hyperoxia on senile plaques and beta-amyloid protein in brain of amyloid protein precursor/presenilin 1 double transgenic mouse

    Institute of Scientific and Technical Information of China (English)

    高宝兵; 龙志敏; 贺桂琼; 孙善全

    2010-01-01

    Objective In order to investigate whether normobaric hyperoxia exert ncumprotective effect on amyloid protein precursor/presenilin 1(APP/PS1)double transgenic Alzheimer's disease(AD) mouse model.Methods Forty APP/PS1 double transgenie mice were randomly divided into 4 groups(A,B,C and D).Mice were treated with 40% oxygen for 8 h per day for 4 weeks in group A and for 8 weeks in group B.Group C and group D were given regular air for 4 weeks and 8 weeks,respectively,as controls.Immunohistochemical staining.Thioflavin S staining.Western blot and ELISA assay were performed on mice brain tissues in all groups after the treatment.Results Immuohistochemical and Thioflavin S staining showed that in hyperoxia-treated mice,number and size of senile plaques in the cerebral cortex and hippocampus were notably decreased,and deposition of AB in the brain of group B decreased more than that of group A.Western blot revealed that in the hyperoxia-treated mice,the levels of C_(99) and C_(83) were greatly increased while the Aβ level notably decreased.compared with controls.However,the expression of holoprotein APP and β-site amyloid cleavage enzyme 1(BACE1)showed no difference among 4 groups.ELISA assay showed that Aβ_(40)((783.6±97.2)pg/m1)and Aβ_(42)((175.3±17.1)pg/ml)were significantly decreased in the brain of 8 weeks hyperoxia-treated mice compared witlI the control group Aβ_(40) ((1251.6±42.3)pg/ml,t=9.36,P<0.01),and A1342((286.8±13.0)pg/ml,t=13.7,P<0.01).Conclusion Treatment with hyperoxia can significantly decrease Aβ levels and lower the number and size of senile plaques in the brain of APP/PS1 transgenic mouse.This study indicates that hyperoxia may exert its neuroprotective effect through decreasing the generation of Aβ or accelerating the clearance of Aβ.%目的 探讨常压高氧(40%O_2,60%空气)处理淀粉样蛋白前体/早老素1(APP/PS1)双重转基因小鼠是否发挥神经保护作用.方法 对APP/PS1双重转基因阿尔茨海默病(AD)模型种

  15. A New F-18 Labeled PET Agent For Imaging Alzheimer's Plaques

    International Nuclear Information System (INIS)

    Amyloid plaques and neurofibrillary tangles are hallmarks of Alzheimer's disease (AD). Advances in development of imaging agents have focused on targeting amyloid plaques. Notable success has been the development of C-11 labeled PIB (Pittsburgh Compound) and a number of studies have demonstrated the utility of this agent. However, the short half life of C-11 (t1/2: 20 min), is a limitation, thus has prompted the development of F-18 labeled agents. Most of these agents are derivatives of amyloid binding dyes; Congo red and Thioflavin. Some of these agents are in clinical trials with encouraging results. We have been exploring new class of agents based on 8-hydroxy quinoline, a weak metal chelator, targeting elevated levels of metals in plaques. Iodine-123 labeled clioquinol showed affinity for amyloid plaques however, it had limited brain uptake and was not successful in imaging in intact animals and humans. We have been successful in synthesizing F-18 labeled 8-hydroxy quinoline. Small animal PET/CT imaging studies with this agent showed high (7-10% ID/g), rapid brain uptake and fast washout of the agent from normal mice brains and delayed washout from transgenic Alzheimer's mice. These promising results encouraged us in further evaluation of this class of compounds for imaging AD plaques.

  16. Amyloid β-Protein as a Substrate Interacts with Extracellular Matrix to Promote Neurite Outgrowth

    Science.gov (United States)

    Koo, Edward H.; Park, Lisa; Selkoe, Dennis J.

    1993-05-01

    Progressive deposition of amyloid β-protein (Aβ) in brain parenchyma and blood vessels is a characteristic feature of Alzheimer disease. Recent evidence suggests that addition of solubilized synthetic Aβ to medium may produce toxic or trophic effects on cultured hippocampal neurons. Because soluble Aβ may not accumulate in significant quantities in brain, we asked whether immobilized Aβ peptide as a substrate alters neurite outgrowth from cultured rat peripheral sensory neurons. This paradigm may closely mimic the conditions in Alzheimer disease brain tissue, in which neurites contact insoluble, extracellular aggregates of β-amyloid. We detected no detrimental effects of Aβ substrate on neurite outgrowth. Rather, Aβ in combination with low doses of laminin or fibronectin enhanced neurite out-growth from these neuronal explants. Our results suggest that insoluble Aβ in the cerebral neuropil may serve as a neurite-promoting matrix, perhaps explaining the apparent regenerative response of neurites observed around amyloid plaques in Alzheimer disease. Moreover, in concert with the recent discovery of Aβ production by cultured neurons, our data suggest that Aβ plays a normal physiological role in brain by complexing with the extracellular matrix.

  17. Imaging unstable plaque.

    Science.gov (United States)

    Sriranjan, Rouchelle S; Tarkin, Jason M; Evans, Nicholas R; Chowdhury, Mohammed M; Rudd, James H

    2016-09-01

    Recent advances in imaging technology have enabled us to utilise a range of diagnostic approaches to better characterise high-risk atherosclerotic plaque. The aim of this article is to review current and emerging techniques used to detect and quantify unstable plaque in the context of large and small arterial systems and will focus on both invasive and non-invasive imaging techniques. While the diagnosis of clinically relevant atherosclerosis still relies heavily on anatomical assessment of arterial luminal stenosis, evolving multimodal cross-sectional imaging techniques that encompass novel molecular probes can provide added information with regard to plaque composition and overall disease burden. Novel molecular probes currently being developed to track precursors of plaque rupture such as inflammation, micro-calcification, hypoxia and neoangiogenesis are likely to have translational applications beyond diagnostics and have the potential to play a part in quantifying early responses to therapeutic interventions and more accurate cardiovascular risk stratification. PMID:27273430

  18. Corneal mucus plaques.

    Science.gov (United States)

    Fraunfelder, F T; Wright, P; Tripathi, R C

    1977-02-01

    Corneal mucus plaques adhered to the anterior corneal surface in 17 of 67 advanced cases of keratoconjunctivitis sicca. The plaques were translucent to opaque and varied in size and shape, from multiple isolated islands to bizarre patterns involving more than half the corneal surface. Ultrastructurally, they consisted of mucus mixed with desquamated degenerating epithelial cells and proteinaceous and lipoidal material. The condition may be symptomatic but can be controlled and prevented in most cases by topical ocular application of 10% acetylcysteine.

  19. Model Hirano bodies protect against tau-independent and tau-dependent cell death initiated by the amyloid precursor protein intracellular domain.

    Directory of Open Access Journals (Sweden)

    Matthew Furgerson

    Full Text Available The main pathological hallmarks of Alzheimer's disease are amyloid-beta plaques and neurofibrillary tangles, which are primarily composed of amyloid precursor protein (APP and tau, respectively. These proteins and their role in the mechanism of neurodegeneration have been extensively studied. Hirano bodies are a frequently occurring pathology in Alzheimer's disease as well as other neurodegenerative diseases. However, the physiological role of Hirano bodies in neurodegenerative diseases has yet to be determined. We have established cell culture models to study the role of Hirano bodies in amyloid precursor protein and tau-induced cell death mechanisms. Exogenous expression of APP and either of its c-terminal fragments c31 or Amyloid Precursor Protein Intracellular Domain c58 (AICDc58 enhance cell death. The presence of tau is not required for this enhanced cell death. However, the addition of a hyperphosphorylated tau mimic 352PHPtau significantly increases cell death in the presence of both APP and c31 or AICDc58 alone. The mechanism of cell death induced by APP and its c-terminal fragments and tau was investigated. Fe65, Tip60, p53, and caspases play a role in tau-independent and tau-dependent cell death. In addition, apoptosis was determined to contribute to cell death. The presence of model Hirano bodies protected against cell death, indicating Hirano bodies may play a protective role in neurodegeneration.

  20. NO-flurbiprofen reduces amyloid β, is neuroprotective in cell culture, and enhances cognition in response to cholinergic blockade

    Science.gov (United States)

    Abdul-Hay, Samer O.; Luo, Jia; Ashghodom, Rezene T.; Thatcher, Gregory R.J.

    2009-01-01

    The nonsteroidal anti-inflamatory drug (NSAID) flurbiprofen is a selective amyloid lowering agent (SALA) which has been studied clinically in Alzheimer’s disease. HCT-1026 is an ester prodrug of flurbiprofen incorporating a nitrate carrier moiety that in vivo provides NO bioactivity and an improved safety profile. In vitro, HCT-1026 retained the COX inhibitory and NSAID activity of flurbiprofen, but at concentrations at which levels of Aβ1–42 were lowered by flurbiprofen, Aβ1–42 levels were elevated 200% by HCT-1026. Conversely, at lower concentrations, HCT-1026 behaved as a SALA with greater potency than flurbiprofen. The difference in concentration responses between flurbiprofen and HCT-1026 in vitro suggests different cellular targets; and in no case did a combination of nitrate drug with flurbiprofen provide similar actions. In vivo, HCT-1026 was observed to reverse cognitive deficits induced by scopolamine in two behavioral assays; activity that was also shown by a classical nitrate drug, but not by flurbiprofen. The ability to restore aversive memory and spatial working and reference memory after cholinergic blockade has been demonstrated by other agents that stimulate NO/cGMP signaling. These observations add positively to the preclinical profile of HCT-1026 and NO chimeras in Alzheimer’s disease. PMID:19702655

  1. Enhanced External Counterpulsation Treatment May Intervene The Advanced Atherosclerotic Plaque Progression by Inducing The Variations of Mechanical Factors: A 3D FSI Study Based on in vivo Animal Experiment.

    Science.gov (United States)

    Du, Jianhang; Wang, Liang

    2015-12-01

    Growing evidences suggest that long-term enhanced external counter-pulsation (EECP) treatment can inhibit the initiation of atherosclerotic lesion by improving the hemodynamic environment in aortas. However, whether this kind procedure will intervene the progression of advanced atherosclerotic plaque remains elusive and causes great concern in its clinical application presently. In the current paper, a pilot study combining animal experiment and numerical simulation was conducted to investigate the acute mechanical stress variations during EECP intervention, and then to assess the possible chronic effects. An experimentally induced hypercholesterolemic porcine model was developed and the basic hemodynamic measurement was performed in vivo before and during EECP treatment. Meanwhile, A 3D fluid-structure interaction (FSI) model of blood vessel with symmetric local stenosis was developed for the numerical calculation of some important mechanical factors. The results show that EECP augmented 12.21% of the plaque wall stress (PWS), 57.72% of the time average wall shear stress (AWSS) and 43.67% of the non-dimensional wall shear stress gradient (WSSGnd) at throat site of the stenosis. We suggest that long-term EECP treatment may intervene the advanced plaque progression by inducing the significant variations of some important mechanical factors, but its proper effects will need a further research combined follow-up observation in clinic. PMID:27263260

  2. Effect of catalpol on senile plaques and spatial learning and memory ability in amyloid-β protein precursor/presenilin 1 double transgenic mice%梓醇对淀粉样蛋白前体/早老素1双转基因小鼠老年斑和学习记忆的影响

    Institute of Scientific and Technical Information of China (English)

    宋冲; 楚亚楠; 贺桂琼; 刘刚; 王凌唏; 周泽芬; 姚秋会

    2013-01-01

    目的 观察梓醇对淀粉样蛋白前体、早老素1(APP/PSI)双转基因小鼠老年斑和学习记忆能力的影响.方法 将3个月龄的APP/PS1双转基因小鼠按照随机数字表法分为梓醇治疗组和生理盐水对照组,每组10只,并以10只同月龄的相同遗传背景的C57小鼠作为正常对照组.用梓醇(每天5 mg/kg)和等量生理盐水腹腔注射阿尔茨海默病(AD)模型小鼠3周,应用免疫组织化学检测各组小鼠老年斑数量的变化;应用Morris水迷宫检测小鼠空间学习记忆能力的变化.结果 免疫组织化学结果显示:与生理盐水对照组(6.0±0.6)比较,梓醇治疗组小鼠老年斑数量(个)明显减少(2.3±0.7,t=3.500,P=0.025).行为学结果显示:(1)在可视平台实验中,3组小鼠找到平台的平均潜伏期和搜索的平均路径差异无统计学意义.(2)隐蔽平台下,梓醇治疗组小鼠找到平台的时间及搜索的路径较生理盐水对照组小鼠明显缩短;与正常对照组比较,差异无统计学意义.(3)在探索实验中,60 s内梓醇治疗组(6.4±0.5)小鼠穿越平台次数(次)明显高于生理盐水对照组(2.9±0.4,t=5.592,P=0.001),而与正常对照组(6.8±0.6)比较差异无统计学意义(t=0.418,P=0.682).结论 梓醇治疗能显著减少AD模型小鼠脑内老年斑数量,改善小鼠的空间学习记忆能力.%Objective To investigate whether catalpol affects senile plaque formation and spatial learning and memory ability in the amyloid-β protein precursor/presenilin 1 (APP/PSI) double transgenic mice.Methods Three month-old APP/PS1 double transgenic mice were randomly divided into catalpoltreated and saline-treated groups (n =10),with C57 mice of the same age and genetic background as normal control group (n =10).The catalpol (in a dose of 5 mg · kg-1 · d-1) and the same amount of saline were peritoneally injected into Alzheimer' s disease (AD) model mice for 3 weeks.Immunohistochemical staining was performed to examine senile

  3. Extraskeletal problems and amyloid.

    Science.gov (United States)

    Drüeke, T B

    1999-12-01

    The major clinical manifestations of dialysis-associated A beta 2M amyloidosis are chronic arthralgias, destructive arthropathy and the carpal tunnel syndrome. For dialysis patients who have been maintained on renal replacement therapy for more than 10-15 years, this complication may become a major physical handicap. It may even be life-threatening in some instances due to cervical cord compression. Amyloid deposits in joint areas precede clinical symptoms and signs by several years. Systemic deposits may also occur but their clinical manifestations are infrequent. The diagnosis of dialysis arthropathy associated with beta 2-microglobulin-associated (A beta 2M) amyloidosis mostly relies on indirect clinical and radiological evidence. Histologic proof is rarely obtained in vivo. The pathogenesis of the disease is complex. It includes reduced elimination of beta 2M and potentially also as impaired degradation of A beta 2M as well as enhanced production of A beta 2M amyloid fibrils. Non enzymatic modifications of beta 2M probably play a role, including beta 2M protein modification with advanced glycation end-products (AGE) and advanced oxidation protein products. Modified beta 2M, collagen and proteoglycans appear actively involved in the induction of a local inflammatory response and beta 2M amyloid formation. There is also evidence in favor of treatment-related factors such as the type of hemodialysis membrane and the purity of dialysis water. Hopefully, the translation of our improving knowledge of all the factors involved will lead to a better treatment and eventually to the prevention of this dramatic complication of dialysis.

  4. Olive-Oil-Derived Oleocanthal Enhances β-Amyloid Clearance as a Potential Neuroprotective Mechanism against Alzheimer’s Disease: In Vitro and in Vivo Studies

    Science.gov (United States)

    2013-01-01

    Oleocanthal, a phenolic component of extra-virgin olive oil, has been recently linked to reduced risk of Alzheimer’s disease (AD), a neurodegenerative disease that is characterized by accumulation of β-amyloid (Aβ) and tau proteins in the brain. However, the mechanism by which oleocanthal exerts its neuroprotective effect is still incompletely understood. Here, we provide in vitro and in vivo evidence for the potential of oleocanthal to enhance Aβ clearance from the brain via up-regulation of P-glycoprotein (P-gp) and LDL lipoprotein receptor related protein-1 (LRP1), major Aβ transport proteins, at the blood-brain barrier (BBB). Results from in vitro and in vivo studies demonstrated similar and consistent pattern of oleocanthal in controlling Aβ levels. In cultured mice brain endothelial cells, oleocanthal treatment increased P-gp and LRP1 expression and activity. Brain efflux index (BEI%) studies of 125I-Aβ40 showed that administration of oleocanthal extracted from extra-virgin olive oil to C57BL/6 wild-type mice enhanced 125I-Aβ40 clearance from the brain and increased the BEI% from 62.0 ± 3.0% for control mice to 79.9 ± 1.6% for oleocanthal treated mice. Increased P-gp and LRP1 expression in the brain microvessels and inhibition studies confirmed the role of up-regulation of these proteins in enhancing 125I-Aβ40 clearance after oleocanthal treatment. Furthermore, our results demonstrated significant increase in 125I-Aβ40 degradation as a result of the up-regulation of Aβ degrading enzymes following oleocanthal treatment. In conclusion, these findings provide experimental support that potential reduced risk of AD associated with extra-virgin olive oil could be mediated by enhancement of Aβ clearance from the brain. PMID:23414128

  5. Olive-oil-derived oleocanthal enhances β-amyloid clearance as a potential neuroprotective mechanism against Alzheimer's disease: in vitro and in vivo studies.

    Science.gov (United States)

    Abuznait, Alaa H; Qosa, Hisham; Busnena, Belnaser A; El Sayed, Khalid A; Kaddoumi, Amal

    2013-06-19

    Oleocanthal, a phenolic component of extra-virgin olive oil, has been recently linked to reduced risk of Alzheimer's disease (AD), a neurodegenerative disease that is characterized by accumulation of β-amyloid (Aβ) and tau proteins in the brain. However, the mechanism by which oleocanthal exerts its neuroprotective effect is still incompletely understood. Here, we provide in vitro and in vivo evidence for the potential of oleocanthal to enhance Aβ clearance from the brain via up-regulation of P-glycoprotein (P-gp) and LDL lipoprotein receptor related protein-1 (LRP1), major Aβ transport proteins, at the blood-brain barrier (BBB). Results from in vitro and in vivo studies demonstrated similar and consistent pattern of oleocanthal in controlling Aβ levels. In cultured mice brain endothelial cells, oleocanthal treatment increased P-gp and LRP1 expression and activity. Brain efflux index (BEI%) studies of (125)I-Aβ40 showed that administration of oleocanthal extracted from extra-virgin olive oil to C57BL/6 wild-type mice enhanced (125)I-Aβ40 clearance from the brain and increased the BEI% from 62.0 ± 3.0% for control mice to 79.9 ± 1.6% for oleocanthal treated mice. Increased P-gp and LRP1 expression in the brain microvessels and inhibition studies confirmed the role of up-regulation of these proteins in enhancing (125)I-Aβ40 clearance after oleocanthal treatment. Furthermore, our results demonstrated significant increase in (125)I-Aβ40 degradation as a result of the up-regulation of Aβ degrading enzymes following oleocanthal treatment. In conclusion, these findings provide experimental support that potential reduced risk of AD associated with extra-virgin olive oil could be mediated by enhancement of Aβ clearance from the brain. PMID:23414128

  6. Degeneration of beta-amyloid-associated cholinergic structures in transgenic APP SW mice.

    Science.gov (United States)

    Lüth, Hans-Joachim; Apelt, Jenny; Ihunwo, Amadi O; Arendt, Thomas; Schliebs, Reinhard

    2003-07-01

    Cholinergic dysfunction is a consistent feature of Alzheimer's disease, and the interrelationship between beta-amyloid deposits, inflammation and early cholinergic cell loss is still not fully understood. To characterize the mechanisms by which beta-amyloid and pro-inflammatory cytokines may exert specific degenerating actions on cholinergic cells ultrastructural investigations by electron microscopy were performed in brain sections from transgenic Tg2576 mice that express the Swedish double mutation of the human amyloid precursor protein and progressively develop beta-amyloid plaques during aging. Both light and electron microscopical investigations of the cerebral cortex of 19-month-old transgenic mice revealed a number of pathological tissue responses in close proximity of beta-amyloid plaques, such as activated microglia, astroglial proliferation, increased number of fibrous astrocytes, brain edema, degeneration of nerve cells, dendrites and axon terminals. Ultrastructural detection of choline acetyl transferase (ChAT)-immunostaining in cerebral cortical sections of transgenic mice clearly demonstrated degeneration of ChAT-immunoreactive fibres in the environment of beta-amyloid plaques and activated glial cells suggesting a role of beta-amyloid and/or inflammation in specific degeneration of cholinergic synaptic structures. PMID:12788508

  7. Sulfonated dyes attenuate the toxic effects of beta-amyloid in a structure-specific fashion.

    Science.gov (United States)

    Pollack, S J; Sadler, I I; Hawtin, S R; Tailor, V J; Shearman, M S

    1995-09-15

    We recently reported that several sulfate-containing glycosaminoglycans, a class of compounds associated with the beta-amyloid plaques of Alzheimer's disease, attenuate the toxic effects of beta-amyloid fragments beta 25-35 and beta 1-40. The amyloid-binding sulfonated dye Congo Red was shown to have a similar effect. Using two clonal cell lines, we now demonstrate that several sulfonated dyes attenuate beta-amyloid toxicity and that the protective effect appears specific for compounds whose sulfonate groups can interact with the beta-pleated structure of aggregated amyloid. These results suggest that by binding beta-amyloid these compounds may prevent toxic interactions of the peptide with cells.

  8. Clinical use of amyloid-positron emission tomography neuroimaging: Practical and bioethical considerations.

    Science.gov (United States)

    Witte, Michael M; Foster, Norman L; Fleisher, Adam S; Williams, Monique M; Quaid, Kimberly; Wasserman, Michael; Hunt, Gail; Roberts, J Scott; Rabinovici, Gil D; Levenson, James L; Hake, Ann Marie; Hunter, Craig A; Van Campen, Luann E; Pontecorvo, Michael J; Hochstetler, Helen M; Tabas, Linda B; Trzepacz, Paula T

    2015-09-01

    Until recently, estimation of β-amyloid plaque density as a key element for identifying Alzheimer's disease (AD) pathology as the cause of cognitive impairment was only possible at autopsy. Now with amyloid-positron emission tomography (amyloid-PET) neuroimaging, this AD hallmark can be detected antemortem. Practitioners and patients need to better understand potential diagnostic benefits and limitations of amyloid-PET and the complex practical, ethical, and social implications surrounding this new technology. To complement the practical considerations, Eli Lilly and Company sponsored a Bioethics Advisory Board to discuss ethical issues that might arise from clinical use of amyloid-PET neuroimaging with patients being evaluated for causes of cognitive decline. To best address the multifaceted issues associated with amyloid-PET neuroimaging, we recommend this technology be used only by experienced imaging and treating physicians in appropriately selected patients and only in the context of a comprehensive clinical evaluation with adequate explanations before and after the scan. PMID:27239516

  9. The Role of Oxidative Stress-Induced Epigenetic Alterations in Amyloid-β Production in Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Li Zuo

    2015-01-01

    Full Text Available An increasing number of studies have proposed a strong correlation between reactive oxygen species (ROS-induced oxidative stress (OS and the pathogenesis of Alzheimer’s disease (AD. With over five million people diagnosed in the United States alone, AD is the most common type of dementia worldwide. AD includes progressive neurodegeneration, followed by memory loss and reduced cognitive ability. Characterized by the formation of amyloid-beta (Aβ plaques as a hallmark, the connection between ROS and AD is compelling. Analyzing the ROS response of essential proteins in the amyloidogenic pathway, such as amyloid-beta precursor protein (APP and beta-secretase (BACE1, along with influential signaling programs of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB and c-Jun N-terminal kinase (JNK, has helped visualize the path between OS and Aβ overproduction. In this review, attention will be paid to significant advances in the area of OS, epigenetics, and their influence on Aβ plaque assembly. Additionally, we aim to discuss available treatment options for AD that include antioxidant supplements, Asian traditional medicines, metal-protein-attenuating compounds, and histone modifying inhibitors.

  10. Helicobacter pylori filtrate impairs spatial learning and memory in rats and increases β-amyloid by enhancing expression of presenilin-2

    Directory of Open Access Journals (Sweden)

    Xiu-Lian eWang

    2014-04-01

    Full Text Available Helicobacter pylori (H.pylori infection is related with a high risk of Alzheimer’s Disease (AD, but the intrinsic link between H.pylori infection and AD development is still missing. In the present study, we explored the effect of H.pylori infection on cognitive function and β-amyloid production in rats. We found that intraperitoneal injection of H.pylori filtrate induced spatial learning and memory deficit in rats with a simultaneous retarded dendritic spine maturation in hippocampus. Injection of H.pylori filtrate significantly increased Aβ42 both in the hippocampus and cortex, together with an increased level of presenilin-2 (PS-2, one key component of γ-secretase involved in Aβ production. Incubation of H.pylori filtrate with N2a cells which over-express APP also resulted in increased PS-2 expression and Aβ42 overproduction. Injection of Escherichia coli (E.coli filtrate, another common intestinal bacterium, had no effect on cognitive function in rats and Aβ production in rats and cells. These data suggest a specific effect of H.pylori on cognition and Aβ production. We conclude that soluble surface fractions of H.pylori may promote Aβ42 formation by enhancing the activity of γ-secretase, thus induce cognitive impairment through interrupting the synaptic function.

  11. Preclinical studies of potential amyloid binding PET/SPECT ligands in Alzheimer's disease

    International Nuclear Information System (INIS)

    Visualizing the neuropathological hallmarks amyloid plaques and neurofibrillary tangles of Alzheimer's disease in vivo using positron emission tomography (PET) or single photon emission computed tomography will be of great value in diagnosing the individual patient and will also help in our understanding of the disease. The successful introduction of [11C]PIB as a PET tracer for the amyloid plaques less than 10 years ago started an intensive research, and numerous new compounds for use in molecular imaging of the amyloid plaques have been developed. The candidates are based on dyes like thioflavin T, Congo red and chrysamine G, but also on other types such as benzoxazoles, curcumin and stilbenes. In the present review, we present methods of the radiochemistry and preclinical evaluation as well as the main properties of some of these compounds.

  12. Amyloid-associated nucleic acid hybridisation.

    Directory of Open Access Journals (Sweden)

    Sebastian Braun

    Full Text Available Nucleic acids promote amyloid formation in diseases including Alzheimer's and Creutzfeldt-Jakob disease. However, it remains unclear whether the close interactions between amyloid and nucleic acid allow nucleic acid secondary structure to play a role in modulating amyloid structure and function. Here we have used a simplified system of short basic peptides with alternating hydrophobic and hydrophilic amino acid residues to study nucleic acid - amyloid interactions. Employing biophysical techniques including X-ray fibre diffraction, circular dichroism spectroscopy and electron microscopy we show that the polymerized charges of nucleic acids concentrate and enhance the formation of amyloid from short basic peptides, many of which would not otherwise form fibres. In turn, the amyloid component binds nucleic acids and promotes their hybridisation at concentrations below their solution K(d, as shown by time-resolved FRET studies. The self-reinforcing interactions between peptides and nucleic acids lead to the formation of amyloid nucleic acid (ANA fibres whose properties are distinct from their component polymers. In addition to their importance in disease and potential in engineering, ANA fibres formed from prebiotically-produced peptides and nucleic acids may have played a role in early evolution, constituting the first entities subject to Darwinian evolution.

  13. Ashwagandha (Withania somnifera reverses β-amyloid1-42 induced toxicity in human neuronal cells: implications in HIV-associated neurocognitive disorders (HAND.

    Directory of Open Access Journals (Sweden)

    Kesava Rao Venkata Kurapati

    Full Text Available Alzheimer's disease (AD is characterized by progressive dysfunction of memory and higher cognitive functions with abnormal accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles throughout cortical and limbic brain regions. At present no curative treatment is available, and research focuses on drugs for slowing disease progression or providing prophylaxis. Withania somnifera (WS also known as 'ashwagandha' is used widely in Ayurvedic medicine as a nerve tonic and memory enhancer. However, there is a paucity of data on the potential neuroprotective effects of W.somnifera against β-Amyloid (1-42-induced neuropathogenesis. In the present study, we have tested the neuroprotective effects of methanol:Chloroform (3:1 extract of ashwagandha against β-amyloid induced toxicity and HIV-1Ba-L (clade B infection using a human neuronal SK-N-MC cell line. Our results showed that β-amyloid induced cytotoxic effects in SK-N-MC cells as shown by decreased cell growth when tested individually. Also, confocal microscopic analysis showed decreased spine density, loss of spines and decreased dendrite diameter, total dendrite and spine area in clade B infected SK-N-MC cells compared to uninfected cells. However, when ashwagandha was added to β-amyloid treated and HIV-1 infected samples, the toxic effects were neutralized. Further, the MTT cell viability assays and the peroxisome proliferator-activated receptor-γ (PPARγ levels supported these observations indicating the neuroprotective effect of WS root extract against β-amyloid and HIV-1Ba-L (clade B induced neuro-pathogenesis.

  14. Chronic over-expression of heat shock protein 27 attenuates atherogenesis and enhances plaque remodeling: a combined histological and mechanical assessment of aortic lesions.

    Directory of Open Access Journals (Sweden)

    Charles M Cuerrier

    Full Text Available AIMS: Expression of Heat Shock Protein-27 (HSP27 is reduced in human coronary atherosclerosis. Over-expression of HSP27 is protective against the early formation of lesions in atherosclerosis-prone apoE(-/- mice (apoE(-/-HSP27(o/e - however, only in females. We now seek to determine if chronic HSP27 over-expression is protective in a model of advanced atherosclerosis in both male and female apoE(-/- mice. METHODS AND RESULTS: After 12 weeks on a high fat diet, serum HSP27 levels rose more than 16-fold in male and female apoE(-/-HSP27(o/e mice, although females had higher levels than males. Relative to apoE(-/- mice, female apoE(-/-HSP27(o/e mice showed reductions in aortic lesion area of 35% for en face and 30% for cross-sectional sinus tissue sections - with the same parameters reduced by 21% and 24% in male cohorts; respectively. Aortic plaques from apoE(-/-HSP27(o/e mice showed almost 50% reductions in the area occupied by cholesterol clefts and free cholesterol, with fewer macrophages and reduced apoptosis but greater intimal smooth muscle cell and collagen content. The analysis of the aortic mechanical properties showed increased vessel stiffness in apoE(-/-HSP27(o/e mice (41% in female, 34% in male compare to apoE(-/- counterparts. CONCLUSIONS: Chronic over-expression of HSP27 is atheroprotective in both sexes and coincides with reductions in lesion cholesterol accumulation as well as favorable plaque remodeling. These data provide new clues as to how HSP27 may improve not only the composition of atherosclerotic lesions but potentially their stability and resilience to plaque rupture.

  15. Dental plaque identification at home

    Science.gov (United States)

    ... your teeth. Plaque is the major cause of tooth decay and gum disease ( gingivitis ). It is hard to ... the plaque is not removed, it can cause tooth decay or cause the gums to bleed easily (gingivitis) ...

  16. Efflux transport of serum amyloid P component at the blood–brain barrier

    OpenAIRE

    Veszelka, Szilvia; Laszy, Judit; Pázmány, Tamás; Németh, László; Obál, Izabella; Fábián, László; Szabó, Gábor; Ábrahám, Csongor S.; Deli, Mária A.; Urbányi, Zoltán

    2013-01-01

    Serum amyloid P component (SAP), a member of the innate immune system, does not penetrate the brain in physiological conditions; however, SAP is a stabilizing component of the amyloid plaques in neurodegenerative diseases. We investigated the cerebrovascular transport of human SAP in animal experiments and in culture blood–brain barrier (BBB) models. After intravenous injection, no SAP could be detected by immunohistochemistry or ELISA in healthy rat brains. Salmonella typhi...

  17. LRP1 in Brain Vascular Smooth Muscle Cells Mediates Local Clearance of Alzheimer's Amyloid

    OpenAIRE

    Kanekiyo, Takahisa; Liu, Chia-Chen; Shinohara, Mitsuru; Li, Jie; Bu, Guojun

    2012-01-01

    Impaired clearance of amyloid-β (Aβ) is a major pathogenic event for Alzheimer’s disease (AD). Aβ depositions in brain parenchyma as senile plaques and along cerebrovasculature as cerebral amyloid angiopathy (CAA) are hallmarks of AD. A major pathway that mediates brain Aβ clearance is the cerebrovascular system where Aβ is eliminated through the blood-brain barrier (BBB) and/or degraded by cerebrovascular cells along the interstitial fluid drainage pathway. An Aβ clearance receptor, the low-...

  18. Alzheimer's disease amyloid peptides interact with DNA, as proved by surface plasmon resonance.

    Science.gov (United States)

    Barrantes, Alejandro; Camero, Sergio; Garcia-Lucas, Angel; Navarro, Pedro J; Benitez, María J; Jiménez, Juan S

    2012-10-01

    According to the amyloid hypothesis, abnormal processing of the β-amyloid precursor protein in Alzheimer's disease patients increases the production of β-amyloid toxic peptides, which, after forming highly aggregated fibrillar structures, lead to extracellular plaques formation, neuronal loss and dementia. However, a great deal of evidence has point to intracellular small oligomers of amyloid peptides, probably transient intermediates in the process of fibrillar structures formation, as the most toxic species. In order to study the amyloid-DNA interaction, we have selected here three different forms of the amyloid peptide: Aβ1-40, Aβ25-35 and a scrambled form of Aβ25-35. Surface Plasmon Resonance was used together with UV-visible spectroscopy, Electrophoresis and Electronic Microscopy to carry out this study. Our results prove that, similarly to the full length Aβ1-42, all conformations of toxic amyloid peptides, Aβ1-40 and Aβ25-35, may bind DNA. In contrast, the scrambled form of Aβ25-35, a non-aggregating and nontoxic form of this peptide, could not bind DNA. We conclude that although the amyloid-DNA interaction is closely related to the amyloid aggregation proneness, this cannot be the only factor which determines the interaction, since small oligomers of amyloid peptides may also bind DNA if their predominant negatively charged amino acid residues are previously neutralized.

  19. Small molecule agents that target amyloid-β aggregation in Alzheimer's disease

    OpenAIRE

    Jones, Michael Roy

    2015-01-01

    Alzheimer’s disease (AD) is the most common form of dementia and currently there is no cure. AD is characterized by the formation of two pathological hallmarks; aggregated forms of the amyloid-β (Aβ) peptide called Aβ plaques and hyperphosphorylated tau proteins, called neurofibrillary tangles (NFT). Aβ is enzymatically cleaved from the amyloid precursor protein (APP) to afford a 38-43 amino acid residue peptide with Aβ1-40 and Aβ1-42 being the most common. Plaque deposits have been shown to ...

  20. Beta-secretase-cleaved amyloid precursor protein in Alzheimer brain: a morphologic study

    DEFF Research Database (Denmark)

    Sennvik, Kristina; Bogdanovic, N; Volkmann, Inga;

    2004-01-01

    beta-amyloid (Abeta) is the main constituent of senile plaques seen in Alzheimer's disease. Abeta is derived from the amyloid precursor protein (APP) via proteolytic cleavage by proteases beta- and gamma-secretase. In this study, we examined content and localization of beta-secretase-cleaved APP...... the beta-sAPP immunostaining to be stronger and more extensive in gray matter in Alzheimer disease (AD) cases than controls. The axonal beta-sAPP staining was patchy and unevenly distributed for the AD cases, indicating impaired axonal transport. beta-sAPP was also found surrounding senile plaques...

  1. Cystatin C is Associated With Plaque Phenotype and Plaque Burden

    Directory of Open Access Journals (Sweden)

    Yufeng Wen

    2016-03-01

    Full Text Available Background/Aims: The relationship between carotid artery plaque burden, phenotype and serum cystatin C at normal and impaired renal function is still unclear. Methods: Demographic characteristics, carotid ultrasonography and other relevant information of 1,477 patients were collected. The association of carotid artery plaque burden, plaque phenotype with serum cystatin C was evaluated by strategy analysis based on renal function. Results: Serum cystatin C (OR=2.05, 95% CI: 1.83-2.29, POR=1.60, 95%CI: 1.43-1.78, POR=1.21, 95%CI: 1.10-1.32, P Conclusion: In normal renal function, serum cystatin C may confer stability of plaques. In mildly impaired renal function, serum cystatin C is a risk predictor of plaques. In normal renal function circumstances, serum cystatin C may benefit to the stability of plaques. In mild impaired renal function circumstances, serum cystatin C are a risk predictors of plaques.

  2. Calcium ionophore A23187 specifically decreases the secretion of beta-secretase cleaved amyloid precursor protein during apoptosis in primary rat cortical cultures

    DEFF Research Database (Denmark)

    Sennvik, K; Benedikz, Eirikur; Fastbom, J;

    2001-01-01

    Alzheimer's disease (AD) is characterized by the degeneration and loss of neurons, intracellular neurofibrillary tangles and the accumulation of extracellular senile plaques consisting mainly of beta-amyloid (A beta). A beta is generated from the amyloid precursor protein (APP) by sequential beta...

  3. β-淀粉样肽对线粒体的损伤及其在阿尔茨海默病中的作用%Mitochondria injury by amyloid-β peptide and it's function in Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    杨秀明

    2012-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disease, which characterized by extracellular amyloid-β peptide (Aβ) plaques and intracellular neurofibrillary tangles(NFTs). The etiological factors and pathogenesis are still unclear. Amyloid-β peptide locates in mitochondria and it can induce a series of disorders in mitochondrial function, such as decreasing in ATP production, promoting oxidative stress, brokening the balance of mitochondrial fission/fusion and enhancing cellular apoptosis, and so on.%阿尔茨海默病(Alzheimer′s disease,AD)是以老年斑(senile plaque,SP)和神经纤维缠结(neurofibrillary tangles,NFTs)为主要病理特征的中枢神经系统退行性疾病,其病因及发病机制至今仍不明确.AD的病变产物β-淀粉样肽(amyloid-βpeptide,Aβ)在线粒体内沉积导致线粒体功能障碍,如ATP产生减少、氧化应激增强、细胞凋亡增强以及线粒体分裂/融合异常等,进而引起AD的一系列病理变化.

  4. Monte Carlo dosimetry of I-125 ophthalmic plaques

    International Nuclear Information System (INIS)

    I-125 seeds, mounted on the surface of gold-alloy plaques (1.0 to 2.0 cm in diameter), are used to treat intraocular malignancies. Currently available dose-computation algorithms ignore the perturbing influence of the plaque, assuming the seeds to be immersed in an infinite, homogeneous medium. The authors used a theoretical but physically and geometrically realistic approach, the Monte Carlo method, to calculate the absorbed dose in water arising from I-125 seeds backed by ophthalmic plaques. Preliminary results indicate that the plaque enhances dose by 2% very close to the seed and reduces dose by 4% to 7% at distances beyond 1 cm. Results are presented for various plaque dimensions, alloy compositions, and I-125 seed types in current clinical use

  5. Spectral CT of carotid atherosclerotic plaque: comparison with histology

    International Nuclear Information System (INIS)

    To distinguish components of vulnerable atherosclerotic plaque by imaging their energy response using spectral CT and comparing images with histology. After spectroscopic calibration using phantoms of plaque surrogates, excised human carotid atherosclerotic plaques were imaged using MARS CT using a photon-processing detector with a silicon sensor layer and microfocus X-ray tube (50 kVp, 0.5 mA) at 38-μm voxel size. The plaques were imaged, sectioned and re-imaged using four threshold energies: 10, 16, 22 and 28 keV; then sequentially stained with modified Von Kossa, Perl's Prussian blue and Oil-Red O, and photographed. Relative Hounsfield units across the energies were entered into a linear algebraic material decomposition model to identify the unknown plaque components. Lipid, calcium, iron and water-like components of plaque have distinguishable energy responses to X-ray, visible on spectral CT images. CT images of the plaque surface correlated very well with histological photographs. Calcium deposits (>1,000 μm) in plaque are larger than iron deposits (<100 μm), but could not be distinguished from each other within the same voxel using the energy range available. Spectral CT displays energy information in image form at high spatial resolution, enhancing the intrinsic contrast of lipid, calcium and iron within atheroma. (orig.)

  6. Investigating the structural changes of β-amyloid peptide aggregation using attenuated-total-reflection surface-enhanced Raman spectroscopy

    Science.gov (United States)

    Chiu, K.-C.; Yu, L.-Y.; Yih, J.-N.; Chen, S.-J.

    2007-02-01

    This study utilizes a surface-enhanced Raman spectroscopy (SERS) based on the attenuated-total-reflection (ATR) method to investigate that the structural information of the biomolecular monolayer on sensing surface can be dynamically observed with a higher signal-to-noise ratio signal. The secondary structures of long oligonucleotides and their influence on the DNA hybridization on the sensing surface are investigated. The SERS spectrum provides the structural information of the oligonucleotides with the help of a silver colloidal nanoparticle monolayer by control of the size and distribution of the nanoparticles adapted as a Raman active substrate. It is found that the ring-breathing modes of adenine, thymine, guanine, and cytosine in Raman fingerprint associated with three 60mer oligonucleotides with prominent secondary structures are lower than those observed for the two oligonucleotides with no obvious secondary structures. It is also determined that increasing the DNA hybridization temperature from 35°C to 45°C reduces secondary structure effects. The ATR-SERS biosensing technique will be used to provide valuable structural information regarding the short-term reversible interactions and long-term polymerization events in the Aβ aggregates on the sensing surface.

  7. Specific binding of DNA to aggregated forms of Alzheimer's disease amyloid peptides.

    Science.gov (United States)

    Camero, Sergio; Ayuso, Jose M; Barrantes, Alejandro; Benítez, María J; Jiménez, Juan S

    2013-04-01

    Anomalous protein aggregation is closely associated to age-related mental illness. Extraneuronal plaques, mainly composed of aggregated amyloid peptides, are considered as hallmarks of Alzheimer's disease. According to the amyloid cascade hypothesis, this disease starts as a consequence of an abnormal processing of the amyloid precursor protein resulting in an excess of amyloid peptides. Nuclear localization of amyloid peptide aggregates together with amyloid-DNA interaction, have been repeatedly reported. In this paper we have used surface plasmon resonance and electron microscopy to study the structure and behavior of different peptides and proteins, including β-lactoglobulin, bovine serum albumin, myoglobin, histone, casein and the amyloid-β peptides related to Alzheimer's disease Aβ25-35 and Aβ1-40. The main purpose of this study is to investigate whether proneness to DNA interaction is a general property displayed by aggregated forms of proteins, or it is an interaction specifically related to the aggregated forms of those particular proteins and peptides related to neurodegenerative diseases. Our results reveal that those aggregates formed by amyloid peptides show a particular proneness to interact with DNA. They are the only aggregated structures capable of binding DNA, and show more affinity for DNA than for other polyanions like heparin and polyglutamic acid, therefore strengthening the hypothesis that amyloid peptides may, by means of interaction with nuclear DNA, contribute to the onset of Alzheimer's disease.

  8. The neuritic plaque facilitates pathological conversion of tau in an Alzheimer's disease mouse model

    Science.gov (United States)

    Li, Tong; Braunstein, Kerstin E.; Zhang, Juhong; Lau, Ashley; Sibener, Leslie; Deeble, Christopher; Wong, Philip C.

    2016-01-01

    A central question in Alzheimer's Disease (AD) is whether the neuritic plaque is necessary and sufficient for the development of tau pathology. Hyperphosphorylation of tau is found within dystrophic neurites surrounding β-amyloid deposits in AD mouse models but the pathological conversion of tau is absent. Likewise, expression of a human tau repeat domain in mice is insufficient to drive the pathological conversion of tau. Here we developed an Aβ-amyloidosis mouse model that expresses the human tau repeat domain and show that in these mice, the neuritic plaque facilitates the pathological conversion of wild-type tau. We show that this tau fragment seeds the neuritic plaque-dependent pathological conversion of wild-type tau that spreads from the cortex and hippocampus to the brain stem. These results establish that in addition to the neuritic plaque, a second determinant is required to drive the conversion of wild-type tau. PMID:27373369

  9. Lipid rafts participate in aberrant degradative autophagic-lysosomal pathway of amyloid-beta peptide in Alzheimer’s disease

    Institute of Scientific and Technical Information of China (English)

    Xin Zhou; Chun Yang; Yufeng Liu; Peng Li; Huiying Yang; Jingxing Dai; Rongmei Qu; Lin Yuan

    2014-01-01

    Amyloid-beta peptide is the main component of amyloid plaques, which are found in Alzhei-mer’s disease. The generation and deposition of amyloid-beta is one of the crucial factors for the onset and progression of Alzheimer’s disease. Lipid rafts are glycolipid-rich liquid domains of the plasma membrane, where certain types of protein tend to aggregate and intercalate. Lipid rafts are involved in the generation of amyloid-beta oligomers and the formation of amyloid-beta peptides. In this paper, we review the mechanism by which lipid rafts disturb the aberrant deg-radative autophagic-lysosomal pathway of amyloid-beta, which plays an important role in the pathological process of Alzheimer’s disease. Moreover, we describe this mechanism from the view of the Two-system Theory of fasciology and thus, suggest that lipid rafts may be a new target of Alzheimer’s disease treatment.

  10. Alzheimer's disease therapeutics targeted to the control of amyloid precursor protein translation: maintenance of brain iron homeostasis.

    Science.gov (United States)

    Bandyopadhyay, Sanghamitra; Rogers, Jack T

    2014-04-15

    The neurotoxicity of amyloid beta (Aβ), a major cleavage product of the amyloid precursor protein (APP), is enhanced by iron, as found in the amyloid plaques of Alzheimer's disease (AD) patients. By contrast, the long-known neuroprotective activity of APP is evident after α-secretase cleavage of the precursor to release sAPPα, and depends on the iron export actions of APP itself. The latter underlie its neurotrophic and protective effects in facilitating the homeostatic actions of ferroportin mediated-iron export. Thus APP-dependent iron export may alleviate oxidative stress by minimizing labile iron thus protecting neurons from iron overload during stroke and hemorrhage. Consistent with this, altered phosphorylation of iron-regulatory protein-1 (IRP1) and its signaling processes play a critical role in modulating APP translation via the 5' untranslated region (5'UTR) of its transcript. The APP 5'UTR region encodes a functional iron-responsive element (IRE) RNA stem loop that represents a potential target for modulating APP production. Targeted regulation of APP gene expression via the modulation of 5'UTR sequence function represents a novel approach for the potential treatment of AD since altering APP translation can be used to improve both the protective brain iron balance and provide anti-amyloid efficacy. Approved drugs including paroxetine and desferrioxamine and several novel compounds have been identified that suppress abnormal metal-promoted Aβ accumulation with a subset of these acting via APP 5'UTR-dependent mechanisms to modulate APP translation and cleavage to generate the non-toxic sAPPα.

  11. Cholesterol enhances amyloid {beta} deposition in mouse retina by modulating the activities of A{beta}-regulating enzymes in retinal pigment epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jiying [Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519 (Japan); Ohno-Matsui, Kyoko, E-mail: k.ohno.oph@tmd.ac.jp [Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519 (Japan); Morita, Ikuo [Section of Cellular Physiological Chemistry, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519 (Japan)

    2012-08-10

    Highlights: Black-Right-Pointing-Pointer Cholesterol-treated RPE produces more A{beta} than non-treated RPE. Black-Right-Pointing-Pointer Neprilysin expression and activity decreased in cholesterol-treated RPE. Black-Right-Pointing-Pointer {alpha}-Secretase expression and activity decreased in cholesterol-treated RPE. Black-Right-Pointing-Pointer Cholesterol-enriched diet induced subRPE deposits in aged mice. Black-Right-Pointing-Pointer A{beta} were present in cholesterol-enriched-diet-induced subRPE deposits in aged mice. -- Abstract: Subretinally-deposited amyloid {beta} (A{beta}) is a main contributor of developing age-related macular degeneration (AMD). However, the mechanism causing A{beta} deposition in AMD eyes is unknown. Hypercholesterolemia is a significant risk for developing AMD. Thus, we investigated the effects of cholesterol on A{beta} production in retinal pigment epithelial (RPE) cells in vitro and in the mouse retina in vivo. RPE cells isolated from senescent (12-month-old) C57BL/6 mice were treated with 10 {mu}g/ml cholesterol for 48 h. A{beta} amounts in culture supernatants were measured by ELISA. Activity and expression of enzymes and proteins that regulate A{beta} production were examined by activity assay and real time PCR. The retina of mice fed cholesterol-enriched diet was examined by transmission electron microscopy. Cholesterol significantly increased A{beta} production in cultured RPE cells. Activities of A{beta} degradation enzyme; neprilysin (NEP) and anti-amyloidogenic secretase; {alpha}-secretase were significantly decreased in cell lysates of cholesterol-treated RPE cells compared to non-treated cells, but there was no change in the activities of {beta}- or {gamma}-secretase. mRNA levels of NEP and {alpha}-secretase (ADAM10 and ADAM17) were significantly lower in cholesterol-treated RPE cells than non-treated cells. Senescent (12-month-old) mice fed cholesterol-enriched chow developed subRPE deposits containing A{beta}, whereas

  12. The CCAAT/enhancer binding protein (C/EBP δ is differently regulated by fibrillar and oligomeric forms of the Alzheimer amyloid-β peptide

    Directory of Open Access Journals (Sweden)

    Nilsson Lars NG

    2011-04-01

    Full Text Available Abstract Background The transcription factors CCAAT/enhancer binding proteins (C/EBP α, β and δ have been shown to be expressed in brain and to be involved in regulation of inflammatory genes in concert with nuclear factor κB (NF-κB. In general, C/EBPα is down-regulated, whereas both C/EBPβ and δ are up-regulated in response to inflammatory stimuli. In Alzheimer's disease (AD one of the hallmarks is chronic neuroinflammation mediated by astrocytes and microglial cells, most likely induced by the formation of amyloid-β (Aβ deposits. The inflammatory response in AD has been ascribed both beneficial and detrimental roles. It is therefore important to delineate the inflammatory mediators and signaling pathways affected by Aβ deposits with the aim of defining new therapeutic targets. Methods Here we have investigated the effects of Aβ on expression of C/EBP family members with a focus on C/EBPδ in rat primary astro-microglial cultures and in a transgenic mouse model with high levels of fibrillar Aβ deposits (tg-ArcSwe by western blot analysis. Effects on DNA binding activity were analyzed by electrophoretic mobility shift assay. Cross-talk between C/EBPδ and NF-κB was investigated by analyzing binding to a κB site using a biotin streptavidin-agarose pull-down assay. Results We show that exposure to fibril-enriched, but not oligomer-enriched, preparations of Aβ inhibit up-regulation of C/EBPδ expression in interleukin-1β-activated glial cultures. Furthermore, we observed that, in aged transgenic mice, C/EBPα was significantly down-regulated and C/EBPβ was significantly up-regulated. C/EBPδ, on the other hand, was selectively down-regulated in the forebrain, a part of the brain showing high levels of fibrillar Aβ deposits. In contrast, no difference in expression levels of C/EBPδ between wild type and transgenic mice was detected in the relatively spared hindbrain. Finally, we show that interleukin-1β-induced C/EBPδ DNA

  13. Alzheimer's disease: neuritic plaques and neurofibrillary tangles in human brain identified by FTIR spectroscopy

    Science.gov (United States)

    Choo, Lin-P'ing; Jackson, Michael; Halliday, William C.; Mantsch, Henry H.

    1994-01-01

    The abnormal abundance of (beta) -amyloid plaques and neurofibrillary tangles are the hallmark of Alzheimer's disease (AD). Human central nervous system (CNS) grey matter was probed for characteristics arising from these pathological features. In AD but not normal grey matter, an IR band at 1615 cm-1 is seen, characteristic of a protein in an aggregated state. We speculate that this band arises from (beta) A4-amyloid protein. AD, and 18q- grey matter spectra show increased intensity of phosphate bands in accordance with known hyperphosphorylation of proteins found in neurofibrillary tangles. These spectral features may be useful in the diagnosis of AD.

  14. Impact of amyloid imaging on drug development in Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Mathis, Chester A. [Department of Radiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213 (United States)], E-mail: mathisca@upmc.edu; Lopresti, Brian J. [Department of Radiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213 (United States); Klunk, William E. [Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213 (United States)

    2007-10-15

    Imaging agents capable of assessing amyloid-beta (A{beta}) content in vivo in the brains of Alzheimer's disease (AD) subjects likely will be important as diagnostic agents to detect A{beta} plaques in the brain as well as to help test the amyloid cascade hypothesis of AD and as an aid to assess the efficacy of anti-amyloid therapeutics currently under development and in clinical trials. Positron emission tomography (PET) imaging studies of amyloid deposition in human subjects with several A{beta} imaging agents are currently underway. We reported the first PET studies of the carbon 11-labeled thioflavin-T derivative Pittsburgh Compound B in 2004, and this work has subsequently been extended to include a variety of subject groups, including AD patients, mild cognitive impairment patients and healthy controls. The ability to quantify regional A{beta} plaque load in the brains of living human subjects has provided a means to begin to apply this technology as a diagnostic agent to detect regional concentrations of A{beta} plaques and as a surrogate marker of therapeutic efficacy in anti-amyloid drug trials.

  15. Amyloid beta1–42 and the phoshorylated tau threonine 231 in brains of aged cynomolgus monkeys (Macaca fascicularis)

    DEFF Research Database (Denmark)

    Darusman, Huda Shalahudin; Gjedde, Albert; Sajuthi, Dondin;

    2014-01-01

    Pathological hallmarks indicative of Alzheimer's disease (AD), which are the plaques of amyloid beta1-42 and neurofibrillary tangles, were found in brain of aged cynomolgus monkey. The aim of this study was to investigate if aged monkeys exhibiting spatial memory impairment and levels of biomarkers...... indicative of AD, had brain lesions similar to human patients suffering from senile dementia. Generating immunohistochemistry technique to biomarkers of amyloid beta1-42 and the phosphorylated tau 231, our study assessed the amyloidopathy, such as indicative to the senile plaques and cerebral amyloid......, the amyloids were found to deposit in the small veins and capillaries. In one of the affected individuals, phosphorylated tau was positively stained intracellularly of the neurons, indicating a possibility of an early stage of the formation of tangles. These findings add to the body of evidence of the utility...

  16. Altered motility of plaque-associated microglia in a model of Alzheimer's disease.

    Science.gov (United States)

    Gyoneva, Stefka; Swanger, Sharon A; Zhang, Jing; Weinshenker, David; Traynelis, Stephen F

    2016-08-25

    Alzheimer's disease (AD), the most common form of dementia in the elderly, is characterized by the presence of extracellular plaques composed of amyloid β (Aβ) peptides and intracellular tau aggregates. The plaques are surrounded by microglia, the brain's resident immune cells, which likely participate in the clearance of Aβ by phagocytosis. The microglia that are associated with plaques display an abnormal ameboid morphology and do not respond to tissue damage, in contrast to microglia in healthy brains. Here, we used time lapse confocal microscopy to perform a detailed real-time examination of microglial motility in acute hippocampal brain slices from the 5xFAD mouse model of AD, which was crossed to Cx3cr1(GFP/GFP) mice to achieve microglia-specific GFP expression for visualization. During baseline conditions, microglia around plaques appeared hypermotile, moving the processes that were pointing away from plaques at higher speed than microglia not associated with plaques. Yet, neither plaque-associated, nor plaque-free microglia were able to extend processes toward sites of modest mechanical damage. Application of the selective adenosine A2A receptor antagonist preladenant, which restores microglial response to cellular damage in a mouse model of Parkinson's disease, reduced the hypermotility of plaque-associated microglia, but did not restore motility toward damaged cells in slices from 5xFAD mice. Our results suggest that process hypermotility and resistance to A2A antagonism during response to tissue damage may represent unique functional phenotypes of plaque-associated microglia that impair their ability to function properly in the AD brain. PMID:27288150

  17. Effects of Amyloid Precursor Protein 17 Peptide on the Protection of Diabetic Encephalopathy and Improvement of Glycol Metabolism in the Diabetic Rat

    Directory of Open Access Journals (Sweden)

    Heng Meng

    2013-01-01

    Full Text Available Researchers have proposed that amyloid precursor protein 17 peptide (APP17 peptide, an active fragment of amyloid precursor protein (APP in the nervous system, has therapeutic effects on neurodegeneration. Diabetic encephalopathy (DE is a neurological disease caused by diabetes. Here we use multiple experimental approaches to investigate the effect of APP17 peptide on changes in learning behavior and glycol metabolism in rats. It was found that rats with DE treated by APP17 peptide showed reversed behavioral alternation. The [18F]-FDG-PET images and other results all showed that the APP17 peptide could promote glucose metabolism in the brain of the DE rat model. Meanwhile, the insulin signaling was markedly increased as shown by increased phosphorylation of Akt and enhanced GLUT4 activation. Compared with the DE group, the activities of SOD, GSH-Px, and CAT in the rat hippocampal gyrus were increased, while MDA decreased markedly in the DE + APP17 peptide group. No amyloid plaques in the cortex and the hippocampus were detected in either group, indicating that the experimental animals in the current study were not suffering from Alzheimer’s disease. These results indicate that APP17 peptide could be used to treat DE effectively.

  18. Cerebral amyloid angiopathy

    Science.gov (United States)

    ... Fenichel GM, Jankovic J, Mazziotta JC, eds. Bradley's Neurology in Clinical Practice . 6th ed. Philadelphia, PA: Elsevier ... al. Course of cerebral amyloid angiopathy-related inflammation. Neurology. 2007;68:1411-1416. PMID: 17452586 www.ncbi. ...

  19. Mechanical model of vulnerable atherosclerotic plaque rupture

    Institute of Scientific and Technical Information of China (English)

    SU; Haijun; ZHANG; Mei; ZHANG; Yun

    2004-01-01

    Rupture of atherosclerotic plaque is the main trigger of acute cardiovascular events, but the mechanism of plaque rupture is still unknown. We have constructed a model describing the motion of the fibrous cap of the plaque using the theory of elastic mechanics and studied the stability of the plaque theoretically. It has shown that plaque rupture is the result of a dynamic interplay between factors intrinsic to the plaque itself and extrinsic factors. We have proposed a new mechanism of plaque rupture, given a new explanation about the nonlinear dynamic progress of atherosclerosis and suggested a method to identify the vulnerable plaques to manage atherosclerosis.

  20. A novel approach to the identification and quantitative elemental analysis of amyloid deposits-Insights into the pathology of Alzheimer's disease

    International Nuclear Information System (INIS)

    There is considerable interest in the role of metals such as iron, copper, and zinc in amyloid plaque formation in Alzheimer's disease. However to convincingly establish their presence in plaques in vivo, a sensitive technique is required that is both quantitatively accurate and avoids isolation of plaques or staining/fixing brain tissue, since these processes introduce contaminants and redistribute elements within the tissue. Combining the three ion beam techniques of scanning transmission ion microscopy, Rutherford back scattering spectrometry and particle induced X-ray emission in conjunction with a high energy (MeV) proton microprobe we have imaged plaques in freeze-dried unstained brain sections from CRND-8 mice, and simultaneously quantified iron, copper, and zinc. Our results show increased metal concentrations within the amyloid plaques compared with the surrounding tissue: iron (85 ppm compared with 42 ppm), copper (16 ppm compared to 6 ppm), and zinc (87 ppm compared to 34 ppm).

  1. A new DNA vaccine fused with the C3d-p28 induces a Th2 immune response against amyloid-beta*

    Institute of Scientific and Technical Information of China (English)

    Wanshu Guo; Sha Sha; Tongzi Jiang; Xiaona Xing; Yunpeng Cao

    2013-01-01

    To enhance anti-amyloid-beta (Aβ) antibody generation and induce a Th2 immune response, we constructed a new DNA vaccine p(Aβ3-10 )10-C3d-p28.3 encoding ten repeats of Aβ3-10 and three copies of C3d-p28 as a molecular adjuvant. In this study, we administered this adjuvant intramus-cularly to female C57BL/6J mice at 8-10 weeks of age. Enzyme linked immunosorbent assay was used to detect the titer of serum anti-Aβ antibody, isotypes, and cytokines in splenic T cel s. A 3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay was used to detect the prolifera-tion rate of splenic T cel s. Brain sections from a 12-month-old APP/PS1 transgenic mouse were used for detecting the binding capacities of anti-Aβ antibodies to Aβ plaques. The p(Aβ3-10)10-C3d-p28.3 vaccine induced high titers of anti-amyloid-βantibodies, which bound to Aβplaques in APP/PS1 transgenic mouse brain tissue, demonstrating that the vaccine is effective against plaques in a mouse model of Alzheimer’s disease. Moreover, the vaccine elicited a pre-dominantly IgG1 humoral response and low levels of interferon-γ in ex vivo cultured splenocytes, indicating that the vaccine could shift the cel ular immune response towards a Th2 phenotype. This indicated that the vaccine did not elicit a detrimental immune response and had a favorable safety profile. Our results indicate that the p(Aβ3-10)10-C3d-p28.3 vaccine is a promising immunothera-peutic option for Aβvaccination in Alzheimer’s disease.

  2. A double layer plaque assay using spread plate technique for enumeration of bacteriophage MS2.

    Science.gov (United States)

    Cormier, Jiemin; Janes, Marlene

    2014-02-01

    Bacteriophage MS2 is used widely as a model organism to estimate pathogenic virus survival in various environments, and is usually quantified by plaque assay. Although current plaque assays work well in enumeration of MS2 in environmental samples, quantification of MS2 calls for better visibility and higher consistency. In an attempt to improve the visibility and consistency of the current plaque assay, spread plate technique was introduced, instead of the pour plate technique used commonly in existing methods. Other parameters that influence the outcome of the plaque assay were also compared. Using spread plate technique resulted in an increase of plaque size by approximately 50% and contributed to a better visibility. Addition of supplements (glucose, CaCl2 and thiamine); reduction of agar thickness and hardness, also contributed to enhanced plaque visibility and increased plaque count. Among all the conditions tested, a supplemented thin bottom agar (10ml 1% agar) and a supplemented thin top agar (10ml 0.45% agar) with spread plate technique gave the maximum countable plaques with a minimum standard deviation. When compared to other methods, it produced significantly higher plaque count and lower variation. The optimized plaque assay significantly improved visibility and consistency of the existing plaque assay methods and could be used in quantification of MS2.

  3. Immunotherapy against amyloid pathology in Alzheimer's disease.

    Science.gov (United States)

    Galimberti, Daniela; Ghezzi, Laura; Scarpini, Elio

    2013-10-15

    The first drugs developed for Alzheimer's disease (AD), anticholinesterase inhibitors (AchEI), increase acetylcholine levels, previously demonstrated to be reduced in AD. To date, four AchEI are approved for the treatment of mild to moderate AD. A further therapeutic option available for moderate to severe AD is memantine. These treatments are symptomatic, whereas drugs under development are supposed to modify pathological steps leading to AD, thus acting on the evolution of the disease. For this reason they are currently termed "disease modifying" drugs. To block the progression of the disease, they have to interfere with pathogenic steps at the basis of clinical symptoms, including the deposition of extracellular amyloid beta (Aβ) plaques and of intracellular neurofibrillary tangles. The most innovative approach is represented by the vaccination and passive immunization against Aβ peptide. In this article, current knowledge about concluded and ongoing clinical trials with both vaccination with different antigens and passive immunization will be reviewed and discussed.

  4. Does aluminium bind to histidine? An NMR investigation of amyloid β12 and amyloid β16 fragments.

    Science.gov (United States)

    Narayan, Priya; Krishnarjuna, Bankala; Vishwanathan, Vinaya; Jagadeesh Kumar, Dasappa; Babu, Sudhir; Ramanathan, Krishna Venkatachala; Easwaran, Kalpathy Ramaier Katchap; Nagendra, Holenarasipur Gundurao; Raghothama, Srinivasarao

    2013-07-01

    Aluminium and zinc are known to be the major triggering agents for aggregation of amyloid peptides leading to plaque formation in Alzheimer's disease. While zinc binding to histidine in Aβ (amyloid β) fragments has been implicated as responsible for aggregation, not much information is available on the interaction of aluminium with histidine. In the NMR study of the N-terminal Aβ fragments, DAEFRHDSGYEV (Aβ12) and DAEFRHDSGYEVHHQK (Aβ16) presented here, the interactions of the fragments with aluminium have been investigated. Significant chemical shifts were observed for few residues near the C-terminus when aluminium chloride was titrated with Aβ12 and Aβ16 peptides. Surprisingly, it is nonhistidine residues which seem to be involved in aluminium binding. Based on NMR constrained structure obtained by molecular modelling, aluminium-binding pockets in Aβ12 were around charged residues such as Asp, Glu. The results are discussed in terms of native structure propagation, and the relevance of histidine residues in the sequences for metal-binding interactions. We expect that the study of such short amyloid peptide fragments will not only provide clues for plaque formation in aggregated conditions but also facilitate design of potential drugs for these targets. PMID:23464626

  5. Disappearance of La Caille Plaque

    Science.gov (United States)

    2010-04-01

    A bronze plaque erected to the memory of N.-L. de La Caille near the site of his observatory in Central Cape Town, has been stolen by metal thieves. It was designed by the famous architect Sir Herbert Baker.

  6. Galantamine slows down plaque formation and behavioral decline in the 5XFAD mouse model of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Soumee Bhattacharya

    Full Text Available The plant alkaloid galantamine is an established symptomatic drug treatment for Alzheimer's disease (AD, providing temporary cognitive and global relief in human patients. In this study, the 5X Familial Alzheimer's Disease (5XFAD mouse model was used to investigate the effect of chronic galantamine treatment on behavior and amyloid β (Aβ plaque deposition in the mouse brain. Quantification of plaques in untreated 5XFAD mice showed a gender specific phenotype; the plaque density increased steadily reaching saturation in males after 10 months of age, whereas in females the density further increased until after 14 months of age. Moreover, females consistently displayed a higher plaque density in comparison to males of the same age. Chronic oral treatment with galantamine resulted in improved performance in behavioral tests, such as open field and light-dark avoidance, already at mildly affected stages compared to untreated controls. Treated animals of both sexes showed significantly lower plaque density in the brain, i.e., the entorhinal cortex and hippocampus, gliosis being always positively correlated to plaque load. A high dose treatment with a daily uptake of 26 mg/kg body weight was tolerated well and produced significantly larger positive effects than a lower dose treatment (14 mg/kg body weight in terms of plaque density and behavior. These results strongly support that galantamine, in addition to improving cognitive and behavioral symptoms in AD, may have disease-modifying and neuroprotective properties, as is indicated by delayed Aβ plaque formation and reduced gliosis.

  7. Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-β pathology.

    Science.gov (United States)

    Spangenberg, Elizabeth E; Lee, Rafael J; Najafi, Allison R; Rice, Rachel A; Elmore, Monica R P; Blurton-Jones, Mathew; West, Brian L; Green, Kim N

    2016-04-01

    In addition to amyloidplaque and tau neurofibrillary tangle deposition, neuroinflammation is considered a key feature of Alzheimer's disease pathology. Inflammation in Alzheimer's disease is characterized by the presence of reactive astrocytes and activated microglia surrounding amyloid plaques, implicating their role in disease pathogenesis. Microglia in the healthy adult mouse depend on colony-stimulating factor 1 receptor (CSF1R) signalling for survival, and pharmacological inhibition of this receptor results in rapid elimination of nearly all of the microglia in the central nervous system. In this study, we set out to determine if chronically activated microglia in the Alzheimer's disease brain are also dependent on CSF1R signalling, and if so, how these cells contribute to disease pathogenesis. Ten-month-old 5xfAD mice were treated with a selective CSF1R inhibitor for 1 month, resulting in the elimination of ∼80% of microglia. Chronic microglial elimination does not alter amyloid-β levels or plaque load; however, it does rescue dendritic spine loss and prevent neuronal loss in 5xfAD mice, as well as reduce overall neuroinflammation. Importantly, behavioural testing revealed improvements in contextual memory. Collectively, these results demonstrate that microglia contribute to neuronal loss, as well as memory impairments in 5xfAD mice, but do not mediate or protect from amyloid pathology.

  8. Smooth muscle cells healing atherosclerotic plaque disruptions are of local, not blood, origin in apolipoprotein E knockout mice

    DEFF Research Database (Denmark)

    Bentzon, Jacob F; Sondergaard, Claus S; Kassem, Mustafa;

    2007-01-01

    circulating bone marrow-derived progenitor cells. Here, we analyzed the contribution of this mechanism to plaque healing after spontaneous and mechanical plaque disruption in apolipoprotein E knockout (apoE-/-) mice. METHODS AND RESULTS: To determine the origin of SMCs after spontaneous plaque disruption......, irradiated 18-month-old apoE-/- mice were reconstituted with bone marrow cells from enhanced green fluorescent protein (eGFP) transgenic apoE-/- mice and examined when they died up to 9 months later. Plaque hemorrhage, indicating previous plaque disruption, was widely present, but no bone marrow-derived e......GFP+ SMCs were detected. To examine the origin of healing SMCs in a model that recapitulates more features of human plaque rupture and healing, we developed a mechanical technique that produced consistent plaque disruption, superimposed thrombosis, and SMC-mediated plaque healing in apoE-/- mice. Mechanical...

  9. Amyloid Fibril Solubility

    CERN Document Server

    Rizzi, L G

    2015-01-01

    It is well established that amyloid fibril solubility is protein specific, but how solubility depends on the interactions between the fibril building blocks is not clear. Here we use a simple protein model and perform Monte Carlo simulations to directly measure the solubility of amyloid fibrils as a function of the interaction between the fibril building blocks. Our simulations confirms that the fibril solubility depends on the fibril thickness and that the relationship between the interactions and the solubility can be described by a simple analytical formula. The results presented in this study reveal general rules how side-chain side-chain interactions, backbone hydrogen bonding and temperature affect amyloid fibril solubility, which might prove a powerful tool to design protein fibrils with desired solubility and aggregation properties in general.

  10. Effects of bacteriophage traits on plaque formation

    Directory of Open Access Journals (Sweden)

    Kannoly Sherin

    2011-08-01

    Full Text Available Abstract Background The appearance of plaques on a bacterial lawn is one of the enduring imageries in modern day biology. The seeming simplicity of a plaque has invited many hypotheses and models in trying to describe and explain the details of its formation. However, until now, there has been no systematic experimental exploration on how different bacteriophage (phage traits may influence the formation of a plaque. In this study, we constructed a series of isogenic λ phages that differ in their adsorption rate, lysis timing, or morphology so that we can determine the effects if these changes on three plaque properties: size, progeny productivity, and phage concentration within plaques. Results We found that the adsorption rate has a diminishing, but negative impact on all three plaque measurements. Interestingly, there exists a concave relationship between the lysis time and plaque size, resulting in an apparent optimal lysis time that maximizes the plaque size. Although suggestive in appearance, we did not detect a significant effect of lysis time on plaque productivity. Nonetheless, the combined effects of plaque size and productivity resulted in an apparent convex relationship between the lysis time and phage concentration within plaques. Lastly, we found that virion morphology also affected plaque size. We compared our results to the available models on plaque size and productivity. For the models in their current forms, a few of them can capture the qualitative aspects of our results, but not consistently in both plaque properties. Conclusions By using a collection of isogenic phage strains, we were able to investigate the effects of individual phage traits on plaque size, plaque productivity, and average phage concentration in a plaque while holding all other traits constant. The controlled nature of our study allowed us to test several model predictions on plaque size and plaque productivity. It seems that a more realistic theoretical

  11. Protection of the blood-brain barrier by pentosan against amyloid-β-induced toxicity.

    Science.gov (United States)

    Deli, Mária A; Veszelka, Szilvia; Csiszár, Boglárka; Tóth, Andrea; Kittel, Agnes; Csete, Mária; Sipos, Aron; Szalai, Anikó; Fülöp, Lívia; Penke, Botond; Abrahám, Csongor S; Niwa, Masami

    2010-01-01

    Endothelial cells of brain capillaries forming the blood-brain barrier play an important role in the pathogenesis and therapy of Alzheimer's disease. Amyloid-β (Aβ) peptides are key pathological elements in the development of the disease. A blood-brain barrier model, based on primary rat brain endothelial cells was used in which the barrier properties were induced by glial cells. The effects of amyloid peptides have been tested on cell viability and barrier functions. Aβ showed toxic effects on primary rat brain endothelial cells measured by MTT dye conversion and the lactate dehydrogenase release. Morphologically cytoplasmic vacuolization, disruption of the structure of cytoplasmic organelles and tight junctions could be observed in brain endothelial cells. Treatment with Aβ1-42 decreased the electrical resistance, and increased the permeability of brain endothelial cell monolayers for both fluorescein and albumin. Serum amyloid P component which stabilizes Aβ fibrils in cortical amyloid plaques and cerebrovascular amyloid deposits significantly potentiated the barrier-weakening effect of Aβ1-42. Sulfated polysaccharide pentosan could decrease the toxic effects of Aβ peptides in brain endothelial cells. It could also significantly protect the barrier integrity of monolayers from damaging actions of peptides. Pentosan modified the size, and significantly decreased the number of amyloid aggregates demonstrated by atomic force microscopy. The present data further support the toxic effects of amyloid peptides on brain endothelial cells, and can contribute to the development of molecules protecting the blood-brain barrier in Alzheimer's disease.

  12. Amyloid-β colocalizes with apolipoprotein B in absorptive cells of the small intestine

    Directory of Open Access Journals (Sweden)

    Dhaliwal Satvinder S

    2009-10-01

    Full Text Available Abstract Background Amyloid-β is recognized as the major constituent of senile plaque found in subjects with Alzheimer's disease. However, there is increasing evidence that in a physiological context amyloid-β may serve as regulating apolipoprotein, primarily of the triglyceride enriched lipoproteins. To consider this hypothesis further, this study utilized an in vivo immunological approach to explore in lipogenic tissue whether amyloid-β colocalizes with nascent triglyceride-rich lipoproteins. Results In murine absorptive epithelial cells of the small intestine, amyloid-β had remarkable colocalization with chylomicrons (Manders overlap coefficient = 0.73 ± 0.03 (SEM, the latter identified as immunoreactive apolipoprotein B. A diet enriched in saturated fats doubled the abundance of both amyloid-β and apo B and increased the overlap coefficient of the two proteins (0.87 ± 0.02. However, there was no evidence that abundance of the two proteins was interdependent within the enterocytes (Pearson's Coefficient Conclusion The findings of this study are consistent with the possibility that amyloid-β is secreted by enterocytes as an apolipoprotein component of chylomicrons. However, secretion of amyloid-β appears to be independent of chylomicron biogenesis.

  13. Amyloid beta-peptide worsens cognitive impairment following cerebral ischemia-reperfusion injury*****

    Institute of Scientific and Technical Information of China (English)

    Bo Song; Qiang Ao; Ying Niu; Qin Shen; Huancong Zuo; Xiufang Zhang; Yandao Gong

    2013-01-01

    Amyloid β-peptide, a major component of senile plaques in Alzheimer’s disease, has been impli-cated in neuronal cel death and cognitive impairment. Recently, studies have shown that the pathogenesis of cerebral ischemia is closely linked with Alzheimer’s disease. In this study, a rat model of global cerebral ischemia-reperfusion injury was established via occlusion of four arteries;meanwhile, fibril ar amyloid β-peptide was injected into the rat lateral ventricle. The Morris water maze test and histological staining revealed that administration of amyloid β-peptide could further aggravate impairments to learning and memory and neuronal cel death in the hippocampus of rats subjected to cerebral ischemia-reperfusion injury. Western blot showed that phosphorylation of tau protein and the activity of glycogen synthase kinase 3β were significantly stronger in cerebral is-chemia-reperfusion injury rats subjected to amyloidβ-peptide administration than those undergoing cerebral ischemia-reperfusion or amyloidβ-peptide administration alone. Conversely, the activity of protein phosphatase 2A was remarkably reduced in rats with cerebral ischemia-reperfusion injury fol owing amyloidβ-peptide administration. These findings suggest that amyloidβ-peptide can po-tentiate tau phosphorylation induced by cerebral ischemia-reperfusion and thereby aggravate cog-nitive impairment.

  14. Is amyloid-β harmful to the brain? Insights from human imaging studies.

    Science.gov (United States)

    Jagust, William

    2016-01-01

    Although the amyloid-β protein associated with the Alzheimer's disease plaque has been detectable in living people for over a decade, its importance in the pathogenesis of Alzheimer's disease is still debated. The frequent presence of amyloid-β in the brains of cognitively healthy older people has been interpreted as evidence against a causative role. If amyloid-β is crucial to the development of Alzheimer's disease, it should be associated with other Alzheimer's disease-like neurological changes. This review examines whether amyloid-β is associated with other biomarkers indicative of early Alzheimer's disease in normal older people. The preponderance of evidence links amyloid-β to functional change, progressive brain atrophy, and cognitive decline. Individuals at greatest risk of decline seem to be those with evidence of both amyloid-β and findings suggestive of neurodegeneration. The crucial question is thus how amyloid-β is related to brain degeneration and how these two processes interact to cause cognitive decline and dementia.

  15. Beta-protein deposition: a pathogenetic link between Alzheimer's disease and cerebral amyloid angiopathies.

    Science.gov (United States)

    Coria, F; Prelli, F; Castaño, E M; Larrondo-Lillo, M; Fernandez-Gonzalez, J; van Duinen, S G; Bots, G T; Luyendijk, W; Shelanski, M L; Frangione, B

    1988-10-25

    Cerebral amyloid angiopathy (CAA) refers to a group of hereditary (hereditary cerebral hemorrhage with amyloidosis, HCHWA and sporadic (SCAA) disorders characterized by amyloid fibril deposition restricted to the leptomeningeal and cortical vasculature leading to recurrent hemorrhagic and/or ischemic accidents. On clinical and biochemical grounds, two forms of HCHWA can be distinguished. The amyloid subunit of the HCHWA of Icelandic origin is related to Cystatin C, while amyloid from patients of Dutch origin (HCHWA-D) is related to the beta-protein (or A4), the main component of vascular and plaque core amyloid in Alzheimer's disease (AD) and Down's syndrome (DS) [corrected]. SCAA is an increasingly recognized cause of stroke in normotensive individual amounting to 5-10% of all cerebrovascular accidents. We now report the isolation and partial amino acid sequence of the amyloid subunit from a case of SCAA and a new case of HCHWA-D. The recognition that a heterogeneous group of diseases are linked by similar pathological and chemical features suggests that diversity of etiological factors may promote a common pathogenetic mechanism leading to amyloid-beta (A beta) deposition, and open new ways of research in AD and CAA as they are related to dementia and stroke. PMID:3058268

  16. Amyloid β oligomers in Alzheimer's disease pathogenesis, treatment, and diagnosis.

    Science.gov (United States)

    Viola, Kirsten L; Klein, William L

    2015-02-01

    Protein aggregation is common to dozens of diseases including prionoses, diabetes, Parkinson's and Alzheimer's. Over the past 15 years, there has been a paradigm shift in understanding the structural basis for these proteinopathies. Precedent for this shift has come from investigation of soluble Aβ oligomers (AβOs), toxins now widely regarded as instigating neuron damage leading to Alzheimer's dementia. Toxic AβOs accumulate in AD brain and constitute long-lived alternatives to the disease-defining Aβ fibrils deposited in amyloid plaques. Key experiments using fibril-free AβO solutions demonstrated that while Aβ is essential for memory loss, the fibrillar Aβ in amyloid deposits is not the agent. The AD-like cellular pathologies induced by AβOs suggest their impact provides a unifying mechanism for AD pathogenesis, explaining why early stage disease is specific for memory and accounting for major facets of AD neuropathology. Alternative ideas for triggering mechanisms are being actively investigated. Some research favors insertion of AβOs into membrane, while other evidence supports ligand-like accumulation at particular synapses. Over a dozen candidate toxin receptors have been proposed. AβO binding triggers a redistribution of critical synaptic proteins and induces hyperactivity in metabotropic and ionotropic glutamate receptors. This leads to Ca(2+) overload and instigates major facets of AD neuropathology, including tau hyperphosphorylation, insulin resistance, oxidative stress, and synapse loss. Because different species of AβOs have been identified, a remaining question is which oligomer is the major pathogenic culprit. The possibility has been raised that more than one species plays a role. Despite some key unknowns, the clinical relevance of AβOs has been established, and new studies are beginning to point to co-morbidities such as diabetes and hypercholesterolemia as etiological factors. Because pathogenic AβOs appear early in the disease, they

  17. Denitrification in human dental plaque

    Directory of Open Access Journals (Sweden)

    Verstraete Willy

    2010-03-01

    Full Text Available Abstract Background Microbial denitrification is not considered important in human-associated microbial communities. Accordingly, metabolic investigations of the microbial biofilm communities of human dental plaque have focused on aerobic respiration and acid fermentation of carbohydrates, even though it is known that the oral habitat is constantly exposed to nitrate (NO3- concentrations in the millimolar range and that dental plaque houses bacteria that can reduce this NO3- to nitrite (NO2-. Results We show that dental plaque mediates denitrification of NO3- to nitric oxide (NO, nitrous oxide (N2O, and dinitrogen (N2 using microsensor measurements, 15N isotopic labelling and molecular detection of denitrification genes. In vivo N2O accumulation rates in the mouth depended on the presence of dental plaque and on salivary NO3- concentrations. NO and N2O production by denitrification occurred under aerobic conditions and was regulated by plaque pH. Conclusions Increases of NO concentrations were in the range of effective concentrations for NO signalling to human host cells and, thus, may locally affect blood flow, signalling between nerves and inflammatory processes in the gum. This is specifically significant for the understanding of periodontal diseases, where NO has been shown to play a key role, but where gingival cells are believed to be the only source of NO. More generally, this study establishes denitrification by human-associated microbial communities as a significant metabolic pathway which, due to concurrent NO formation, provides a basis for symbiotic interactions.

  18. Overexpression of amyloid precursor protein inhibits neurite outgrowth and disrupts cytoskeleton in N2a cells

    Institute of Scientific and Technical Information of China (English)

    王泽芬; 王建枝

    2004-01-01

    @@ There is considerable evidence suggesting that altered metabolism of β-amyloid precursor protein (APP) and accumulation of its β-amyloid (Aβ) fragment are key features of Alzheimer's disease (AD). APP is a type Ⅰ integral membrane protein and consists of 695-770 amino acids encoded by differentially spliced mRNAs transcribed from a single gene located on human chromosome 21.1 The 695-amino acid APP is expressed preferentially in the brain. Aβ, the major component of senile plaques, is derived by proteolytic processing of APP by β-and γ-secretase and is constitutively released from most cells.

  19. Expression of complement system components during aging and amyloid deposition in APP transgenic mice

    Directory of Open Access Journals (Sweden)

    Wiederhold Karl-Heinz

    2009-11-01

    Full Text Available Abstract Background A causal role of the complement system in Alzheimer's disease pathogenesis has been postulated based on the identification of different activated components up to the membrane attack complex at amyloid plaques in brain. However, histological studies of amyloid plaque bearing APP transgenic mice provided only evidence for an activation of the early parts of the complement cascade. To better understand the contribution of normal aging and amyloid deposition to the increase in complement activation we performed a detailed characterization of the expression of the major mouse complement components. Methods APP23 mice expressing human APP751 with the Swedish double mutation as well as C57BL/6 mice were used at different ages. mRNA was quantified by Realtime PCR and the age- as well as amyloid induced changes determined. The protein levels of complement C1q and C3 were analysed by Western blotting. Histology was done to test for amyloid plaque association and activation of the complement cascade. Results High mRNA levels were detected for C1q and some inhibitory complement components. The expression of most activating components starting at C3 was low. Expression of C1q, C3, C4, C5 and factor B mRNA increased with age in control C57BL/6 mice. C1q and C3 mRNA showed a substantial additional elevation during amyloid formation in APP23 mice. This increase was confirmed on the protein level using Western blotting, whereas immunohistology indicated a recruitment of complement to amyloid plaques up to the C3 convertase. Conclusion Early but not late components of the mouse complement system show an age-dependent increase in expression. The response to amyloid deposition is comparatively smaller. The low expression of C3 and C5 and failure to upregulate C5 and downstream components differs from human AD brain and likely contributes to the lack of full complement activation in APP transgenic mice.

  20. Human Islet Amyloid Polypeptide

    DEFF Research Database (Denmark)

    Kosicka, Iga

    2014-01-01

    Diabetes mellitus type II is a metabolic disease affecting millions of people worldwide. The disease is associated with occurence of insoluble, fibrillar, protein aggregates in islets of Langerhans in the pancreas - islet amyloid. The main constituent of these protein fibers is the human islet...

  1. Study of specially labeling amyloid plaques in vivo in Alzheimer transgenic mice with targeted magnetic nano-iron contrast agent%靶向纳米铁磁共振造影剂特异性标记阿尔茨海默病鼠脑内老年斑

    Institute of Scientific and Technical Information of China (English)

    湛彦强; 张苏明; 吴军; 许杰; 尹波; 马铭; 杜桂焕; 刘祖黎; 徐威; 雷浩

    2011-01-01

    目的 开发具有高度特异性的靶向磁共振对比剂,验证其特异性显示阿尔茨海默病(AD)脑内老年斑的可能性及有效性.方法 利用热分解法获得水相的磁性纳米四氧化三铁颗粒(MNPs),经过表面官能化学修饰,完成MNPs与β淀粉样蛋白肽段1-40(Aβ40)及蛋白质转导结合域(protein transduction domain,Tat-PTD)的连接后,制备出特异性与老年斑相结合的靶向纳米铁造影剂Aβ40-MNPs-Tat PTD,通过尾静脉注射人20只AD鼠和20只阴性对照C57小鼠(4、6、9、12月龄各5只)体内,不同的时间点采用7.0 T动物磁共振检测获得磁共振图像,观察靶向纳米造影剂对脑实质内老年斑信号的强化效果,继之处死小鼠后灌流取脑做连续冰冻切片,进行铁染色和Thioflavine S染色组织学验证.结果 所获得的靶向纳米颗粒Aβ40-MNPs-Tat PTD能够在体外进入细胞内进而改变细胞磁共振T2信号强度.尾静脉注射入AD鼠体内后能特异性负性强化AD鼠脑内老年斑病变,经组织学验证,能够与老年斑染色及铁染色相对应.结论 特异靶向性的磁性纳米铁造影剂Aβ40-MNPs-Tat PTD能特异性地针对小鼠脑内的老年斑病变进行负性强化和标记.%Objective To develop specific targeted magnetic biomarkers which can selectively mark the senile plaques in Alzheimer' s disease (AD) and verify its feasibility and validity.Methods Aβ1-40 peptide and Tat-PTD ( Tat-protein transduction domain) was binded with dextran-coated ultrasmall superparamagnetic iron oxide ( USPIO) particles.Visualization of plaques in vivo in Alzheimer transgenic mice was investigated at 7.0 Tesla using T2 sequences after intravenous administration of the targeted nanoiron contrast agent and verified by histological staining.Results The targeted nano-iron contrast agent could enter the cultured neural stem cells,and was able to accelerate T2 relaxation rates of water protons in the cells and negatively reinforce the T2

  2. Reversal of Paralysis and Reduced Inflammation from Peripheral Administration of Amyloid-β in Th1- and Th17-Versions of Experimental Autoimmune Encephalomyelitis

    OpenAIRE

    Grant, Jacqueline L.; Ghosn, Eliver Eid Bou; Axtell, Robert C.; Herges, Katja; Kuipers, Hedwich F.; Woodling, Nathan S.; Andreasson, Katrin; Herzenberg, Leonard A.; Herzenberg, Leonore A.; Steinman, Lawrence

    2012-01-01

    β-amyloid-42 (Aβ42) and β-amyloid-40 (Aβ40), major components of senile plaque deposits in Alzheimer’s disease (AD), are considered neurotoxic and pro-inflammatory. In multiple sclerosis (MS), Aβ42 is upregulated in brain lesions and damaged axons. Here we found, unexpectedly, that treatment with either Aβ42 or Aβ40 peptides reduced motor paralysis and brain inflammation in four different models of experimental autoimmune encephalomyelitis (EAE) with attenuation of motor paralysis, reduction ...

  3. A potential amyloid-imaging probe for Alzheimer's disease

    International Nuclear Information System (INIS)

    Purpose: To screen out the human single-chain fragment variable (scFv) against amyloid β peptide 40 from a human synthetic antibody library, sub-clone its gene into E. coli expression system, and express and purify it for amyloid peptide imaging research. The overload of amyloid β peptide and the appearance of senile plaques in the human brain tissue is one of the hallmark of the Alzheimer's disease, and in vivo imaging of amyloidβ peptide is valuable for the earlier diagnosis of Alzheimer's disease. Methods: Amyloid β peptide 40 was bound on the solid surface of Nunc plates as antigen and a human antibody library constructed with human antibody heavy and light chain variable gene and nucleotides sequence coded (Gly4Ser)3 linker and displayed on the protein surface of filamentous phage was used to screen the binding clones. After five rounds of bio-panning, the host E. coli TG1 was infected with eluted filamentous phage from the last turn of selection. 55 well-separated colonies were picked randomly from the plates and several specific positive clones were identified by ELISA testing, and their binding sites were determined by competitive ELISA with amyloid 13 peptide 40, 1-16, 25-35. The single-chain Fv antibody gene was sequenced and their amino acids sequence was deduced. The scFv antibody gene was sub-cloned into a protokayotic expression vector pET-22b(+) and transformed into bacteria strain BL21 to express the His6-tagged single-chain antibody and the whole cell culture was subjected to SDS-PAGE analysis. The antibody was expressed in inclusion bodies and purified with serial buffers and verified with western blotting and their activity was tested by ELISA against amyloid β peptide 40. Results: ELISA testing showed that 33 clones could bind amyloid β peptide 40 and 10 of these clones could be inhibited by amyloid β peptide 40 itself to below 50% of its original binding activities. Five clones could also be inhibited by amyloid β peptide 1-16. DNA

  4. Amyloid Aggregation and Membrane Disruption by Amyloid Proteins

    Science.gov (United States)

    Ramamoorthy, Ayyalusamy

    2013-03-01

    Amyloidogenesis has been the focus of intense basic and clinical research, as an increasing number of amyloidogenic proteins have been linked to common and incurable degenerative diseases including Alzheimer's, type II diabetes, and Parkinson's. Recent studies suggest that the cell toxicity is mainly due to intermediates generated during the assembly process of amyloid fibers, which have been proposed to attack cells in a variety of ways. Disruption of cell membranes is believed to be one of the key components of amyloid toxicity. However, the mechanism by which this occurs is not fully understood. Our research in this area is focused on the investigation of the early events in the aggregation and membrane disruption of amyloid proteins, Islet amyloid polypeptide protein (IAPP, also known as amylin) and amyloid-beta peptide, on the molecular level. Structural insights into the mechanisms of membrane disruption by these amyloid proteins and the role of membrane components on the membrane disruption will be presented.

  5. Current and future treatment of amyloid diseases.

    Science.gov (United States)

    Ankarcrona, M; Winblad, B; Monteiro, C; Fearns, C; Powers, E T; Johansson, J; Westermark, G T; Presto, J; Ericzon, B-G; Kelly, J W

    2016-08-01

    There are more than 30 human proteins whose aggregation appears to cause degenerative maladies referred to as amyloid diseases or amyloidoses. These disorders are named after the characteristic cross-β-sheet amyloid fibrils that accumulate systemically or are localized to specific organs. In most cases, current treatment is limited to symptomatic approaches and thus disease-modifying therapies are needed. Alzheimer's disease is a neurodegenerative disorder with extracellular amyloid β-peptide (Aβ) fibrils and intracellular tau neurofibrillary tangles as pathological hallmarks. Numerous clinical trials have been conducted with passive and active immunotherapy, and small molecules to inhibit Aβ formation and aggregation or to enhance Aβ clearance; so far such clinical trials have been unsuccessful. Novel strategies are therefore required and here we will discuss the possibility of utilizing the chaperone BRICHOS to prevent Aβ aggregation and toxicity. Type 2 diabetes mellitus is symptomatically treated with insulin. However, the underlying pathology is linked to the aggregation and progressive accumulation of islet amyloid polypeptide as fibrils and oligomers, which are cytotoxic. Several compounds have been shown to inhibit islet amyloid aggregation and cytotoxicity in vitro. Future animal studies and clinical trials have to be conducted to determine their efficacy in vivo. The transthyretin (TTR) amyloidoses are a group of systemic degenerative diseases compromising multiple organ systems, caused by TTR aggregation. Liver transplantation decreases the generation of misfolded TTR and improves the quality of life for a subgroup of this patient population. Compounds that stabilize the natively folded, nonamyloidogenic, tetrameric conformation of TTR have been developed and the drug tafamidis is available as a promising treatment. PMID:27165517

  6. Amyloids here, amyloids there…What’s wrong with them?

    OpenAIRE

    Gharibyan, Anna

    2012-01-01

    Amyloid formation is inherent property of proteins which under certain circumstances can become a pathologic feature of a group of diseases called amyloidosis. There are about 30 known human amyloidosis and more than 27 identified proteins involved in these pathologies.  Besides these proteins, there are a growing number of proteins non-related to diseases shown to form amyloid-like structures in vitro, which make them excellent tools for studying amyloid formation mechanisms, physicochemical...

  7. Synergistic effects of high fat feeding and apolipoprotein E deletion on enterocytic amyloid-beta abundance

    Directory of Open Access Journals (Sweden)

    Dhaliwal Satvinder S

    2008-04-01

    Full Text Available Abstract Background Amyloid-β (Aβ, a key protein found in amyloid plaques of subjects with Alzheimer's disease is expressed in the absorptive epithelial cells of the small intestine. Ingestion of saturated fat significantly enhances enterocytic Aβ abundance whereas fasting abolishes expression. Apolipoprotein (apo E has been shown to directly modulate Aβ biogenesis in liver and neuronal cells but it's effect in enterocytes is not known. In addition, apo E modulates villi length, which may indirectly modulate Aβ as a consequence of differences in lipid absorption. This study compared Aβ abundance and villi length in wild-type (WT and apo E knockout (KO mice maintained on either a low-fat or high-fat diet. Wild-type C57BL/6J and apo E KO mice were randomised for six-months to a diet containing either 4% (w/w unsaturated fats, or chow comprising 16% saturated fats and 1% cholesterol. Quantitative immunohistochemistry was used to assess Aβ abundance in small intestinal enterocytes. Apo E KO mice given the low-fat diet had similar enterocytic Aβ abundance compared to WT controls. Results The saturated fat diet substantially increased enterocytic Aβ in WT and in apo E KO mice, however the effect was greater in the latter. Villi height was significantly greater in apo E KO mice than for WT controls when given the low-fat diet. However, WT mice had comparable villi length to apo E KO when fed the saturated fat and cholesterol enriched diet. There was no effect of the high-fat diet on villi length in apo E KO mice. Conclusion The findings of this study are consistent with the notion that lipid substrate availability modulates enterocytic Aβ. Apo E may influence enterocytic lipid availability by modulating absorptive capacity.

  8. Depletion of spleen macrophages delays AA amyloid development: a study performed in the rapid mouse model of AA amyloidosis.

    Directory of Open Access Journals (Sweden)

    Katarzyna Lundmark

    Full Text Available AA amyloidosis is a systemic disease that develops secondary to chronic inflammatory diseases Macrophages are often found in the vicinity of amyloid deposits and considered to play a role in both formation and degradation of amyloid fibrils. In spleen reside at least three types of macrophages, red pulp macrophages (RPM, marginal zone macrophages (MZM, metallophilic marginal zone macrophages (MMZM. MMZM and MZM are located in the marginal zone and express a unique collection of scavenger receptors that are involved in the uptake of blood-born particles. The murine AA amyloid model that resembles the human form of the disease has been used to study amyloid effects on different macrophage populations. Amyloid was induced by intravenous injection of amyloid enhancing factor and subcutaneous injections of silver nitrate and macrophages were identified with specific antibodies. We show that MZMs are highly sensitive to amyloid and decrease in number progressively with increasing amyloid load. Total area of MMZMs is unaffected by amyloid but cells are activated and migrate into the white pulp. In a group of mice spleen macrophages were depleted by an intravenous injection of clodronate filled liposomes. Subsequent injections of AEF and silver nitrate showed a sustained amyloid development. RPMs that constitute the majority of macrophages in spleen, appear insensitive to amyloid and do not participate in amyloid formation.

  9. Mechanical Stresses in Carotid Plaques

    DEFF Research Database (Denmark)

    Samuel, Samuel Alberg

    simulationer, som tillod beregning af longitudinelle stress-niveauer i den fibrøse kappe. Afhandlingen indeholder tre artikler, som beskriver denne metode. Den første; “Mechanical Stresses in Carotid Plaques using MRI-Based Fluid Structure Interaction Models”, beskriver i detaljer metoden til at danne de...

  10. Nuclear Molecular Imaging for Vulnerable Atherosclerotic Plaques

    OpenAIRE

    Lee, Soo Jin; Paeng, Jin Chul

    2015-01-01

    Atherosclerosis is an inflammatory disease as well as a lipid disorder. Atherosclerotic plaque formed in vessel walls may cause ischemia, and the rupture of vulnerable plaque may result in fatal events, like myocardial infarction or stroke. Because morphological imaging has limitations in diagnosing vulnerable plaque, molecular imaging has been developed, in particular, the use of nuclear imaging probes. Molecular imaging targets various aspects of vulnerable plaque, such as inflammatory cell...

  11. Red autofluorescence of dental plaque bacteria

    NARCIS (Netherlands)

    van der Veen, M. H.; Thomas, R. Z.; Huysmans, M. C. D. N. J. M.; de Soet, J. J.

    2006-01-01

    Red autofluorescence of plaque and its relation to fluorescence of a single species in the biofilm was studied. Fluorescence images of non-disclosed and disclosed plaque of 28 first-year students were captured. The plaque samples were assessed by culture methods and studied for red autofluorescence.

  12. In vivo labeling of amyloid with BF-108.

    Science.gov (United States)

    Suemoto, Takahiro; Okamura, Nobuyuki; Shiomitsu, Tsuyoshi; Suzuki, Masako; Shimadzu, Hiroshi; Akatsu, Hiroyasu; Yamamoto, Takayuki; Kudo, Yukitsuka; Sawada, Tohru

    2004-01-01

    Detection of aggregated amyloid-beta (Abeta) with a non-invasive imaging modality such as positron emission tomography (PET) was suggested to be ideal for the diagnosis of Alzheimer's disease (AD) prior to the onset of clinical symptoms. We have been searching for imaging probe candidates with a high affinity for aggregated Abeta in vitro and in vivo and high lipophilicity, a characteristic that allows for the permeation of the blood-brain barrier (BBB). As analyzed by Thioflavin T (ThT) assay and octanol/water partition coefficient test (PC), 3-diethylamino-6-(2-fluoroethyl)ethylaminoacridine (BF-108) were found to have high affinity for Abeta aggregates in vitro and high lipophilicity. Intravenously administrated BF-108 labeled Abeta aggregates injected into the amygdala as observed under a fluorescence microscope, showing this compound's permeability of BBB and an ability to label Abeta in vivo. BF-108 also labeled neuritic senile plaques (SPs), neurofibrillary tangles, and amyloid-laden vessels in temporal and hippocampal sections from AD patients. Following intravenous administration of BF-108 to an APP23 transgenic (TG) mouse, in vivo labeling of endogenous plaques was seen in brain sections by fluorescence microscopy. These properties suggest the potential utility of BF-108 for in vivo imaging of AD pathology. PMID:14687882

  13. Beta-Amyloid Deposition and Alzheimer's Type Changes Induced by Borrelia Spirochetes

    Energy Technology Data Exchange (ETDEWEB)

    Miklossy,J.; Kis, A.; Radenovic, A.; Miller, L.; Forro, L.; Martins, R.; Reiss, K.; Darbinian, N.; Darekar, P.; et al.

    2006-01-01

    The pathological hallmarks of Alzheimer's disease (AD) consist of {beta}-amyloid plaques and neurofibrillary tangles in affected brain areas. The processes, which drive this host reaction are unknown. To determine whether an analogous host reaction to that occurring in AD could be induced by infectious agents, we exposed mammalian glial and neuronal cells in vitro to Borrelia burgdorferi spirochetes and to the inflammatory bacterial lipopolysaccharide (LPS). Morphological changes analogous to the amyloid deposits of AD brain were observed following 2-8 weeks of exposure to the spirochetes. Increased levels of {beta}-amyloid presursor protein (A{beta}PP) and hyperphosphorylated tau were also detected by Western blots of extracts of cultured cells that had been treated with spirochetes or LPS. These observations indicate that, by exposure to bacteria or to their toxic products, host responses similar in nature to those observed in AD may be induced.

  14. Mechanistic insights into mode of action of potent natural antagonists of BACE-1 for checking Alzheimer’s plaque pathology

    International Nuclear Information System (INIS)

    Highlights: •Accumulation of Aβ plaques is one of the major pathology associated with Alzheimer’s disease. •Inhibition of β-Secretase or BACE-1 offers a viable prospect to check the growth of these plaques. •A large virtual dataset of natural compounds was screened against BACE-1. •Top two hits were analyzed for thermodynamic and structural stability using MD simulations. •Their detailed binding mode of actions were elucidated. -- Abstract: Alzheimer’s is a neurodegenerative disorder resulting in memory loss and decline in cognitive abilities. Accumulation of extracellular beta amyloidal plaques is one of the major pathology associated with this disease. β-Secretase or BACE-1 performs the initial and rate limiting step of amyloidic pathway in which 37–43 amino acid long peptides are generated which aggregate to form plaques. Inhibition of this enzyme offers a viable prospect to check the growth of these plaques. Numerous efforts have been made in recent years for the generation of BACE-1 inhibitors but many of them failed during the preclinical or clinical trials due to drug related or drug induced toxicity. In the present work, we have used computational methods to screen a large dataset of natural compounds to search for small molecules having BACE-1 inhibitory activity with low toxicity to normal cells. Molecular dynamics simulations were performed to analyze molecular interactions between the screened compounds and the active residues of the enzyme. Herein, we report two natural compounds of inhibitory nature active against β-secretase enzyme of amyloidic pathway and are potent lead molecules against Alzheimer’s disease

  15. Mechanistic insights into mode of action of potent natural antagonists of BACE-1 for checking Alzheimer’s plaque pathology

    Energy Technology Data Exchange (ETDEWEB)

    Dhanjal, Jaspreet Kaur [School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067 (India); Goyal, Sukriti [Apaji Institute of Mathematics and Applied Computer Technology, Banasthali University, Tonk 304022, Rajasthan (India); Sharma, Sudhanshu [Department of Biotechnology, Delhi Technological University, New Delhi 110042 (India); Hamid, Rabia [Department of Biochemistry, University of Kashmir, Srinagar 190006 (India); Grover, Abhinav, E-mail: abhinavgr@gmail.com [School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067 (India)

    2014-01-17

    Highlights: •Accumulation of Aβ plaques is one of the major pathology associated with Alzheimer’s disease. •Inhibition of β-Secretase or BACE-1 offers a viable prospect to check the growth of these plaques. •A large virtual dataset of natural compounds was screened against BACE-1. •Top two hits were analyzed for thermodynamic and structural stability using MD simulations. •Their detailed binding mode of actions were elucidated. -- Abstract: Alzheimer’s is a neurodegenerative disorder resulting in memory loss and decline in cognitive abilities. Accumulation of extracellular beta amyloidal plaques is one of the major pathology associated with this disease. β-Secretase or BACE-1 performs the initial and rate limiting step of amyloidic pathway in which 37–43 amino acid long peptides are generated which aggregate to form plaques. Inhibition of this enzyme offers a viable prospect to check the growth of these plaques. Numerous efforts have been made in recent years for the generation of BACE-1 inhibitors but many of them failed during the preclinical or clinical trials due to drug related or drug induced toxicity. In the present work, we have used computational methods to screen a large dataset of natural compounds to search for small molecules having BACE-1 inhibitory activity with low toxicity to normal cells. Molecular dynamics simulations were performed to analyze molecular interactions between the screened compounds and the active residues of the enzyme. Herein, we report two natural compounds of inhibitory nature active against β-secretase enzyme of amyloidic pathway and are potent lead molecules against Alzheimer’s disease.

  16. Involvement of receptor tyrosine kinase Tyro3 in amyloidogenic APP processing and β-amyloid deposition in Alzheimer's disease models.

    Directory of Open Access Journals (Sweden)

    Yan Zheng

    Full Text Available Alzheimer's disease (AD is the most common progressive neurodegenerative disease known to humankind. It is characterized by brain atrophy, extracellular amyloid plaques, and intracellular neurofibril tangles. β-Amyloid cascade is considered the major causative player in AD. Up until now, the mechanisms underlying the process of Aβ generation and accumulation in the brain have not been well understood. Tyro3 receptor belongs to the TAM receptor subfamily of receptor protein tyrosine kinases (RPTKs. It is specifically expressed in the neurons of the neocortex and hippocampus. In this study, we established a cell model stably expressing APPswe mutants and producing Aβ. We found that overexpression of Tyro3 receptor in the cell model significantly decreased Aβ generation and also down-regulated the expression of β-site amyloid precursor protein cleaving enzyme (BACE1. However, the effects of Tyro3 were inhibited by its natural ligand, Gas6, in a concentration-dependent manner. In order to confirm the role of Tyro3 in the progression of AD development, we generated an AD transgenic mouse model accompanied by Tyro3 knockdown. We observed a significant increase in the number of amyloid plaques in the hippocampus in the mouse model. More plaque-associated clusters of astroglia were also detected. The present study may help researchers determine the role of Tyro3 receptor in the neuropathology of AD.

  17. Calcium signaling and amyloid toxicity in Alzheimer disease.

    Science.gov (United States)

    Demuro, Angelo; Parker, Ian; Stutzmann, Grace E

    2010-04-23

    Intracellular Ca(2+) signaling is fundamental to neuronal physiology and viability. Because of its ubiquitous roles, disruptions in Ca(2+) homeostasis are implicated in diverse disease processes and have become a major focus of study in multifactorial neurodegenerative diseases such as Alzheimer disease (AD). A hallmark of AD is the excessive production of beta-amyloid (Abeta) and its massive accumulation in amyloid plaques. In this minireview, we highlight the pathogenic interactions between altered cellular Ca(2+) signaling and Abeta in its different aggregation states and how these elements coalesce to alter the course of the neurodegenerative disease. Ca(2+) and Abeta intersect at several functional levels and temporal stages of AD, thereby altering neurotransmitter receptor properties, disrupting membrane integrity, and initiating apoptotic signaling cascades. Notably, there are reciprocal interactions between Ca(2+) pathways and amyloid pathology; altered Ca(2+) signaling accelerates Abeta formation, whereas Abeta peptides, particularly in soluble oligomeric forms, induce Ca(2+) disruptions. A degenerative feed-forward cycle of toxic Abeta generation and Ca(2+) perturbations results, which in turn can spin off to accelerate more global neuropathological cascades, ultimately leading to synaptic breakdown, cell death, and devastating memory loss. Although no cause or cure is currently known, targeting Ca(2+) dyshomeostasis as an underlying and integral component of AD pathology may result in novel and effective treatments for AD.

  18. Bacterial sex in dental plaque

    Directory of Open Access Journals (Sweden)

    Ingar Olsen

    2013-06-01

    Full Text Available Genes are transferred between bacteria in dental plaque by transduction, conjugation, and transformation. Membrane vesicles can also provide a mechanism for horizontal gene transfer. DNA transfer is considered bacterial sex, but the transfer is not parallel to processes that we associate with sex in higher organisms. Several examples of bacterial gene transfer in the oral cavity are given in this review. How frequently this occurs in dental plaque is not clear, but evidence suggests that it affects a number of the major genera present. It has been estimated that new sequences in genomes established through horizontal gene transfer can constitute up to 30% of bacterial genomes. Gene transfer can be both inter- and intrageneric, and it can also affect transient organisms. The transferred DNA can be integrated or recombined in the recipient's chromosome or remain as an extrachromosomal inheritable element. This can make dental plaque a reservoir for antimicrobial resistance genes. The ability to transfer DNA is important for bacteria, making them better adapted to the harsh environment of the human mouth, and promoting their survival, virulence, and pathogenicity.

  19. Magnetite-Amyloid-β deteriorates activity and functional organization in an in vitro model for Alzheimer’s disease

    Science.gov (United States)

    Teller, Sara; Tahirbegi, Islam Bogachan; Mir, Mònica; Samitier, Josep; Soriano, Jordi

    2015-11-01

    The understanding of the key mechanisms behind human brain deterioration in Alzheimer’ disease (AD) is a highly active field of research. The most widespread hypothesis considers a cascade of events initiated by amyloid-β peptide fibrils that ultimately lead to the formation of the lethal amyloid plaques. Recent studies have shown that other agents, in particular magnetite, can also play a pivotal role. To shed light on the action of magnetite and amyloid-β in the deterioration of neuronal circuits, we investigated their capacity to alter spontaneous activity patterns in cultured neuronal networks. Using a versatile experimental platform that allows the parallel monitoring of several cultures, the activity in controls was compared with the one in cultures dosed with magnetite, amyloid-β and magnetite-amyloid-β complex. A prominent degradation in spontaneous activity was observed solely when amyloid-β and magnetite acted together. Our work suggests that magnetite nanoparticles have a more prominent role in AD than previously thought, and may bring new insights in the understanding of the damaging action of magnetite-amyloid-β complex. Our experimental system also offers new interesting perspectives to explore key biochemical players in neurological disorders through a controlled, model system manner.

  20. Partial Volume Correction in Quantitative Amyloid Imaging

    Science.gov (United States)

    Su, Yi; Blazey, Tyler M.; Snyder, Abraham Z.; Raichle, Marcus E.; Marcus, Daniel S.; Ances, Beau M.; Bateman, Randall J.; Cairns, Nigel J.; Aldea, Patricia; Cash, Lisa; Christensen, Jon J.; Friedrichsen, Karl; Hornbeck, Russ C.; Farrar, Angela M.; Owen, Christopher J.; Mayeux, Richard; Brickman, Adam M.; Klunk, William; Price, Julie C.; Thompson, Paul M.; Ghetti, Bernardino; Saykin, Andrew J.; Sperling, Reisa A.; Johnson, Keith A.; Schofield, Peter R.; Buckles, Virginia; Morris, John C.; Benzinger, Tammie. LS.

    2014-01-01

    Amyloid imaging is a valuable tool for research and diagnosis in dementing disorders. As positron emission tomography (PET) scanners have limited spatial resolution, measured signals are distorted by partial volume effects. Various techniques have been proposed for correcting partial volume effects, but there is no consensus as to whether these techniques are necessary in amyloid imaging, and, if so, how they should be implemented. We evaluated a two-component partial volume correction technique and a regional spread function technique using both simulated and human Pittsburgh compound B (PiB) PET imaging data. Both correction techniques compensated for partial volume effects and yielded improved detection of subtle changes in PiB retention. However, the regional spread function technique was more accurate in application to simulated data. Because PiB retention estimates depend on the correction technique, standardization is necessary to compare results across groups. Partial volume correction has sometimes been avoided because it increases the sensitivity to inaccuracy in image registration and segmentation. However, our results indicate that appropriate PVC may enhance our ability to detect changes in amyloid deposition. PMID:25485714

  1. Hacking the code of amyloid formation: the amyloid stretch hypothesis.

    Science.gov (United States)

    Pastor, M Teresa; Esteras-Chopo, Alexandra; Serrano, Luis

    2007-01-01

    Many research efforts in the last years have been directed towards understanding the factors determining protein misfolding and amyloid formation. Protein stability and amino acid composition have been identified as the two major factors in vitro. The research of our group has been focused on understanding the relationship between amino acid sequence and amyloid formation. Our approach has been the design of simple model systems that reproduce the biophysical properties of natural amyloids. An amyloid sequence pattern was extracted that can be used to detect amyloidogenic hexapeptide stretches in proteins. We have added evidence supporting that these amyloidogenic stretches can trigger amyloid formation by nonamyloidogenic proteins. Some experimental results in other amyloid proteins will be analyzed under the conclusions obtained in these studies. Our conclusions together with evidences from other groups suggest that amyloid formation is the result of the interplay between a decrease of protein stability, and the presence of highly amyloidogenic regions in proteins. As many of these results have been obtained in vitro, the challenge for the next years will be to demonstrate their validity in in vivo systems.

  2. Multimodality Intravascular Imaging Assessment of Plaque Erosion versus Plaque Rupture in Patients with Acute Coronary Syndrome

    Science.gov (United States)

    Kwon, Jee Eun; Mintz, Gary S.; Hong, Young Joon; Lee, Sung Yun; Kim, Ki Seok; Hahn, Joo-Yong; Kumar, Kaup Sharath; Won, Hoyoun; Hyeon, Seong Hyeop; Shin, Seung Yong; Lee, Kwang Je; Kim, Tae Ho; Kim, Chee Jeong; Kim, Sang Wook

    2016-01-01

    Background and Objectives We assessed plaque erosion of culprit lesions in patients with acute coronary syndrome in real world practice. Subjects and Methods Culprit lesion plaque rupture or plaque erosion was diagnosed with optical coherence tomography (OCT). Intravascular ultrasound (IVUS) was used to determine arterial remodeling. Positive remodeling was defined as a remodeling index (lesion/reference EEM [external elastic membrane area) >1.05. Results A total of 90 patients who had plaque rupture showing fibrous-cap discontinuity and ruptured cavity were enrolled. 36 patients showed definite OCT-plaque erosion, while 7 patients had probable OCT-plaque erosion. Overall, 26% (11/43) of definite/probable plaque erosion had non-ST elevation myocardial infarction (NSTEMI) while 35% (15/43) had ST elevation myocardial infarction (STEMI). Conversely, 14.5% (13/90) of plaque rupture had NSTEMI while 71% (64/90) had STEMI (p<0.0001). Among plaque erosion, white thrombus was seen in 55.8% (24/43) of patients and red thrombus in 27.9% (12/43) of patients. Compared to plaque erosion, plaque rupture more often showed positive remodeling (p=0.003) with a larger necrotic core area examined by virtual histology (VH)-IVUS, while negative remodeling was prominent in plaque erosion. Overall, 65% 28/43 of plaque erosions were located in the proximal 30 mm of a culprit vessel-similar to plaque ruptures (72%, 65/90, p=0.29). Conclusion Although most of plaque erosions show nearly normal coronary angiogram, modest plaque burden with negative remodeling and an uncommon fibroatheroma might be the nature of plaque erosion. Multimodality intravascular imaging with OCT and VH-IVUS showed fundamentally different pathoanatomic substrates underlying plaque rupture and erosion. PMID:27482258

  3. An assessment of the vulnerability of carotid plaques: a comparative study between intraplaque neovascularization and plaque echogenicity

    International Nuclear Information System (INIS)

    Carotid plaque echolucency as detected by Color Doppler ultrasonography (CDUS) has been used as a potential marker of plaque vulnerability. However, contrast-enhanced ultrasound (CEUS) has recently been shown to be a valuable method to evaluate the vulnerability and neovascularization within carotid atherosclerotic plaques. The aim of this study was to compare CEUS and CDUS in the assessment of plaque vulnerability using transcranial color Doppler (TCD) monitoring of microembolic signals (MES) as a reference technique. A total of 46 subjects with arterial stenosis (≥ 50%) underwent a carotid duplex ultrasound, TCD monitoring of MES and CEUS (SonoVue doses of 2.0 mL) within a span of 3 days. The agreement between the CEUS, CDUS, and MES findings was assessed with a chi-square test. A p-value less than 0.05 was considered statistically significant. Neovascularization was observed in 30 lesions (44.4%). The vascular risk factors for stroke were similar and there were no age or gender differences between the 2 groups. Using CEUS, MES were identified in 2 patients (12.5%) within class 1 (non-neovascularization) as opposed to 15 patients (50.0%) within class 2 (neovascularization) (p = 0.023). CDUS revealed no significant differences in the appearance of the MES between the 2 groups (hyperechoic and hypoechoic) (p = 0.237). This study provides preliminary evidence to suggest that intraplaque neovascularization detected by CEUS is associated with the presence of MESs, where as plaque echogenicity on traditional CDUS does not. These findings argue that CEUS may better identify high-risk plaques

  4. The effect of amyloid pathology and glucose metabolism on cortical volume loss over time in Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Adriaanse, Sofie M. [VU University Medical Center, Department of Radiology and Nuclear Medicine, Amsterdam (Netherlands); VU University Medical Center, Department of Radiology and Nuclear Medicine, Alzheimer Center, Neuroscience Campus Amsterdam, P.O. Box 7057, Amsterdam (Netherlands); Van Dijk, Koene R.A. [Harvard University, Department of Psychology, Center for Brain Science, Cambridge, MA (United States); Massachusetts General Hospital, Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA (United States); Ossenkoppele, Rik; Tolboom, Nelleke; Zwan, Marissa D.; Barkhof, Frederik; Berckel, Bart N.M. van [VU University Medical Center, Department of Radiology and Nuclear Medicine, Alzheimer Center, Neuroscience Campus Amsterdam, Amsterdam (Netherlands); Reuter, Martin [Massachusetts General Hospital, Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA (United States); Massachusetts Institute of Technology, Computer Science and Artificial Intelligence Laboratory, Division of Health Sciences and Technology, Cambridge, MA (United States); Yaqub, Maqsood; Boellaard, Ronald; Windhorst, Albert D.; Lammertsma, Adriaan A. [VU University Medical Center, Department of Radiology and Nuclear Medicine, Neuroscience Campus Amsterdam, Amsterdam (Netherlands); Flier, Wiesje M. van der; Scheltens, Philip [VU University Medical Center, Department of Neurology, Alzheimer Center, Neuroscience Campus Amsterdam, Amsterdam (Netherlands)

    2014-06-15

    The present multimodal neuroimaging study examined whether amyloid pathology and glucose metabolism are related to cortical volume loss over time in Alzheimer's disease (AD) patients and healthy elderly controls. Structural MRI scans of eleven AD patients and ten controls were available at baseline and follow-up (mean interval 2.5 years). Change in brain structure over time was defined as percent change of cortical volume within seven a-priori defined regions that typically show the strongest structural loss in AD. In addition, two PET scans were performed at baseline: [{sup 11}C]PIB to assess amyloidplaque load and [{sup 18}F]FDG to assess glucose metabolism. [{sup 11}C]PIB binding and [{sup 18}F]FDG uptake were measured in the precuneus, a region in which both amyloid deposition and glucose hypometabolism occur early in the course of AD. While amyloidplaque load at baseline was not related to cortical volume loss over time in either group, glucose metabolism within the group of AD patients was significantly related to volume loss over time (rho = 0.56, p < 0.05). The present study shows that in a group of AD patients amyloidplaque load as measured by [{sup 11}C]PIB behaves as a trait marker (i.e., all AD patients showed elevated levels of amyloid, not related to subsequent disease course), whilst hypometabolism as measured by [{sup 18}F]FDG changed over time indicating that it could serve as a state marker that is predictive of neurodegeneration. (orig.)

  5. The effect of amyloid pathology and glucose metabolism on cortical volume loss over time in Alzheimer's disease

    International Nuclear Information System (INIS)

    The present multimodal neuroimaging study examined whether amyloid pathology and glucose metabolism are related to cortical volume loss over time in Alzheimer's disease (AD) patients and healthy elderly controls. Structural MRI scans of eleven AD patients and ten controls were available at baseline and follow-up (mean interval 2.5 years). Change in brain structure over time was defined as percent change of cortical volume within seven a-priori defined regions that typically show the strongest structural loss in AD. In addition, two PET scans were performed at baseline: [11C]PIB to assess amyloidplaque load and [18F]FDG to assess glucose metabolism. [11C]PIB binding and [18F]FDG uptake were measured in the precuneus, a region in which both amyloid deposition and glucose hypometabolism occur early in the course of AD. While amyloidplaque load at baseline was not related to cortical volume loss over time in either group, glucose metabolism within the group of AD patients was significantly related to volume loss over time (rho = 0.56, p 11C]PIB behaves as a trait marker (i.e., all AD patients showed elevated levels of amyloid, not related to subsequent disease course), whilst hypometabolism as measured by [18F]FDG changed over time indicating that it could serve as a state marker that is predictive of neurodegeneration. (orig.)

  6. Effect of Root Surface Iron Plaque on Se Translocation and Uptake by Fe-Deficient Rice

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Under anaerobic conditions, ferric hydroxide deposits on the surface of rice roots and affects uptake and translocation of certain nutrients. In the present study, rice plants were cultured in Fe-deficient or sufficient solutions and placed in a medium containing selenium (Se) for 2 h. Then, FeSO4 was added at the various concentrations of 0, 10, 40, or 70mg L-1 to induce varying levels of iron plaque on the root surfaces and subsequent uptake of Se was monitored. The uptake of Se was inhibited by the iron plaque, with the effect proportional to the amount of plaque induced. The activity of cysteine synthase was decreased with increasing amounts of iron plaque on the roots. This may be the important reason for iron plaque inhibition of Se translocation. At each level of iron plaque, Fe-deficient rice had more Se than Fe-sufficient rice. Furthermore, with plaque induced by 20 mg Fe L-1, plants from Fe-deficient media accumulated more Se than those from Fe-sufficient media, as the Se concentration was increased from 10 to 30 or 50 mg L-1. We found that phytosiderophores, highly effective iron chelating agents, could desorb selenite from ferrihydrite. Root exudates of the Fe-deficient rice, especially phytosiderophores in the exudates, could enhance Se uptake by rice plants with iron plaque.

  7. Serum amyloid P component scintigraphy in familial amyloid polyneuropathy: regression of visceral amyloid following liver transplantation

    International Nuclear Information System (INIS)

    Familial amyloid polyneuropathy (FAP) associated with transthyretin (TTR) mutations is the commonest type of hereditary amyloidosis. Plasma TTR is produced almost exclusively in the liver and orthotopic liver transplantation is the only available treatment, although the clinical outcome varies. Serum amyloid P component (SAP) scintigraphy is a method for identifying and quantitatively monitoring amyloid deposits in vivo, but it has not previously been used to study the outcome of visceral amyloid deposits in FAP following liver transplantation. Whole body scintigraphy following injection of iodine-123 labelled SAP was performed in 17 patients with FAP associated with TTR Met30 and in five asymptomatic gene carriers. Follow-up studies were performed in ten patients, eight of whom had undergone orthotopic liver transplantation 1-5 years beforehand. There was abnormal uptake of 123I-SAP in all FAP patients, including the kidneys in each case, the spleen in five cases and the adrenal glands in three cases. Renal amyloid deposits were also present in three of the asymptomatic carriers. Follow-up studies 1-5 years after liver transplantation showed that there had been substantial regression of the visceral amyloid deposits in two patients and modest improvement in three cases. The amyloid deposits were unchanged in two patients. In conclusion, 123I-SAP scintigraphy identified unsuspected visceral amyloid in each patient with FAP due to TTR Met30. The universal presence of renal amyloid probably underlies the high frequency of renal failure that occurs in FAP following liver transplantation. The variable capacity of patients to mobilise amyloid deposits following liver transplantation may contribute to their long-term clinical outcome. (orig.)

  8. Serum amyloid P component scintigraphy in familial amyloid polyneuropathy: regression of visceral amyloid following liver transplantation

    Energy Technology Data Exchange (ETDEWEB)

    Rydh, A.; Hietala, S.O.; Aahlstroem, K.R. [Department of Diagnostic Radiology, University Hospital of Northern Sweden, Umeaa (Sweden); Suhr, O. [Department of Internal Medicine, University Hospital of Northern Sweden, Umeaa (Sweden); Pepys, M.B.; Hawkins, P.N. [Immunological Medicine Unit, Department of Medicine, Imperial College School of Medicine, London (United Kingdom)

    1998-07-01

    Familial amyloid polyneuropathy (FAP) associated with transthyretin (TTR) mutations is the commonest type of hereditary amyloidosis. Plasma TTR is produced almost exclusively in the liver and orthotopic liver transplantation is the only available treatment, although the clinical outcome varies. Serum amyloid P component (SAP) scintigraphy is a method for identifying and quantitatively monitoring amyloid deposits in vivo, but it has not previously been used to study the outcome of visceral amyloid deposits in FAP following liver transplantation. Whole body scintigraphy following injection of iodine-123 labelled SAP was performed in 17 patients with FAP associated with TTR Met30 and in five asymptomatic gene carriers. Follow-up studies were performed in ten patients, eight of whom had undergone orthotopic liver transplantation 1-5 years beforehand. There was abnormal uptake of {sup 123}I-SAP in all FAP patients, including the kidneys in each case, the spleen in five cases and the adrenal glands in three cases. Renal amyloid deposits were also present in three of the asymptomatic carriers. Follow-up studies 1-5 years after liver transplantation showed that there had been substantial regression of the visceral amyloid deposits in two patients and modest improvement in three cases. The amyloid deposits were unchanged in two patients. In conclusion, {sup 123}I-SAP scintigraphy identified unsuspected visceral amyloid in each patient with FAP due to TTR Met30. The universal presence of renal amyloid probably underlies the high frequency of renal failure that occurs in FAP following liver transplantation. The variable capacity of patients to mobilise amyloid deposits following liver transplantation may contribute to their long-term clinical outcome. (orig.) With 2 figs., 2 tabs., 22 refs.

  9. Advances in the pathogenesis of Alzheimer’s disease: a re-evaluation of amyloid cascade hypothesis

    Directory of Open Access Journals (Sweden)

    Dong Suzhen

    2012-09-01

    Full Text Available Abstract Alzheimer’s disease (AD is a common neurodegenerative disease characterized clinically by progressive deterioration of memory, and pathologically by histopathological changes including extracellular deposits of amyloid-beta (A-beta peptides forming senile plaques (SP and the intracellular neurofibrillary tangles (NFT of hyperphosphorylated tau in the brain. This review focused on the new developments of amyloid cascade hypothesis with details on the production, metabolism and clearance of A-beta, and the key roles of some important A-beta-related genes in the pathological processes of AD. The most recent research advances in genetics, neuropathology and pathogenesis of the disease were also discussed.

  10. Calcium-enhanced aggregation of serum amyloid P component and its inhibition by the ligands heparin and heparan sulphate. An electron microscopic and immunoelectrophoretic study

    DEFF Research Database (Denmark)

    Nielsen, EH; Sørensen, Inge Juul; Vilsgaard, K;

    1994-01-01

    -like structures were formed already at 2 mM calcium. At 25 mM calcium, large aggregates with a crystalline array occasionally exhibiting cylinders predominated. Binding of the ligands heparin and heparan sulphate to SAP completely abolished the calcium-enhanced aggregation, but the distribution of the SAP...... in the absence of calcium ions. However, aggregation is greatly enhanced even at low concentrations (2 mM) of calcium. SAP's tendency to self-aggregation is abolished after its binding to heparin or heparin sulphate. Furthermore, our TEM studies indicate that purified human SAP freed of its natural ligands has...

  11. Probing amyloid-β pathology in transgenic Alzheimer's disease (tgArcSwe) mice using MALDI imaging mass spectrometry.

    Science.gov (United States)

    Carlred, Louise; Michno, Wojciech; Kaya, Ibrahim; Sjövall, Peter; Syvänen, Stina; Hanrieder, Jörg

    2016-08-01

    The pathological mechanisms underlying Alzheimer's disease (AD) are still not understood. The disease pathology is characterized by the accumulation and aggregation of amyloid-β (Aβ) peptides into extracellular plaques, however the factors that promote neurotoxic Aβ aggregation remain elusive. Imaging mass spectrometry (IMS) is a powerful technique to comprehensively elucidate the spatial distribution patterns of lipids, peptides and proteins in biological tissues. In the present study, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS)-based imaging was used to study Aβ deposition in transgenic mouse brain tissue and to elucidate the plaque-associated chemical microenvironment. The imaging experiments were performed in brain sections of transgenic Alzheimer's disease mice carrying the Arctic and Swedish mutation of amyloid-beta precursor protein (tgArcSwe). Multivariate image analysis was used to interrogate the IMS data for identifying pathologically relevant, anatomical features based on their chemical identity. This include cortical and hippocampal Aβ deposits, whose amyloid peptide content was further verified using immunohistochemistry and laser microdissection followed by MALDI MS analysis. Subsequent statistical analysis on spectral data of regions of interest revealed brain region-specific differences in Aβ peptide aggregation. Moreover, other plaque-associated protein species were identified including macrophage migration inhibitory factor suggesting neuroinflammatory processes and glial cell reactivity to be involved in AD pathology. The presented data further highlight the potential of IMS as a powerful approach in neuropathology. Hanrieder et al. described an imaging mass spectrometry based study on comprehensive spatial profiling of C-terminally truncated Aβ species within individual plaques in tgArcSwe mice. Here, brain region-dependent differences in Aβ truncation and other plaque-associated proteins, such as

  12. Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer's disease.

    Science.gov (United States)

    Rodriguez-Vieitez, Elena; Saint-Aubert, Laure; Carter, Stephen F; Almkvist, Ove; Farid, Karim; Schöll, Michael; Chiotis, Konstantinos; Thordardottir, Steinunn; Graff, Caroline; Wall, Anders; Långström, Bengt; Nordberg, Agneta

    2016-03-01

    Alzheimer's disease is a multifactorial dementia disorder characterized by early amyloid-β, tau deposition, glial activation and neurodegeneration, where the interrelationships between the different pathophysiological events are not yet well characterized. In this study, longitudinal multitracer positron emission tomography imaging of individuals with autosomal dominant or sporadic Alzheimer's disease was used to quantify the changes in regional distribution of brain astrocytosis (tracer (11)C-deuterium-L-deprenyl), fibrillar amyloidplaque deposition ((11)C-Pittsburgh compound B), and glucose metabolism ((18)F-fluorodeoxyglucose) from early presymptomatic stages over an extended period to clinical symptoms. The 52 baseline participants comprised autosomal dominant Alzheimer's disease mutation carriers (n = 11; 49.6 ± 10.3 years old) and non-carriers (n = 16; 51.1 ± 14.2 years old; 10 male), and patients with sporadic mild cognitive impairment (n = 17; 61.9 ± 6.4 years old; nine male) and sporadic Alzheimer's disease (n = 8; 63.0 ± 6.5 years old; five male); for confidentiality reasons, the gender of mutation carriers is not revealed. The autosomal dominant Alzheimer's disease participants belonged to families with known mutations in either presenilin 1 (PSEN1) or amyloid precursor protein (APPswe or APParc) genes. Sporadic mild cognitive impairment patients were further divided into (11)C-Pittsburgh compound B-positive (n = 13; 62.0 ± 6.4; seven male) and (11)C-Pittsburgh compound B-negative (n = 4; 61.8 ± 7.5 years old; two male) groups using a neocortical standardized uptake value ratio cut-off value of 1.41, which was calculated with respect to the cerebellar grey matter. All baseline participants underwent multitracer positron emission tomography scans, cerebrospinal fluid biomarker analysis and neuropsychological assessment. Twenty-six of the participants underwent clinical and imaging follow-up examinations after 2.8 ± 0.6 years. By using linear

  13. Non-plaque-induced gingival lesions

    DEFF Research Database (Denmark)

    Holmstrup, P

    1999-01-01

    The origin of gingival inflammation is occasionally different from that of routine plaque-associated gingivitis, and such non-plaque-associated types of gingivitis often present characteristic clinical features. Examples of such forms of gingivitis are specific bacterial, viral, and fungal infect......-plaque induced gingival inflammation can be caused by allergic reactions to dental restorative materials, toothpastes, mouthwashes, and foods. In addition, gingival inflammation may result from toxic reactions, foreign body reactions, or mechanical and thermal trauma....

  14. Interactions of laminin with the amyloid ß peptide: Implications for Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Morgan C.

    2001-01-01

    Full Text Available Extensive neuronal cell loss is observed in Alzheimer's disease. Laminin immunoreactivity colocalizes with senile plaques, the characteristic extracellular histopathological lesions of Alzheimer brain, which consist of the amyloid ß (Aß peptide polymerized into amyloid fibrils. These lesions have neurotoxic effects and have been proposed to be a main cause of neurodegeneration. In order to understand the pathological significance of the interaction between laminin and amyloid, we investigated the effect of laminin on amyloid structure and toxicity. We found that laminin interacts with the Aß1-40 peptide, blocking fibril formation and even inducing depolymerization of preformed fibrils. Protofilaments known to be intermediate species of Aß fibril formation were also detected as intermediate species of laminin-induced Aß fibril depolymerization. Moreover, laminin-amyloid interactions inhibited the toxic effects on rat primary hippocampal neurons. As a whole, our results indicate a putative anti-amyloidogenic role of laminin which may be of biological and therapeutic interest for controlling amyloidosis, such as those observed in cerebral angiopathy and Alzheimer's disease.

  15. A chemical analog of curcumin as an improved inhibitor of amyloid Abeta oligomerization.

    Directory of Open Access Journals (Sweden)

    Robert A Orlando

    Full Text Available Amyloid-like plaques are characteristic lesions defining the neuropathology of Alzheimer's disease (AD. The size and density of these plaques are closely associated with cognitive decline. To combat this disease, the few therapies that are available rely on drugs that increase neurotransmission; however, this approach has had limited success as it has simply slowed an imminent decline and failed to target the root cause of AD. Amyloid-like deposits result from aggregation of the Aβ peptide, and thus, reducing amyloid burden by preventing Aβ aggregation represents an attractive approach to improve the therapeutic arsenal for AD. Recent studies have shown that the natural product curcumin is capable of crossing the blood-brain barrier in the CNS in sufficient quantities so as to reduce amyloid plaque burden. Based upon this bioactivity, we hypothesized that curcumin presents molecular features that make it an excellent lead compound for the development of more effective inhibitors of Aβ aggregation. To explore this hypothesis, we screened a library of curcumin analogs and identified structural features that contribute to the anti-oligomerization activity of curcumin and its analogs. First, at least one enone group in the spacer between aryl rings is necessary for measureable anti-Aβ aggregation activity. Second, an unsaturated carbon spacer between aryl rings is essential for inhibitory activity, as none of the saturated carbon spacers showed any margin of improvement over that of native curcumin. Third, methoxyl and hydroxyl substitutions in the meta- and para-positions on the aryl rings appear necessary for some measure of improved inhibitory activity. The best lead inhibitors have either their meta- and para-substituted methoxyl and hydroxyl groups reversed from that of curcumin or methoxyl or hydroxyl groups placed in both positions. The simple substitution of the para-hydroxy group on curcumin with a methoxy substitution improved

  16. Differential X-ray phase contrast tomography of Alzheimer plaques in mouse models: perspectives for drug development and clinical imaging techniques

    Science.gov (United States)

    Pinzer, B. R.; Cacquevel, M.; Modregger, P.; Thuering, T.; Stampanoni, M.

    2013-05-01

    Alzheimer's disease (AD) is a looming threat on an ever-ageing population, with devastating effects on the human intellect. A particular characteristic lesion — the extracellular amyloid plaque — accumulates in the brain of AD patients during the course of the disease, and could therefore be used to monitor the progression of the disease, years before the first neurological symptoms appear. In addition, strategies for drug intervention in AD are often based on amyloid reduction, since amyloid plaques are hypothesized to be involved in a chain of reactions leading to the death of neurons. Developments in both fields would benefit from a microscopic technique that is capable of single plaque imaging, ideally in 3D. While such a non-destructive, single-plaque imaging technique does not yet exist for humans, it has been recently shown that synchrotron based differential X-ray phase contrast imaging can be used to visualize individual plaques at μm resolution in mouse models of AD ex-vivo. This method, which relies on a grating interferometer to measure refraction angles induced by fluctuations in the refractive index, yields a precise three-dimensional distribution of single plaques. These data could not only improve the understanding of the evolution of AD or the effectiveness of drugs, but could also help to improve reliable markers for current and future non-invasive clinical imaging techniques. In particular, validation of PET markers with small animal models could be rapidly carried out by co-registration of PET and DPC signals.

  17. Association between amylin and amyloid-β peptides in plasma in the context of apolipoprotein E4 allele.

    Science.gov (United States)

    Qiu, Wei Qiao; Wallack, Max; Dean, Michael; Liebson, Elizabeth; Mwamburi, Mkaya; Zhu, Haihao

    2014-01-01

    Amylin, a pancreatic peptide that readily crosses the blood brain barrier (BBB), and amyloid-beta peptide (Aβ), the main component of amyloid plaques and a major component of Alzheimer's disease (AD) pathology in the brain, share several features. These include having similar β-sheet secondary structures, binding to the same receptor, and being degraded by the same protease. Thus, amylin may be associated with Aβ, but the nature of their relationship remains unclear. In this study, we used human samples to study the relationship between plasma amylin and Aβ in the context of the apolipoprotein E alleles (ApoE). We found that concentrations of Aβ1-42 (PApoE4, BMI, diabetes, stroke, kidney function and lipid profile. This positive association between amylin and Aβ1-42 in plasma was found regardless of the ApoE genotype. In contrast, the relationship between amylin and Aβ1-40 in plasma seen in ApoE4 non-carriers disappeared in the presence of ApoE4. Using AD mouse models, our recent study demonstrates that intraperitoneal (i.p.) injection of synthetic amylin enhances the removal of Aβ from the brain into blood, thus resulting in increased blood levels of both amylin and Aβ. The positive association between amylin and Aβ, especially Aβ1-42, in human blood samples is probably relevant to the findings in the AD mouse models. The presence of ApoE4 may attenuate amylin's capacity to remove Aβ, especially Aβ1-40, from the AD brain.

  18. Current status of vulnerable plaque detection.

    LENUS (Irish Health Repository)

    Sharif, Faisal

    2012-02-01

    Critical coronary stenoses have been shown to contribute to only a minority of acute coronary syndromes (ACS) and sudden cardiac death. Autopsy studies have identified a subgroup of high-risk patients with disrupted vulnerable plaque and modest stenosis. Consequently, a clinical need exists to develop methods to identify these plaques prospectively before disruption and clinical expression of disease. Recent advances in invasive and noninvasive imaging techniques have shown the potential to identify these high-risk plaques. The anatomical characteristics of the vulnerable plaque such as thin cap fibroatheroma and lipid pool can be identified with angioscopy, high frequency intravascular ultrasound, intravascular MRI, and optical coherence tomography. Efforts have also been made to recognize active inflammation in high-risk plaques using intravascular thermography. Plaque chemical composition by measuring electromagnetic radiation using spectroscopy is also an emerging technology to detect vulnerable plaques. Noninvasive imaging with MRI, CT, and PET also holds the potential to differentiate between low and high-risk plaques. However, at present none of these imaging modalities are able to detect vulnerable plaque neither has been shown to definitively predict outcome. Nevertheless in contrast, there has been a parallel development in the physiological assessment of advanced atherosclerotic coronary artery disease. Thus recent trials using fractional flow reserve in patients with modest non flow-limiting stenoses have shown that deferral of PCI with optimal medical therapy in these patients is superior to coronary intervention. Further trials are needed to provide more information regarding the natural history of high-risk but non flow-limiting plaque to establish patient-specific targeted therapy and to refine plaque stabilizing strategies in the future.

  19. Oral biofilm models for mechanical plaque removal

    NARCIS (Netherlands)

    Verkaik, Martinus J.; Busscher, Henk J.; Rustema-Abbing, Minie; Slomp, Anje M.; Abbas, Frank; van der Mei, Henny C.

    2010-01-01

    In vitro plaque removal studies require biofilm models that resemble in vivo dental plaque. Here, we compare contact and non-contact removal of single and dual-species biofilms as well as of biofilms grown from human whole saliva in vitro using different biofilm models. Bacteria were adhered to a sa

  20. Towards a Pharmacophore for Amyloid

    Energy Technology Data Exchange (ETDEWEB)

    Landau, Meytal; Sawaya, Michael R.; Faull, Kym F.; Laganowsky, Arthur; Jiang, Lin; Sievers, Stuart A.; Liu, Jie; Barrio, Jorge R.; Eisenberg, David (UCLA)

    2011-09-16

    Diagnosing and treating Alzheimer's and other diseases associated with amyloid fibers remains a great challenge despite intensive research. To aid in this effort, we present atomic structures of fiber-forming segments of proteins involved in Alzheimer's disease in complex with small molecule binders, determined by X-ray microcrystallography. The fiber-like complexes consist of pairs of {beta}-sheets, with small molecules binding between the sheets, roughly parallel to the fiber axis. The structures suggest that apolar molecules drift along the fiber, consistent with the observation of nonspecific binding to a variety of amyloid proteins. In contrast, negatively charged orange-G binds specifically to lysine side chains of adjacent sheets. These structures provide molecular frameworks for the design of diagnostics and drugs for protein aggregation diseases. The devastating and incurable dementia known as Alzheimer's disease affects the thinking, memory, and behavior of dozens of millions of people worldwide. Although amyloid fibers and oligomers of two proteins, tau and amyloid-{beta}, have been identified in association with this disease, the development of diagnostics and therapeutics has proceeded to date in a near vacuum of information about their structures. Here we report the first atomic structures of small molecules bound to amyloid. These are of the dye orange-G, the natural compound curcumin, and the Alzheimer's diagnostic compound DDNP bound to amyloid-like segments of tau and amyloid-{beta}. The structures reveal the molecular framework of small-molecule binding, within cylindrical cavities running along the {beta}-spines of the fibers. Negatively charged orange-G wedges into a specific binding site between two sheets of the fiber, combining apolar binding with electrostatic interactions, whereas uncharged compounds slide along the cavity. We observed that different amyloid polymorphs bind different small molecules, revealing that a

  1. Network structure of the mussel plaque and its significance for load bearing and adhesion

    Science.gov (United States)

    Filippidi, Emmanouela; Kim, Juntae; Waite, J. Herbert; Helgeson, Matthew; Valentine, Megan T.

    2015-03-01

    Marine mussels attach to rocks, each other, and a variety of surfaces via a flat, wide plaque that is interpenetrated by the collagen fibers of a thin, long thread that connects the plaque to the mussel body. The unusually strong adhesion of the plaque has long been attributed to the molecular design of its adhesive proteins that can form a variety of strong chemical bonds. However, the molecular energies for de-adhesion are orders of magnitude smaller than the macroscopic energies measured. We propose that the mesoscopic design of the plaque is critical in enhancing load bearing and eventually adhesion. We present new results on the structure of the plaque studied via electron microscopy and neutron scattering that exhibit a plaque geometry reminiscent of structural foams. Our studies reveal a collection of pores with an inner network, further connected with an outer network. The final structure can be described by two length scales. A synthetic soft system is constructed in an effort to mimic the two-lengthscale structure of the natural plaques. The structure of the native and synthetic systems is compared with the ultimate goal of evaluating the importance of the mesoscopic structure to mechanics and adhesion. NSF MRSEC IRG-I.

  2. The Luminescent Oligothiophene p-FTAA Converts Toxic Aβ1-42 Species into Nontoxic Amyloid Fibers with Altered Properties.

    Science.gov (United States)

    Civitelli, Livia; Sandin, Linnea; Nelson, Erin; Khattak, Sikander Iqbal; Brorsson, Ann-Christin; Kågedal, Katarina

    2016-04-22

    Aggregation of the amyloid-β peptide (Aβ) in the brain leads to the formation of extracellular amyloid plaques, which is one of the pathological hallmarks of Alzheimer disease (AD). It is a general hypothesis that soluble prefibrillar assemblies of the Aβ peptide, rather than mature amyloid fibrils, cause neuronal dysfunction and memory impairment in AD. Thus, reducing the level of these prefibrillar species by using molecules that can interfere with the Aβ fibrillation pathway may be a valid approach to reduce Aβ cytotoxicity. Luminescent-conjugated oligothiophenes (LCOs) have amyloid binding properties and spectral properties that differ when they bind to protein aggregates with different morphologies and can therefore be used to visualize protein aggregates. In this study, cell toxicity experiments and biophysical studies demonstrated that the LCO p-FTAA was able to reduce the pool of soluble toxic Aβ species in favor of the formation of larger insoluble nontoxic amyloid fibrils, there by counteracting Aβ-mediated cytotoxicity. Moreover, p-FTAA bound to early formed Aβ species and induced a rapid formation of β-sheet structures. These p-FTAA generated amyloid fibrils were less hydrophobic and more resistant to proteolysis by proteinase K. In summary, our data show that p-FTAA promoted the formation of insoluble and stable Aβ species that were nontoxic which indicates that p-FTAA might have therapeutic potential. PMID:26907684

  3. PLAQUE ASSAY OF NEWCASTLE DISEASE VIRUS

    Directory of Open Access Journals (Sweden)

    B. Sardjono

    2012-09-01

    Full Text Available The Newcastle disease virus (NDV was isolated from a 3 months-old indigenous chicken (buras or kampung chicken which showed clinical signs of Newcastle disease (ND. For viral isolation a small part of the spleen and lung were inoculated into 10 days-old embryonated chicken eggs. The physical characteristics of the isolate (A/120 were studied. The hemagglutination of chicken red blood cell showed slow elution, thermostability of hemagglutinin at 56°C was 120 minutes. The vims was able to agglutinate horse erythrocytes but not those of sheep. The biological characteristics on mean death time (MDT of embryonated chicken egg and plaque morphology on chicken embryo fibroblast (CEF primary cell cultures were studied. The MDT was 56 hours, the isolate was velogenic NDV. There were three different plaque morphologies on CEF : 2 mm clear plaques, 1 mm clear plaques, and minute clear plaques which were visible only with microscopic examination.

  4. FKBP12 regulates the localization and processing of amyloid precursor protein in human cell lines

    Indian Academy of Sciences (India)

    Fan-Lun Liu; Ting-Yi Liu; Fan-Lu Kung

    2014-03-01

    One of the pathological hallmarks of Alzheimer’s disease is the presence of insoluble extracellular amyloid plaques. These plaques are mainly constituted of amyloid beta peptide (A), a proteolytic product of amyloid precursor protein (APP). APP processing also generates the APP intracellular domain (AICD). We have previously demonstrated that AICD interacts with FKBP12, a peptidyl-prolyl cis-trans isomerase (PPIase) ubiquitous in nerve systems. This interaction was interfered by FK506, a clinically used immunosuppressant that has recently been reported to be neuroprotective. To elucidate the roles of FKBP12 in the pathogenesis of Alzheimer’s disease, the effect of FKBP12 overexpression on APP processing was evaluated. Our results revealed that APP processing was shifted towards the amyloidogenic pathway, accompanied by a change in the subcellular localization of APP, upon FKBP12 overexpression. This FKBP12-overexpression-induced effect was reverted by FK506. These findings support our hypothesis that FKBP12 may participate in the regulation of APP processing. FKBP12 overexpression may lead to the stabilization of a certain isomer (presumably the cis form) of the Thr668-Pro669 peptide bond in AICD, therefore change its affinity to flotillin-1 or other raft-associated proteins, and eventually change the localization pattern and cause a shift in the proteolytic processing of APP.

  5. Proliferation in the Alzheimer Hippocampus Is due to Microglia, Not Astroglia, and Occurs at Sites of Amyloid Deposition

    Directory of Open Access Journals (Sweden)

    Michael W. Marlatt

    2014-01-01

    Full Text Available Microglia and astrocytes contribute to Alzheimer’s disease (AD etiology and may mediate early neuroinflammatory responses. Despite their possible role in disease progression and despite the fact that they can respond to amyloid deposition in model systems, little is known about whether astro- or microglia can undergo proliferation in AD and whether this is related to the clinical symptoms or to local neuropathological changes. Previously, proliferation was found to be increased in glia-rich regions of the presenile hippocampus. Since their phenotype was unknown, we here used two novel triple-immunohistochemical protocols to study proliferation in astro- or microglia in relation to amyloid pathology. We selected different age-matched cohorts to study whether proliferative changes relate to clinical severity or to neuropathological changes. Proliferating cells were found across the hippocampus but never in mature neurons or astrocytes. Almost all proliferating cells were colabeled with Iba1+, indicating that particularly microglia contribute to proliferation in AD. Proliferating Iba1+ cells was specifically seen within the borders of amyloid plaques, indicative of an active involvement in, or response to, plaque accumulation. Thus, consistent with animal studies, proliferation in the AD hippocampus is due to microglia, occurs in close proximity of plaque pathology, and may contribute to the neuroinflammation common in AD.

  6. Porcine prion protein amyloid.

    Science.gov (United States)

    Hammarström, Per; Nyström, Sofie

    2015-01-01

    Mammalian prions are composed of misfolded aggregated prion protein (PrP) with amyloid-like features. Prions are zoonotic disease agents that infect a wide variety of mammalian species including humans. Mammals and by-products thereof which are frequently encountered in daily life are most important for human health. It is established that bovine prions (BSE) can infect humans while there is no such evidence for any other prion susceptible species in the human food chain (sheep, goat, elk, deer) and largely prion resistant species (pig) or susceptible and resistant pets (cat and dogs, respectively). PrPs from these species have been characterized using biochemistry, biophysics and neurobiology. Recently we studied PrPs from several mammals in vitro and found evidence for generic amyloidogenicity as well as cross-seeding fibril formation activity of all PrPs on the human PrP sequence regardless if the original species was resistant or susceptible to prion disease. Porcine PrP amyloidogenicity was among the studied. Experimentally inoculated pigs as well as transgenic mouse lines overexpressing porcine PrP have, in the past, been used to investigate the possibility of prion transmission in pigs. The pig is a species with extraordinarily wide use within human daily life with over a billion pigs harvested for human consumption each year. Here we discuss the possibility that the largely prion disease resistant pig can be a clinically silent carrier of replicating prions.

  7. The polyphenol oleuropein aglycone protects TgCRND8 mice against Aß plaque pathology.

    Directory of Open Access Journals (Sweden)

    Cristina Grossi

    Full Text Available The claimed beneficial effects of the Mediterranean diet include prevention of several age-related dysfunctions including neurodegenerative diseases and Alzheimer-like pathology. These effects have been related to the protection against cognitive decline associated with aging and disease by a number of polyphenols found in red wine and extra virgin olive oil. The double transgenic TgCRND8 mice (overexpressing the Swedish and Indiana mutations in the human amyloid precursor protein, aged 1.5 and 4, and age-matched wild type control mice were used to examine in vivo the effects of 8 weeks dietary supplementation of oleuropein aglycone (50 mg/kg of diet, the main polyphenol found in extra virgin olive oil. We report here that dietary supplementation of oleuropein aglycone strongly improves the cognitive performance of young/middle-aged TgCRND8 mice, a model of amyloid-ß deposition, respect to age-matched littermates with un-supplemented diet. Immunofluorescence analysis of cerebral tissue in oleuropein aglycone-fed transgenic mice showed remarkably reduced ß-amyloid levels and plaque deposits, which appeared less compact and "fluffy"; moreover, microglia migration to the plaques for phagocytosis and a remarkable reduction of the astrocyte reaction were evident. Finally, oleuropein aglycone-fed mice brain displayed an astonishingly intense autophagic reaction, as shown by the increase of autophagic markers expression and of lysosomal activity. Data obtained with cultured cells confirmed the latter evidence, suggesting mTOR regulation by oleuropein aglycone. Our results support, and provide mechanistic insights into, the beneficial effects against Alzheimer-associated neurodegeneration of a polyphenol enriched in the extra virgin olive oil, a major component of the Mediterranean diet.

  8. The desmosomal plaque and the cytoskeleton.

    Science.gov (United States)

    Franke, W W; Cowin, P; Schmelz, M; Kapprell, H P

    1987-01-01

    Two major plasma membrane domains are involved in the architectural organization of the cytoskeleton. Both are junctions of the adherens category characterized by the presence of dense plaques associated with the cytoplasmic surface of their membranes. The plaques serve as specific anchorage structures for two different types of cytoplasmic filaments. Intermediate-sized filaments (IF) of several types, i.e. cytokeratin IF in epithelial cells, desmin IF in cardiac myocytes and vimentin IF in arachnoidal cells of meninges, meningiomas and several other cells, attach to the desmosomal plaques, whereas actin-containing microfilaments associate with non-desmosomal adhering junctions such as the zonula adherens, fascia adherens and punctum adherens. The plaques of both kinds of adhering junctions contain a common acidic polypeptide of Mr 83,000 identical to 'band 5 protein' of bovine snout epidermal desmosomes. However, other plaque components are mutually exclusive to one of the two subclasses of adhering junctions. The desmosomal plaque structure, which does not contain vinculin and alpha-actinin, comprises representatives of cytoplasmic, non-membrane-integrated proteins such as desmoplakin(s) and the cytoplasmic portions of transmembrane glycoproteins such as 'band 3 glycoprotein'. The analysis of both categories of junction-associated plaques should provide a basis for understanding the establishment and the dynamics of junction-cytoskeleton interaction.

  9. Multidetector row computed tomography may accurately estimate plaque vulnerability. Does MDCT accurately estimate plaque vulnerability? (Pro)

    International Nuclear Information System (INIS)

    Over the past decade, multidetector row computed tomography (MDCT) has become the most reliable and established of the noninvasive examination techniques for detecting coronary heart disease. Now MDCT is chasing intravascular ultrasound (IVUS) in terms of spatial resolution. Among the components of vulnerable plaque, MDCT may detect lipid-rich plaque, the lipid pool, and calcified spots using computed tomography number. Plaque components are detected by MDCT with high accuracy compared with IVUS and angioscopy when assessing vulnerable plaque. The TWINS study and TOGETHAR trial demonstrated that angioscopic loss of yellow color occurred independently of volumetric plaque change by statin therapy. These 2 studies showed that plaque stabilization and regression reflect independent processes mediated by different mechanisms and time course. Noncalcified plaque and/or low-density plaque was found to be the strongest predictor of cardiac events, regardless of lesion severity, and act as a potential marker of plaque vulnerability. MDCT may be an effective tool for early triage of patients with chest pain who have a normal electrocardiogram (ECG) and cardiac enzymes in the emergency department. MDCT has the potential ability to analyze coronary plaque quantitatively and qualitatively if some problems are resolved. MDCT may become an essential tool for detecting and preventing coronary artery disease in the future. (author)

  10. Aβ-40 Y10F Increases βfibrils Formation but Attenuates the Neurotoxicity of Amyloid-β Peptide

    Directory of Open Access Journals (Sweden)

    Zhaofeng Jiang

    2012-04-01

    Full Text Available Alzheimer’s disease (AD is characterized by the abnormal aggregation of amyloid-β peptide (Aβ in extracellular deposits known as senile plaques. The tyrosine residue (Tyr-10 is believed to be important in Aβ-induced neurotoxicity due to the formation of tyrosyl radicals. To reduce the likelihood of cross-linking, here we designed an Aβ-40 analogue (Aβ-40 Y10F in which the tyrosine residue was substituted by a structurally similar residue, phenylalanine. The aggregation rate was determined by the Thioflavin T (ThT assay, in which Aβ-40 Y10F populated an ensemble of folded conformations much quicker and stronger than the wild type Aβ. Biophysical tests subsequently confirmed the results of the ThT assay, suggesting the measured increase of β-aggregation may arise predominantly from enhancement of hydrophobicity upon substitution and thus the propensity of intrinsic β-sheet formation. Nevertheless, Aβ-40 Y10F exhibited remarkably decreased neurotoxicity compared to Aβ-40 which could be partly due to the reduced generation of hydrogen peroxide. These findings may lead to further understanding of the structural perturbation of Aβ to its fibrillation.

  11. Multiple low-dose infusions of human umbilical cord blood cells improve cognitive impairments and reduce amyloid-β-associated neuropathology in Alzheimer mice.

    Science.gov (United States)

    Darlington, Donna; Deng, Juan; Giunta, Brian; Hou, Huayan; Sanberg, Cyndy D; Kuzmin-Nichols, Nicole; Zhou, Hua-Dong; Mori, Takashi; Ehrhart, Jared; Sanberg, Paul R; Tan, Jun

    2013-02-01

    Alzheimer's disease (AD) is the most common progressive age-related dementia in the elderly and the fourth major cause of disability and mortality in that population. The disease is pathologically characterized by deposition of β-amyloid plaques neurofibrillary tangles in the brain. Current strategies for the treatment of AD are symptomatic only. As such, they are less than efficacious in terms of significantly slowing or halting the underlying pathophysiological progression of the disease. Modulation by cell therapy may be new promising disease-modifying therapy. Recently, we showed reduction in amyloid-β (Aβ) levels/β-amyloid plaques and associated astrocytosis following low-dose infusions of mononuclear human umbilical cord blood cells (HUCBCs). Our current study extended our previous findings by examining cognition via (1) the rotarod test, (2) a 2-day version of the radial-arm water maze test, and (3) a subsequent observation in an open pool platform test to characterize the effects of monthly peripheral HUCBC infusion (1×10(6) cells/μL) into the transgenic PSAPP mouse model of cerebral amyloidosis (bearing mutant human APP and presenilin-1 transgenes) from 6 to 12 months of age. We show that HUCBC therapy correlates with decreased (1) cognitive impairment, (2) Aβ levels/β-amyloid plaques, (3) amyloidogenic APP processing, and (4) reactive microgliosis after a treatment of 6 or 10 months. As such, this report lays the groundwork for an HUCBC therapy as potentially novel alternative to oppose AD at the disease-modifying level.

  12. Magnetic force microscopy of atherosclerotic plaque

    Directory of Open Access Journals (Sweden)

    Alexeeva T.A.

    2014-03-01

    Full Text Available In this work by methods of scanning probe microscopy, namely by atomic force microscopy and magnetic force microscopy the fragments of atherosclerotic plaque section of different nature were investigated. The fragments of atherosclerotic vessels with elements of immature plaque were taken during the coiled artery bypass surgery by alloprosthesis. As the result of investigation we found magnetically ordered phase of endogenous origin in the fragment of solid plaque of mixed structure. This phase is presents biogenic magnetic nanoparticles and their clusters with average size characteristic of 200-400 nm.

  13. Amyloid-linked cellular toxicity triggered by bacterial inclusion bodies

    International Nuclear Information System (INIS)

    The aggregation of proteins in the form of amyloid fibrils and plaques is the characteristic feature of some pathological conditions ranging from neurodegenerative disorders to systemic amyloidoses. The mechanisms by which the aggregation processes result in cell damage are under intense investigation but recent data indicate that prefibrillar aggregates are the most proximate mediators of toxicity rather than mature fibrils. Since it has been shown that prefibrillar forms of the nondisease-related misfolded proteins are highly toxic to cultured mammalian cells we have studied the cytoxicity associated to bacterial inclusion bodies that have been recently described as protein deposits presenting amyloid-like structures. We have proved that bacterial inclusion bodies composed by a misfolding-prone β-galactosidase fusion protein are clearly toxic for mammalian cells but the β-galactosidase wild type enzyme forming more structured thermal aggregates does not impair cell viability, despite it also binds and enter into the cells. These results are in the line that the most cytotoxic aggregates are early prefibrilar assemblies but discard the hypothesis that the membrane destabilization is Key event to subsequent disruption of cellular processes, such as ion balance, oxidative state and the eventually cell death

  14. Aspects of structural landscape of human islet amyloid polypeptide

    International Nuclear Information System (INIS)

    The human islet amyloid polypeptide (hIAPP) co-operates with insulin to maintain glycemic balance. It also constitutes the amyloid plaques that aggregate in the pancreas of type-II diabetic patients. We have performed extensive in silico investigations to analyse the structural landscape of monomeric hIAPP, which is presumed to be intrinsically disordered. For this, we construct from first principles a highly predictive energy function that describes a monomeric hIAPP observed in a nuclear magnetic resonance experiment, as a local energy minimum. We subject our theoretical model of hIAPP to repeated heating and cooling simulations, back and forth between a high temperature regime where the conformation resembles a random walker and a low temperature limit where no thermal motions prevail. We find that the final low temperature conformations display a high level of degeneracy, in a manner which is fully in line with the presumed intrinsically disordered character of hIAPP. In particular, we identify an isolated family of α-helical conformations that might cause the transition to amyloidosis, by nucleation

  15. Aspects of structural landscape of human islet amyloid polypeptide

    Energy Technology Data Exchange (ETDEWEB)

    He, Jianfeng, E-mail: hjf@bit.edu.cn; Dai, Jin, E-mail: daijing491@gmail.com [School of Physics, Beijing Institute of Technology, Beijing 100081 (China); Li, Jing, E-mail: jinglichina@139.com [Institute of Biopharmaceutical Research, Yangtze River Pharmaceutical Group Beijing Haiyan Pharmaceutical Co., Ltd, Beijing 102206 (China); Peng, Xubiao, E-mail: xubiaopeng@gmail.com [Department of Physics and Astronomy, Uppsala University, P.O. Box 803, S-75108 Uppsala (Sweden); Niemi, Antti J., E-mail: Antti.Niemi@physics.uu.se [School of Physics, Beijing Institute of Technology, Beijing 100081 (China); Department of Physics and Astronomy, Uppsala University, P.O. Box 803, S-75108 Uppsala (Sweden); Laboratoire de Mathematiques et Physique Theorique CNRS UMR 6083, Fédération Denis Poisson, Université de Tours, Parc de Grandmont, F37200 Tours (France)

    2015-01-28

    The human islet amyloid polypeptide (hIAPP) co-operates with insulin to maintain glycemic balance. It also constitutes the amyloid plaques that aggregate in the pancreas of type-II diabetic patients. We have performed extensive in silico investigations to analyse the structural landscape of monomeric hIAPP, which is presumed to be intrinsically disordered. For this, we construct from first principles a highly predictive energy function that describes a monomeric hIAPP observed in a nuclear magnetic resonance experiment, as a local energy minimum. We subject our theoretical model of hIAPP to repeated heating and cooling simulations, back and forth between a high temperature regime where the conformation resembles a random walker and a low temperature limit where no thermal motions prevail. We find that the final low temperature conformations display a high level of degeneracy, in a manner which is fully in line with the presumed intrinsically disordered character of hIAPP. In particular, we identify an isolated family of α-helical conformations that might cause the transition to amyloidosis, by nucleation.

  16. Toxic β-Amyloid (Aβ) Alzheimer's Ion Channels: From Structure to Function and Design

    Science.gov (United States)

    Nussinov, Ruth

    2012-02-01

    Full-length amyloid beta peptides (Aβ1-40/42) form neuritic amyloid plaques in Alzheimer's disease (AD) patients and are implicated in AD pathology. Recent biophysical and cell biological studies suggest a direct mechanism of amyloid beta toxicity -- ion channel mediated loss of calcium homeostasis. Truncated amyloid beta fragments (Aβ11-42 and Aβ17-42), commonly termed as non-amyloidogenic are also found in amyloid plaques of Alzheimer's disease (AD) and in the preamyloid lesions of Down's syndrome (DS), a model system for early onset AD study. Very little is known about the structure and activity of these smaller peptides although they could be key AD and DS pathological agents. Using complementary techniques of explicit solvent molecular dynamics (MD) simulations, atomic force microscopy (AFM), channel conductance measurements, cell calcium uptake assays, neurite degeneration and cell death assays, we have shown that non-amyloidogenic Aβ9-42 and Aβ17-42 peptides form ion channels with loosely attached subunits and elicit single channel conductances. The subunits appear mobile suggesting insertion of small oligomers, followed by dynamic channel assembly and dissociation. These channels allow calcium uptake in APP-deficient cells and cause neurite degeneration in human cortical neurons. Channel conductance, calcium uptake and neurite degeneration are selectively inhibited by zinc, a blocker of amyloid ion channel activity. Thus truncated Aβ fragments could account for undefined roles played by full length Aβs and provide a novel mechanism of AD and DS pathology. The emerging picture from our large-scale simulations is that toxic ion channels formed by β-sheets are highly polymorphic, and spontaneously break into loosely interacting dynamic units (though still maintaining ion channel structures as imaged with AFM), that associate and dissociate leading to toxic ion flux. This sharply contrasts intact conventional gated ion channels that consist of tightly

  17. Cerebroprotective effect of Huanglian Jiedu decoction on amyloid protein precursor/presenilin-1 double transgenic mice

    Institute of Scientific and Technical Information of China (English)

    Xin Qiu; Guohua Chen; Gui Mei; Yuegu Wang; Kaixin Wang; Tao Wang; Pei Feng

    2011-01-01

    Huanglian Jiedu decoction (HLJDD) has been shown to improve cerebral blood flow, and reduce lipid peroxidation damage to the brain and its energy metabolism. The present study was designed to observe the cerebroprotective effect of HLJDD on an Alzheimer's disease rodent model,presenilin-1/amyloid protein precursor double transgenic mice. HLJDD reduced serum interleukin-6 and interleukin-1β levels, decreased β-amyloid precursor protein gene and senile plaque expression, resisted oxidation, and reduced free radical-induced injury, thereby improving the learning and memory of these mice. Moreover, HLJDD at 433 mg/kg per day exhibited better effects compared with that at 865 or 216 mg/kg per day, and donepezil hydrochloride at 30 mg/kg per day.Thus, these results suggest that HLJDD may have protective effects against Alzheimer's disease.

  18. Structure-based design of non-natural amino-acid inhibitors of amyloid fibril formation

    Energy Technology Data Exchange (ETDEWEB)

    Sievers, Stuart A.; Karanicolas, John; Chang, Howard W.; Zhao, Anni; Jiang, Lin; Zirafi, Onofrio; Stevens, Jason T.; Münch, Jan; Baker, David; Eisenberg, David (UCLA); (UWASH); (UL); (Kansas); (Ulm)

    2011-09-20

    Many globular and natively disordered proteins can convert into amyloid fibrils. These fibrils are associated with numerous pathologies as well as with normal cellular functions, and frequently form during protein denaturation. Inhibitors of pathological amyloid fibril formation could be useful in the development of therapeutics, provided that the inhibitors were specific enough to avoid interfering with normal processes. Here we show that computer-aided, structure-based design can yield highly specific peptide inhibitors of amyloid formation. Using known atomic structures of segments of amyloid fibrils as templates, we have designed and characterized an all-D-amino-acid inhibitor of the fibril formation of the tau protein associated with Alzheimer's disease, and a non-natural L-amino-acid inhibitor of an amyloid fibril that enhances sexual transmission of human immunodeficiency virus. Our results indicate that peptides from structure-based designs can disrupt the fibril formation of full-length proteins, including those, such as tau protein, that lack fully ordered native structures. Because the inhibiting peptides have been designed on structures of dual-{beta}-sheet 'steric zippers', the successful inhibition of amyloid fibril formation strengthens the hypothesis that amyloid spines contain steric zippers.

  19. Coronary Plaque Volume and Composition Assessed by Computed Tomography Angiography in Patients With Late-Onset Major Depression

    DEFF Research Database (Denmark)

    Devantier, Torben Albert; Nørgaard, Bjarne Linde; Ovrehus, Kristian Altern;

    2013-01-01

    Background: Depression is a stronger predictor for the onset of or death from clinical coronary artery disease than traditional cardiovascular risk factors. The association between depression and coronary artery disease has previously been investigated in non-contrast enhanced computed tomography...... studies with conflicting results. The aim of this study was to further elucidate the depression-coronary artery disease relation by use of coronary computed tomography angiography. Methods: The calcified and noncalcified coronary plaque volumes were determined by semiautomatic volumetric quantification in...... 28 patients with late-onset major depression and 27 controls. The calcified plaque proportion, i.e., the calcified plaque volume divided by the total plaque volume, was used to assess the plaque composition. Results: There was no statistically significant difference in the total (p = 0.48), calcified...

  20. Oleuropein aglycone protects transgenic C. elegans strains expressing Aβ42 by reducing plaque load and motor deficit.

    Directory of Open Access Journals (Sweden)

    Luisa Diomede

    Full Text Available The presence of amyloid aggregates of the 42 amino acid peptide of amyloid beta (Aβ42 in the brain is the characteristic feature of Alzheimer's disease (AD. Amyloid beta (Aβ deposition is also found in muscle fibers of individuals affected by inclusion body myositis (sIBM, a rare muscular degenerative disease affecting people over 50. Both conditions are presently lacking an effective therapeutic treatment. There is increasing evidence to suggest that natural polyphenols may prevent the formation of toxic amyloid aggregates; this applies also to oleuropein aglycone (OLE, the most abundant polyphenol in extra virgin olive oil, previously shown to hinder amylin and Aβ aggregation. Here we evaluated the ability of OLE to interfere with Aβ proteotoxicity in vivo by using the transgenic CL2006 and CL4176 strains of Caenorhabditis elegans, simplified models of AD and of sIBM, which express human Aβ in the cytoplasm of body wall muscle cells. OLE-fed CL2006 worms displayed reduced Aβ plaque deposition, less abundant toxic Aβ oligomers, remarkably decreased paralysis and increased lifespan with respect to untreated animals. A protective effect was also observed in CL4176 worms but only when OLE was administered before the induction of the Aβ transgene expression. These effects were specific, dose-related, and not mediated by the known polyphenolic anti-oxidant activity, suggesting that, in this model organism, OLE interferes with the Aβ aggregation skipping the appearance of toxic species, as already shown in vitro for Aβ42.

  1. Atherosclerotic Aortic Plaques Detected by Transesophageal Echocardiography

    Institute of Scientific and Technical Information of China (English)

    赵云; 朱文玲; 倪超; 郭丽琳; 曾勇; 方理刚

    2002-01-01

    Objective To evaluate the predictive value of atherosclerotic aortic plaques in coronary artery disease (CAD) Methods In 50patients with suspected coronary artery disease, transesophageal echocardiography was performed to examine their thoracic aortas 2 weeks before or after coronary angiography. In the cases of coronary angiography studied, stenosis of the coronary artery ≥ 50 % was considered to be due to coronary artery disease,whereas the thickness of the intima ≥ 1.3 mm was taken to be the criteria for the presence of an atherosclerotic aortic plaque on the transesophageal echocardiographic test. Results Among the 50 patients, 37 cases were diagnosed as CAD and 13 cases were considered to be normal. The plaques of the thoracic aorta were observed in 34cases in the CAD group and 3 cases in the normal group. The sensitivity and specificity of aortic plaques for CAD were 91.9 % and 76.9%, respectively. The positive and negative predictive values of the aortic plaques for CAD were 91.9% and 76.9%, respectively. The accuracy was 88.0%. 80 percent of the patients with single- yes sel disease had thoracic aortic plaques, 92 percent of the patients with two-vessel disease and 100 percent of the patients with three-vessel disease had thoracic aortic plaques. There was a significant difference in the thickness of aortic intimas between the normal group and the CAD group. Conclusions Detectingatherosclerotic plaques in the thoracic aorta with transesophageal echocardiography may be of great value in predicting the presence and extent of coronary artery disease.

  2. Carotid plaque age is a feature of plaque stability inversely related to levels of plasma insulin.

    Directory of Open Access Journals (Sweden)

    Sara Hägg

    Full Text Available BACKGROUND: The stability of atherosclerotic plaques determines the risk for rupture, which may lead to thrombus formation and potentially severe clinical complications such as myocardial infarction and stroke. Although the rate of plaque formation may be important for plaque stability, this process is not well understood. We took advantage of the atmospheric (14C-declination curve (a result of the atomic bomb tests in the 1950s and 1960s to determine the average biological age of carotid plaques. METHODOLOGY/PRINCIPAL FINDING: The cores of carotid plaques were dissected from 29 well-characterized, symptomatic patients with carotid stenosis and analyzed for (14C content by accelerator mass spectrometry. The average plaque age (i.e. formation time was 9.6±3.3 years. All but two plaques had formed within 5-15 years before surgery. Plaque age was not associated with the chronological ages of the patients but was inversely related to plasma insulin levels (p = 0.0014. Most plaques were echo-lucent rather than echo-rich (2.24±0.97, range 1-5. However, plaques in the lowest tercile of plaque age (most recently formed were characterized by further instability with a higher content of lipids and macrophages (67.8±12.4 vs. 50.4±6.2, p = 0.00005; 57.6±26.1 vs. 39.8±25.7, p<0.0005, respectively, less collagen (45.3±6.1 vs. 51.1±9.8, p<0.05, and fewer smooth muscle cells (130±31 vs. 141±21, p<0.05 than plaques in the highest tercile. Microarray analysis of plaques in the lowest tercile also showed increased activity of genes involved in immune responses and oxidative phosphorylation. CONCLUSIONS/SIGNIFICANCE: Our results show, for the first time, that plaque age, as judge by relative incorporation of (14C, can improve our understanding of carotid plaque stability and therefore risk for clinical complications. Our results also suggest that levels of plasma insulin might be involved in determining carotid plaque age.

  3. Nanomechanical properties of single amyloid fibrils

    Science.gov (United States)

    Sweers, K. K. M.; Bennink, M. L.; Subramaniam, V.

    2012-06-01

    Amyloid fibrils are traditionally associated with neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease or Creutzfeldt-Jakob disease. However, the ability to form amyloid fibrils appears to be a more generic property of proteins. While disease-related, or pathological, amyloid fibrils are relevant for understanding the pathology and course of the disease, functional amyloids are involved, for example, in the exceptionally strong adhesive properties of natural adhesives. Amyloid fibrils are thus becoming increasingly interesting as versatile nanobiomaterials for applications in biotechnology. In the last decade a number of studies have reported on the intriguing mechanical characteristics of amyloid fibrils. In most of these studies atomic force microscopy (AFM) and atomic force spectroscopy play a central role. AFM techniques make it possible to probe, at nanometer length scales, and with exquisite control over the applied forces, biological samples in different environmental conditions. In this review we describe the different AFM techniques used for probing mechanical properties of single amyloid fibrils on the nanoscale. An overview is given of the existing mechanical studies on amyloid. We discuss the difficulties encountered with respect to the small fibril sizes and polymorphic behavior of amyloid fibrils. In particular, the different conformational packing of monomers within the fibrils leads to a heterogeneity in mechanical properties. We conclude with a brief outlook on how our knowledge of these mechanical properties of the amyloid fibrils can be exploited in the construction of nanomaterials from amyloid fibrils.

  4. Functional Amyloid Formation within Mammalian Tissue.

    Directory of Open Access Journals (Sweden)

    2005-11-01

    Full Text Available Amyloid is a generally insoluble, fibrous cross-beta sheet protein aggregate. The process of amyloidogenesis is associated with a variety of neurodegenerative diseases including Alzheimer, Parkinson, and Huntington disease. We report the discovery of an unprecedented functional mammalian amyloid structure generated by the protein Pmel17. This discovery demonstrates that amyloid is a fundamental nonpathological protein fold utilized by organisms from bacteria to humans. We have found that Pmel17 amyloid templates and accelerates the covalent polymerization of reactive small molecules into melanin-a critically important biopolymer that protects against a broad range of cytotoxic insults including UV and oxidative damage. Pmel17 amyloid also appears to play a role in mitigating the toxicity associated with melanin formation by sequestering and minimizing diffusion of highly reactive, toxic melanin precursors out of the melanosome. Intracellular Pmel17 amyloidogenesis is carefully orchestrated by the secretory pathway, utilizing membrane sequestration and proteolytic steps to protect the cell from amyloid and amyloidogenic intermediates that can be toxic. While functional and pathological amyloid share similar structural features, critical differences in packaging and kinetics of assembly enable the usage of Pmel17 amyloid for normal function. The discovery of native Pmel17 amyloid in mammals provides key insight into the molecular basis of both melanin formation and amyloid pathology, and demonstrates that native amyloid (amyloidin may be an ancient, evolutionarily conserved protein quaternary structure underpinning diverse pathways contributing to normal cell and tissue physiology.

  5. Plaque fluid as a bacterial milieu.

    Science.gov (United States)

    Edgar, W M; Higham, S M

    1990-06-01

    Studies of the extracellular, free concentrations of substrates, growth factors, inhibitors, and end-products of metabolism to which the intact plaque microflora is exposed in situ can assist in the understanding of factors controlling plaque pathogenicity. Information is becoming increasingly available from analysis of fluid separated by centrifugation of plaques collected at various intervals after an intra-oral pulse of dietary or experimental substrate, or different procedures or treatments having cariostatic potential. Such analytical results give more information than those obtained by analysis of aqueous or other extracts, because they yield values of substrate concentration representing those occurring at the bacterial cell surface. The largest body of information concerns extracellular levels of acid end-products of sugar catabolism in relation to food quality or sequence, and of amino acids and other products of nitrogen metabolism, in relation to studies of the detailed metabolic events of the Stephan curve, and of the demineralizing effect of the plaque environment. Areas where little information is available and which merit further study include plaque clearance of salivary and other components with anti-caries activity (e.g., antibodies, enzymes, fluorides, cations, other antimicrobials, etc.), and substrate concentrations to determine gradients for diffusion into and out of plaque. PMID:2191982

  6. Survival of bacteria from human dental plaque under various transport conditions.

    Science.gov (United States)

    Hoover, C I; Newbrun, E

    1977-09-01

    The effects of transport media, temperature, and anaerobiosis on the survival of bacteria from human supragingival dental plaque were studied. Individual samples were obtained by passing sterile, unwaxed dental floss through the interproximal spaces. The plaque-bearing portion of floss was immediately placed in vials containing reduced transport fluid, viability-preserving microbistatic medium, or reduced salt solution transport fluid. Plaque samples were dispersed by ultrasonic oscillation, serially diluted, and plated in duplicate on MM10-sucrose-blood agar, mitis salivarius bacitracin agar, and Rogosa tomato juice agar. Initial viable counts (time 0) were compared with viable count determinations after 48- and 72-h storage. Quantitative recovery (>30%) of various groups of oral bacteria was accomplished from both reduced transport fluid and viability-preserving microbistatic medium after 48- and 72-h storage. Storage of dental plaque in reduced salt solution proved unsatisfactory for most bacteria (less than 10% survival). Since growth of some bacteria may occur in viability-preserving microbistatic medium and the charcoal present interferes with colonly enumeration on low-dilution plates, we found reduced transport fluid to be the most suitable medium for transport and recovery of bacteria from supragingival dental plaque. Subzero storage (-196 and -40 degrees C) did not enhance the survival of bacteria from dental plaque; storage at moderate (5 and 20 degrees C) temperatures gave better recovery of viable bacteria. Survival after anaerobic or aerobic storage was comparable for total colony-forming units; however, anaerobic storage enhanced survival of Streptococcus mutans and Lactobacillus. Since these organisms are specifically associated with dental caries, anaerobic techniques are preferred for caries activity testing of plaque.

  7. Surface Mediated Self-Assembly of Amyloid Peptides

    Science.gov (United States)

    Fakhraai, Zahra

    2015-03-01

    Amyloid fibrils have been considered as causative agents in many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, type II diabetes and amyloidosis. Amyloid fibrils form when proteins or peptides misfold into one dimensional crystals of stacked beta-sheets. In solution, amyloid fibrils form through a nucleation and growth mechanism. The rate limiting nucleation step requires a critical concentration much larger than those measured in physiological conditions. As such the exact origins of the seeds or oligomers that result in the formation of fully mature fibrils in the body remain topic intense studies. It has been suggested that surfaces and interfaces can enhance the fibrillization rate. However, studies of the mechanism and kinetics of the surface-mediated fibrillization are technologically challenging due to the small size of the oligomer and protofibril species. Using smart sample preparation technique to dry the samples after various incubation times we are able to study the kinetics of fibril formation both in solution and in the vicinity of various surfaces using high-resolution atomic force microscopy. These studies elucidate the role of surfaces in catalyzing amyloid peptide formation through a nucleation-free process. The nucleation free self-assembly is rapid and requires much smaller concentrations of peptides or proteins. We show that this process resembles diffusion limited aggregation and is governed by the peptide adhesion rate, two -dimensional diffusion of the peptides on the surface, and preferential interactions between the peptides. These studies suggest an alternative pathway for amyloid formation may exist, which could lead to new criteria for disease prevention and alternative therapies. Research was partially supported by a seed grant from the National Institute of Aging of the National Institutes of Health (NIH) under Award Number P30AG010124 (PI: John Trojanowski) and the University of Pennsylvania.

  8. MR imaging determination of multiple sclerosis activity on non-contrast-enhanced study

    International Nuclear Information System (INIS)

    The location of Gd-DTPA-enhancing multiple sclerosis (MS) plaques on MR imaging has been found to correspond to the site of new neurologic deficits; however, characteristics differentiating new from old plaques on nonenhanced T2-weighted images have not been described. In the present study, nonenhanced MS characteristics (mean pixel intensity, size and contour) of plaques that enhanced with gadolinium were compared to characteristics of plaques that did not enhance. The gadolinium-enhancing plaques, in general, had a lower mean pixel value and were less well defined on T2-weighted images than nonenhancing lesions. Their intensity, however, increased relative to adjacent plaques on more heavily weighted T2-images

  9. DECT evaluation of noncalcified coronary artery plaque

    Energy Technology Data Exchange (ETDEWEB)

    Ravanfar Haghighi, Rezvan [Medical Imaging Research Center and Colorectal Research Center, Shiraz University of Medical Science, Shiraz 719 363 5899 (Iran, Islamic Republic of); Chatterjee, S. [BGVS Chemical Engineering Building (Old), Indian Institute of Science, Bangalore 560012 (India); Tabin, Milo; Singh, Rishi P.; Sharma, Munish; Krishna, Karthik [Department of Forensic Medicine, All India Institute of Medical Sciences, New Delhi 110029 (India); Sharma, Sanjiv; Jagia, Priya [Department of Cardiac-Radiology, All India Institute of Medical Sciences, New Delhi 110029 (India); Ray, Ruma; Arava, Sudhir [Department of Pathology, All India Institute of Medical Sciences, New Delhi 110029 (India); Yadav, Rakesh [Department of Cardiology, All India Institute of Medical Sciences, New Delhi 110029 (India); Vani, V. C. [Department of Instrumentation and Applied Physics, Indian Institute of Science, Bangalore 560012 (India); Lakshmi, R.; Kumar, Pratik, E-mail: drpratikkumar@gmail.com [Department of Cardiac-Biochemistry, All India Institute of Medical Sciences, New Delhi 110029 (India); Mandal, Susama R. [Department of Medical Physics Unit IRCH, All India Institute of Medical Sciences, New Delhi 110029 (India)

    2015-10-15

    Purpose: Composition of the coronary artery plaque is known to have critical role in heart attack. While calcified plaque can easily be diagnosed by conventional CT, it fails to distinguish between fibrous and lipid rich plaques. In the present paper, the authors discuss the experimental techniques and obtain a numerical algorithm by which the electron density (ρ{sub e}) and the effective atomic number (Z{sub eff}) can be obtained from the dual energy computed tomography (DECT) data. The idea is to use this inversion method to characterize and distinguish between the lipid and fibrous coronary artery plaques. Methods: For the purpose of calibration of the CT machine, the authors prepare aqueous samples whose calculated values of (ρ{sub e}, Z{sub eff}) lie in the range of (2.65 × 10{sup 23} ≤ ρ{sub e} ≤ 3.64 × 10{sup 23}/cm{sup 3}) and (6.80 ≤ Z{sub eff} ≤ 8.90). The authors fill the phantom with these known samples and experimentally determine HU(V{sub 1}) and HU(V{sub 2}), with V{sub 1},V{sub 2} = 100 and 140 kVp, for the same pixels and thus determine the coefficients of inversion that allow us to determine (ρ{sub e}, Z{sub eff}) from the DECT data. The HU(100) and HU(140) for the coronary artery plaque are obtained by filling the channel of the coronary artery with a viscous solution of methyl cellulose in water, containing 2% contrast. These (ρ{sub e}, Z{sub eff}) values of the coronary artery plaque are used for their characterization on the basis of theoretical models of atomic compositions of the plaque materials. These results are compared with histopathological report. Results: The authors find that the calibration gives ρ{sub e} with an accuracy of ±3.5% while Z{sub eff} is found within ±1% of the actual value, the confidence being 95%. The HU(100) and HU(140) are found to be considerably different for the same plaque at the same position and there is a linear trend between these two HU values. It is noted that pure lipid type plaques

  10. Functional Expression of Dental Plaque Microbiota

    Directory of Open Access Journals (Sweden)

    Scott Norman Peterson

    2014-08-01

    Full Text Available Dental caries remains a significant public health problem and is considered pandemic worldwide. The prediction of dental caries based on profiling of microbial species involved in disease and equally important, the identification of species conferring dental health has proven more difficult than anticipated due to high interpersonal and geographical variability of dental plaque microbiota. We have used RNA-Seq to perform global gene expression analysis of dental plaque microbiota derived from 19 twin pairs that were either concordant (caries-active or caries-free or discordant for dental caries. The transcription profiling allowed us to define a functional core microbiota consisting of nearly 60 species. Similarities in gene expression patterns allowed a preliminary assessment of the relative contribution of human genetics, environmental factors and caries phenotype on the microbiota’s transcriptome. Correlation analysis of transcription allowed the identification of numerous functional networks, suggesting that inter-personal environmental variables may co-select for groups of genera and species. Analysis of functional role categories allowed the identification of dominant functions expressed by dental plaque biofilm communities, that highlight the biochemical priorities of dental plaque microbes to metabolize diverse sugars and cope with the acid and oxidative stress resulting from sugar fermentation. The wealth of data generated by deep sequencing of expressed transcripts enables a greatly expanded perspective concerning the functional expression of dental plaque microbiota.

  11. Control study of MRI and histopathology in early atherosclerotic plaque of rabbits

    International Nuclear Information System (INIS)

    Objective: To explore the diagnostic value of MRI in the early atherosclerosis. Materials and Methods: Atherosclerosis was induced in 20 New Zealand White male rabbits with high cholesterol diet. Rabbits underwent serial MRI at 9 and 18 weeks after high cholesterol diet. Axial T1 and fat-suppressed PDWI spin echo images of the abdominal aorta were obtained above and below the right renal arteries. The signal intensity and morphologic features of plaque in the various phases after high cholesterol diet in MRI were analyzed and compared with those of histopathology. Results: Plaque could be observed in all animals on MRI at 9 weeks after high cholesterol diet, and mild enhancement of the plaque could be noted on enhanced imaging. Imaging effect was the best at T1 sequence. Plaque size increased gradually at 18 weeks. Plaque and vessel wall were all enrichment. In histopathology, foam cells, collagen and matrix fiber component can be seen in the various phases. Conclusion: The conventional MRI technique can be used to assess the formation and development of the early atherosclerosis dynamically and histologically. (authors)

  12. Estrogen protects neuronal cells from amyloid beta-induced apoptosis via regulation of mitochondrial proteins and function

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    Iwamoto Sean

    2006-11-01

    Full Text Available Abstract Background Neurodegeneration in Alzheimer's disease is associated with increased apoptosis and parallels increased levels of amyloid beta, which can induce neuronal apoptosis. Estrogen exposure prior to neurotoxic insult of hippocampal neurons promotes neuronal defence and survival against neurodegenerative insults including amyloid beta. Although all underlying molecular mechanisms of amyloid beta neurotoxicity remain undetermined, mitochondrial dysfunction, including altered calcium homeostasis and Bcl-2 expression, are involved in neurodegenerative vulnerability. Results In this study, we investigated the mechanism of 17β-estradiol-induced prevention of amyloid beta-induced apoptosis of rat hippocampal neuronal cultures. Estradiol treatment prior to amyloid beta exposure significantly reduced the number of apoptotic neurons and the associated rise in resting intracellular calcium levels. Amyloid beta exposure provoked down regulation of a key antiapoptotic protein, Bcl-2, and resulted in mitochondrial translocation of Bax, a protein known to promote cell death, and subsequent release of cytochrome c. E2 pretreatment inhibited the amyloid beta-induced decrease in Bcl-2 expression, translocation of Bax to the mitochondria and subsequent release of cytochrome c. Further implicating the mitochondria as a target of estradiol action, in vivo estradiol treatment enhanced the respiratory function of whole brain mitochondria. In addition, estradiol pretreatment protected isolated mitochondria against calcium-induced loss of respiratory function. Conclusion Therefore, we propose that estradiol pretreatment protects against amyloid beta neurotoxicity by limiting mitochondrial dysfunction via activation of antiapoptotic mechanisms.

  13. Amyloid Goiter Secondary to Ulcerative Colitis

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    Bunyamin Aydin

    2016-01-01

    Full Text Available Diffuse amyloid goiter (AG is an entity characterized by the deposition of amyloid in the thyroid gland. AG may be associated with either primary or secondary amyloidosis. Secondary amyloidosis is rarely caused by inflammatory bowel diseases. Secondary amyloidosis is relatively more common in the patients with Crohn’s disease, whereas it is highly rare in patients with ulcerative colitis. Diffuse amyloid goiter caused by ulcerative colitis is also a rare condition. In the presence of amyloid in the thyroid gland, medullary thyroid cancer should be kept in mind in the differential diagnosis. Imaging techniques and biochemical tests are not very helpful in the diagnosis of secondary amyloid goiter and the definitive diagnosis is established based on the histopathologic analysis and histochemical staining techniques. In this report, we present a 35-year-old male patient with diffuse amyloid goiter caused by secondary amyloidosis associated with ulcerative colitis.

  14. Amyloid Goiter Secondary to Ulcerative Colitis.

    Science.gov (United States)

    Aydin, Bunyamin; Koca, Yavuz Savas; Koca, Tugba; Yildiz, Ihsan; Gerek Celikden, Sevda; Ciris, Metin

    2016-01-01

    Diffuse amyloid goiter (AG) is an entity characterized by the deposition of amyloid in the thyroid gland. AG may be associated with either primary or secondary amyloidosis. Secondary amyloidosis is rarely caused by inflammatory bowel diseases. Secondary amyloidosis is relatively more common in the patients with Crohn's disease, whereas it is highly rare in patients with ulcerative colitis. Diffuse amyloid goiter caused by ulcerative colitis is also a rare condition. In the presence of amyloid in the thyroid gland, medullary thyroid cancer should be kept in mind in the differential diagnosis. Imaging techniques and biochemical tests are not very helpful in the diagnosis of secondary amyloid goiter and the definitive diagnosis is established based on the histopathologic analysis and histochemical staining techniques. In this report, we present a 35-year-old male patient with diffuse amyloid goiter caused by secondary amyloidosis associated with ulcerative colitis. PMID:27051538

  15. Effect of delmopinol hydrochloride mouthrinse on plaque formation and gingivitis in "rapid" and "slow" plaque formers.

    Science.gov (United States)

    Zee, K; Rundegren, J; Attström, R

    1997-07-01

    The aim of the present study was to investigate differences in the plaque and gingivitis inhibiting effect of delmopinol rinsing between "rapid" and "slow" plaque formers. 23 subjects (12 "rapid" and 11 "slow" plaque formers) were selected from 71 healthy young adults. The selection was based on the plaque index on the buccal surfaces of all premolars and 1st molars after 3-days without plaque control. The 23 subjects were randomly assigned into 3 groups with different mouthrinses, i.e., 0.1% delmopinol, 0.2% delmopinol, and placebo. The study was double-blind with parallel design between the "rapid" and "slow" plaque formers and cross-over design between 2 active periods and a placebo period. Each rinsing period lasted for 5 days. During the 3 test periods, the subjects refrained from all oral hygiene and rinsed 2x daily with either one of the 3 solutions. Gingival crevicular fluid (GCF) was collected from buccal surfaces of upper canines and premolars and bleeding on probing (BOP) recorded at 6 sites around each tooth before and after each test period. Plaque assessment, including plaque index (PI) and standardized color slides for planimetric analyses obtained from the canines and premolars, were only recorded after each test period. Results showed that the mean PI and planimetry values for both the "rapid" and "slow" plaque formers were lower than the placebo, for either the 0.1% or the 0.2% delmopinol mouthrinse. The differences between the" rapid" and "slow" plaque formers were not statistically significant. There was a small reduction in BOP in both groups for the delmopinol periods, as against a slight increase in the placebo period; the difference between the placebo group and the 2 groups of plaque formers was not statistically significant (p>0.6 for both 0.1% and 0.2% delmopinol). Results suggested that both 0.1% and 0.2% delmopinol reduce plaque formation and gingivitis to a similar extent in subjects with extreme rates of plaque formation. PMID:9226389

  16. Micro-CT imaging of Randall's plaques.

    Science.gov (United States)

    Williams, James C; Lingeman, James E; Coe, Fredric L; Worcester, Elaine M; Evan, Andrew P

    2015-01-01

    Micro-computed tomographic imaging (micro-CT) provides unprecedented information on stone structure and mineral composition. High-resolution micro-CT even allows visualization of the lumens of tubule and/or vessels within Randall's plaque, on stones or in papillary biopsies, thus giving a non-destructive way to study these sites of stone adhesion. This paper also shows an example of a stone growing on a different anchoring mechanism: a mineral plug within the lumen of a Bellini duct (BD plug). Micro-CT shows striking structural differences between stones that have grown on Randall's plaque and those that have grown on BD plugs. Thus, Randall's plaque can be distinguished by micro-CT, and this non-destructive method shows great promise in helping to elucidate the different mechanisms by which small stones are retained in the kidney during the development of nephrolithiasis. PMID:25096802

  17. DNA aptamers detecting generic amyloid epitopes

    OpenAIRE

    Mitkevich, Olga V.; Kochneva-Pervukhova, Natalia V; Surina, Elizaveta R.; Benevolensky, Sergei V.; Kushnirov, Vitaly V.; Ter-Avanesyan, Michael D.

    2012-01-01

    Amyloids are fibrillar protein aggregates resulting from non-covalent autocatalytic polymerization of various structurally and functionally unrelated proteins. Previously we have selected DNA aptamers, which bind specifically to the in vitro assembled amyloid fibrils of the yeast prionogenic protein Sup35. Here we show that such DNA aptamers can be used to detect SDS-insoluble amyloid aggregates of the Sup35 protein, and of some other amyloidogenic proteins, including mouse PrP, formed in yea...

  18. Amyloid myopathy: a diagnostic challenge

    Directory of Open Access Journals (Sweden)

    Heli Tuomaala

    2009-08-01

    Full Text Available Amyloid myopathy (AM is a rare manifestation of primary systemic amyloidosis (AL. Like inflammatory myopathies, it presents with proximal muscle weakness and an increased creatine kinase level. We describe a case of AL with severe, rapidly progressive myopathy as the initial symptom. The clinical manifestation and muscle biopsy were suggestive of inclusion body myositis. AM was not suspected until amyloidosis was seen in the gastric mucosal biopsy. The muscle biopsy was then re-examined more specifically, and Congo red staining eventually showed vascular and interstitial amyloid accumulation, which led to a diagnosis of AM. The present case illustrates the fact that the clinical picture of AM can mimic that of inclusion body myositis.

  19. Towards a Pharmacophore for Amyloid

    Science.gov (United States)

    Landau, Meytal; Sawaya, Michael R.; Faull, Kym F.; Laganowsky, Arthur; Jiang, Lin; Sievers, Stuart A.; Liu, Jie; Barrio, Jorge R.; Eisenberg, David

    2011-01-01

    Diagnosing and treating Alzheimer's and other diseases associated with amyloid fibers remains a great challenge despite intensive research. To aid in this effort, we present atomic structures of fiber-forming segments of proteins involved in Alzheimer's disease in complex with small molecule binders, determined by X-ray microcrystallography. The fiber-like complexes consist of pairs of β-sheets, with small molecules binding between the sheets, roughly parallel to the fiber axis. The structures suggest that apolar molecules drift along the fiber, consistent with the observation of nonspecific binding to a variety of amyloid proteins. In contrast, negatively charged orange-G binds specifically to lysine side chains of adjacent sheets. These structures provide molecular frameworks for the design of diagnostics and drugs for protein aggregation diseases. PMID:21695112

  20. Association between Randall's Plaque and Calcifying Nanoparticles

    Science.gov (United States)

    Ciftcioglu, Neva; Vejdani, Kaveh; Lee, Olivia; Mathew, Grace; Aho, Katja M.; Kajander, Olavi; McKay, David S.; Jones, Jeff A.; Hayat, Matthew; Stoller, Marshall L.

    2007-01-01

    Randall's plaques, first described by Alexander Randall in the 1930s, are small subepithelial calcifications in the renal papillae (RP) that also extend deeply into the renal medulla. Despite the strong correlation between the presence of these plaques and the formation of renal stones, the precise origin and pathogenesis of Randall s plaque formation remain elusive. The discovery of calcifying nanoparticles (CNP) and their detection in many calcifying processes of human tissues has raised hypotheses about their possible involvement in renal stone formation. We collected RP and blood samples from 17 human patients who had undergone laparoscopic nephrectomy due to neoplasia. Homogenized RP tissues and serum samples were cultured for CNP. Scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDS) analysis were performed on fixed RP samples. Immunohistochemical staining (IHS) was applied on the tissue samples using CNP-specific monoclonal antibody (mAb). Randall s plaques were visible on gross inspection in 11 out of 17 collected samples. Cultures of all serum samples and 13 tissue homogenates had CNP growth within 4 weeks. SEM revealed spherical apatite formations in 14 samples, with calcium and phosphate peaks detected by EDS analysis. IHS was positive in 9 out of 17 samples. A strong link was found between the presence of Randall s plaques and the detection of CNP, also referred to as nanobacteria. These results suggest new insights into the etiology of Randall's plaque formation, and will help us understand the pathogenesis of stone formation. Further studies on this topic may lead us to new approaches on early diagnosis and novel medical therapies of kidney stone formation.

  1. Cobalt60 plaques in recurrent retinoblastoma

    International Nuclear Information System (INIS)

    Cobalt60 plaque irradiation is one treatment option for patients with recurrent retinoblastoma following conventional external beam irradiation (ERT). Tumorocidal doses can be delivered without excessive risk of normal tissue injury. In patients not considered candidates for xenon arc or cryotherapy, 60Co is an alternative to enucleation. Between 1968 and 1987, 85 patients were treated with 60Co plaques, 72 of whom had failed prior ERT. Age at diagnosis ranged from 1 week to 4 years. There are 37 males and 35 females. Seventy-one patients had bilateral disease and one had unilateral. Three patients had both eyes plaqued. Prior ERT ranged from 30 to 70 Gy (mean 4200 Gy). Time from initial therapy to failure ranged from 13 to 60 months. Cobalt plaques of 10 mm, 15 mm, or 10 x 15 mm were used depending on tumor size and location. Dose prescribed to the apex of the tumor ranged from 30 to 50 Gy (median 40 Gy) given over 3 to 8 days. Twelve patients had two plaque applications; three patients had three plaque applications. All patients were followed with routine ophthalmoscopic examinations. Follow-up ranged from 2 to 22 years (mean 8.7). Seven patients died of metastatic disease; 10 patients developed non-ocular second tumors. Thirty patients required enucleation. Twenty-two patients had clear tumor progression, two patients had radiation complications, and six patients had a combination of tumor growth and complications. Cobalt60 can salvage eyes in retinoblastoma patients failing ERT. Currently, the authors are using I125 in an attempt to spare normal ocular tissue and reduce subsequent complications

  2. Cobalt60 plaques in recurrent retinoblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Fass, D.; McCormick, B.; Abramson, D.; Ellsworth, R. (Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, NY, NY (USA))

    1991-08-01

    Cobalt60 plaque irradiation is one treatment option for patients with recurrent retinoblastoma following conventional external beam irradiation (ERT). Tumorocidal doses can be delivered without excessive risk of normal tissue injury. In patients not considered candidates for xenon arc or cryotherapy, 60Co is an alternative to enucleation. Between 1968 and 1987, 85 patients were treated with 60Co plaques, 72 of whom had failed prior ERT. Age at diagnosis ranged from 1 week to 4 years. There are 37 males and 35 females. Seventy-one patients had bilateral disease and one had unilateral. Three patients had both eyes plaqued. Prior ERT ranged from 30 to 70 Gy (mean 4200 Gy). Time from initial therapy to failure ranged from 13 to 60 months. Cobalt plaques of 10 mm, 15 mm, or 10 {times} 15 mm were used depending on tumor size and location. Dose prescribed to the apex of the tumor ranged from 30 to 50 Gy (median 40 Gy) given over 3 to 8 days. Twelve patients had two plaque applications; three patients had three plaque applications. All patients were followed with routine ophthalmoscopic examinations. Follow-up ranged from 2 to 22 years (mean 8.7). Seven patients died of metastatic disease; 10 patients developed non-ocular second tumors. Thirty patients required enucleation. Twenty-two patients had clear tumor progression, two patients had radiation complications, and six patients had a combination of tumor growth and complications. Cobalt60 can salvage eyes in retinoblastoma patients failing ERT. Currently, the authors are using I125 in an attempt to spare normal ocular tissue and reduce subsequent complications.

  3. Epigallocatechin-3-gallate rapidly remodels PAP85-120, SEM1(45-107, and SEM2(49-107 seminal amyloid fibrils

    Directory of Open Access Journals (Sweden)

    Laura M. Castellano

    2015-09-01

    Full Text Available Semen harbors amyloid fibrils formed by proteolytic fragments of prostatic acid phosphatase (PAP248-286 and PAP85-120 and semenogelins (SEM1 and SEM2 that potently enhance HIV infectivity. Amyloid but not soluble forms of these peptides enhance HIV infection. Thus, agents that remodel these amyloid fibrils could prevent HIV transmission. Here, we confirm that the green tea polyphenol, epigallocatechin-3-gallate (EGCG, slowly remodels fibrils formed by PAP248-286 termed SEVI (semen derived enhancer of viral infection and also exerts a direct anti-viral effect. We elucidate for the first time that EGCG remodels PAP85-120, SEM1(45-107, and SEM2(49-107 fibrils more rapidly than SEVI fibrils. We establish EGCG as the first small molecule that can remodel all four classes of seminal amyloid. The combined anti-amyloid and anti-viral properties of EGCG could have utility in preventing HIV transmission.

  4. MR Imaging of Coronary Arteries and Plaques.

    Science.gov (United States)

    Dweck, Marc R; Puntman, Valentina; Vesey, Alex T; Fayad, Zahi A; Nagel, Eike

    2016-03-01

    Cardiac magnetic resonance offers the promise of radiation-free imaging of the coronary arteries, providing information with respect to luminal stenosis, plaque burden, high-risk plaque characteristics, and disease activity. In combination, this would provide a comprehensive, individualized assessment of coronary atherosclerosis that could be used to improve patient risk stratification and to guide treatment. However, the technical challenges involved with delivering upon this promise are considerable, requiring sophisticated approaches to both data acquisition and post-processing. In this review, we describe the current status of this technology, its capabilities, its limitations, and what will be required in the future to translate this technology into routine clinical practice. PMID:26965732

  5. Synthesis optimization of 2-(4-N-[11C]methylaminophenyl)-6-hydroxybenzothiazole ([11C]PIB), β-amyloid PET imaging tracer for Alzheimer's disease diagnosis.

    Science.gov (United States)

    Coliva, A; Monterisi, C; Apollaro, A; Gatti, D; Penso, M; Gianolli, L; Perani, D; Gilardi, M C; Carpinelli, A

    2015-11-01

    [11C]PIB is the most used amyloid plaques-specific positron-emitting radiotracers. The radiosynthesis of this compound, carried out by methylation of its precursor with [11C]methyl triflate in 2-butanone, has been improved optimizing the initial concentration and the purification method. Two HPLC methods were compared: good radiochemical yields, specific activities, and chemical purity above 98% were achieved by using as eluant acetonitrile/citrate and formulation in 10% ethanol.

  6. Pro-inflammatory interleukin-18 increases Alzheimer’s disease-associated amyloid-β production in human neuron-like cells

    Directory of Open Access Journals (Sweden)

    Sutinen Elina M

    2012-08-01

    Full Text Available Abstract Background Alzheimer’s disease (AD involves increased accumulation of amyloid-β (Aβ plaques and neurofibrillary tangles as well as neuronal loss in various regions of the neocortex. Neuroinflammation is also present, but its role in AD is not fully understood. We previously showed increased levels of pro-inflammatory cytokine interleukin-18 (IL-18 in different regions of AD brains, where it co-localized with Aβ-plaques, as well as the ability of IL-18 to increase expression of glycogen synthase kinase-3β (GSK-3β and cyclin dependent kinase 5, involved in hyperphosphorylation of tau-protein. Elevated IL-18 has been detected in several risk conditions for AD, including obesity, type-II diabetes, and cardiovascular diseases as well as in stress. Methods We differentiated SH-SY5Y neuroblastoma cells as neuron-like and exposed them to IL-18 for various times. We examined the protein levels of amyloid-β precursor protein (APP and its processing products, its cleaving enzymes, involved in amyloidogenic processing of APP, and markers of apoptosis. Results IL-18 increased protein levels of the β-site APP-cleaving enzyme BACE-1, the N-terminal fragment of presenilin-1 and slightly presenilin enhancer 2, both of which are members of the γ-secretase complex, as well as Fe65, which is a binding protein of the C-terminus of APP and one regulator for GSK-3β. IL-18 also increased APP expression and phosphorylation, which preceded increased BACE-1 levels. Further, IL-18 altered APP processing, increasing Aβ40 production in particular, which was inhibited by IL-18 binding protein. Increased levels of soluble APPβ were detected in culture medium after the IL-18 exposure. IL-18 also increased anti-apoptotic bcl-xL levels, which likely counteracted the minor increase of the pro-apoptotic caspase-3. Lactate dehydrogenase activity in culture medium was unaffected. Conclusions The IL-18 induction of BACE-1, APP processing, and Aβ is likely to be

  7. Solitary osteosclerotic plasmacytoma: association with demyelinating polyneuropathy and amyloid deposition

    Energy Technology Data Exchange (ETDEWEB)

    Voss, S.D.; Hall, F.M. [Dept. of Radiology, Beth Israel Deaconess Medical Center, Boston, MA (United States); Harvard Medical School, Boston, MA (United States); Murphey, M.D. [Dept. of Radiologic Pathology, Armed Forces Institute of Pathology, Washington, DC (United States); Dept. of Radiology and Nuclear Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD (United States); Department of Radiology, University of Maryland School of Medicine, Baltimore, Maryland (United States)

    2001-09-01

    A 51-year-old man presented with a 1-year history of polyneuropathy necessitating the use of a wheelchair. Initial diagnosis was idiopathic chronic inflammatory demyelinating polyneuropathy (CIDP) and associated monoclonal gammopathy. Investigations for multiple myeloma, including bone marrow aspiration and biopsy, were negative. What was initially felt to be an incidental osteosclerotic focus noted on the radiographic bone survey was eventually shown to be a solitary osteosclereotic plasmacytoma with associated amyloid. This dramatically altered treatment. This case emphasizes the importance of including osteosclerotic plasmacytoma in the differential diagnosis of a focal sclerotic bone lesion in the clinical setting of polyneuropathy. These lesions are less likely to progress to multiple myeloma than lytic plasma cell neoplasms, and the presence of polyneuropathy often results in earlier diagnosis and treatment with enhanced prospect of cure. The finding of amyloid deposition within the osteosclerotic lesion may be of prognostic importance. (orig.)

  8. Shear-induced amyloid fibrillization: the role of inertia.

    Science.gov (United States)

    McBride, Samantha A; Sanford, Sean P; Lopez, Juan M; Hirsa, Amir H

    2016-04-14

    Agitation of protein is known to induce deleterious effects on protein stability and structure, with extreme agitation sometimes resulting in complete aggregation into amyloid fibrils. Many mechanisms have been proposed to explain how protein becomes unstable when subjected to flow, including alignment of protein species, shear-induced unfolding, simple mixing, or fragmentation of existing fibrils to create new seeds. Here a shearing flow was imposed on a solution of monomeric human insulin via a rotating Couette device with a small hydrophobic fluid interface. The results indicate that even very low levels of shear are capable of accelerating amyloid fibril formation. Simulations of the flow suggest that the shear enhances fibrillization kinetics when flow inertia is non-negligible and the resulting meridional circulation allows for advection of bulk protein to the hydrophobic interface. PMID:26956731

  9. Immunotherapy for the treatment of Alzheimer's disease: amyloid-β or tau, which is the right target?

    Directory of Open Access Journals (Sweden)

    Castillo-Carranza DL

    2013-12-01

    Full Text Available Diana L Castillo-Carranza,1,2 Marcos J Guerrero-Muñoz,1,2 Rakez Kayed1–31Mitchell Center for Neurodegenerative Diseases, 2Departments of Neurology, Neuroscience, and Cell Biology, 3Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX, USAAbstract: Alzheimer's disease (AD is characterized by the presence of amyloid plaques composed mainly of amyloid-β (Aβ protein. Overproduction or slow clearance of Aβ initiates a cascade of pathologic events that may lead to formation of neurofibrillary tangles, neuronal cell death, and dementia. Although immunotherapy in animal models has been demonstrated to be successful at removing plaques or prefibrillar forms of Aβ, clinical trials have yielded disappointing results. The lack of substantial cognitive improvement obtained by targeting Aβ raises the question of whether or not this is the correct target. Another important pathologic process in the AD brain is tau aggregation, which seems to become independent once initiated. Recent studies targeting tau in AD mouse models have displayed evidence of cognitive improvement, providing a novel therapeutic approach for the treatment of AD. In this review, we describe new advances in immunotherapy targeting Aβ peptide and tau protein, as well as future directions.Keywords: immunotherapy, Alzheimer's disease, β-amyloid, tau

  10. The relationship between complement factor C3, APOE ε4, amyloid and tau in Alzheimer's disease.

    Science.gov (United States)

    Bonham, Luke W; Desikan, Rahul S; Yokoyama, Jennifer S

    2016-01-01

    Inflammation is becoming increasingly recognized as an important contributor to Alzheimer's disease (AD) pathogenesis. As a part of the innate immune system, the complement cascade enhances the body's ability to destroy and remove pathogens and has recently been shown to influence Alzheimer's associated amyloid and tau pathology. However, little is known in humans about the effects of the complement system and genetic modifiers of AD risk like the ε4 allele of apolioprotein E (APOE ε4) on AD pathobiology. We evaluated cerebrospinal fluid (CSF) protein levels from 267 individuals clinically diagnosed as cognitively normal, mild cognitive impairment, and AD. Using linear models, we assessed the relationship between APOE ε4 genotype, CSF Complement 3 (C3), CSF amyloid-β (amyloid) and CSF hyperphosphorylated tau (ptau). We found a significant interaction between APOE ε4 and CSF C3 on both CSF amyloid and CSF ptau. We also found that CSF C3 is only associated with CSF ptau after accounting for CSF amyloid. Our results support a conceptual model of the AD pathogenic cascade where a synergistic relationship between the complement cascade (C3) and APOE ε4 results in elevated Alzheimer's neurodegeneration and in turn, amyloid further regulates the effect of the complement cascade on downstream tau pathology. PMID:27357286

  11. Specific Inhibition of β-Secretase Processing of the Alzheimer Disease Amyloid Precursor Protein

    Directory of Open Access Journals (Sweden)

    Saoussen Ben Halima

    2016-03-01

    Full Text Available Development of disease-modifying therapeutics is urgently needed for treating Alzheimer disease (AD. AD is characterized by toxic β-amyloid (Aβ peptides produced by β- and γ-secretase-mediated cleavage of the amyloid precursor protein (APP. β-secretase inhibitors reduce Aβ levels, but mechanism-based side effects arise because they also inhibit β-cleavage of non-amyloid substrates like Neuregulin. We report that β-secretase has a higher affinity for Neuregulin than it does for APP. Kinetic studies demonstrate that the affinities and catalytic efficiencies of β-secretase are higher toward non-amyloid substrates than toward APP. We show that non-amyloid substrates are processed by β-secretase in an endocytosis-independent manner. Exploiting this compartmentalization of substrates, we specifically target the endosomal β-secretase by an endosomally targeted β-secretase inhibitor, which blocked cleavage of APP but not non-amyloid substrates in many cell systems, including induced pluripotent stem cell (iPSC-derived neurons. β-secretase inhibitors can be designed to specifically inhibit the Alzheimer process, enhancing their potential as AD therapeutics without undesired side effects.

  12. Destruction of amyloid fibrils by graphene through penetration and extraction of peptides.

    Science.gov (United States)

    Yang, Zaixing; Ge, Cuicui; Liu, Jiajia; Chong, Yu; Gu, Zonglin; Jimenez-Cruz, Camilo A; Chai, Zhifang; Zhou, Ruhong

    2015-11-28

    Current therapies for Alzheimer's disease (AD) can provide a moderate symptomatic reduction or delay progression at various stages of the disease, but such treatments ultimately do not arrest the advancement of AD. As such, novel approaches for AD treatment and prevention are urgently needed. We here provide both experimental and computational evidence that pristine graphene and graphene-oxide nanosheets can inhibit Aβ peptide monomer fibrillation and clear mature amyloid fibrils, thus impacting the central molecular superstructures correlated with AD pathogenesis. Our molecular dynamics simulations for the first time reveal that graphene nanosheets can penetrate and extract a large number of peptides from pre-formed amyloid fibrils; these effects seem to be related to exceptionally strong dispersion interactions between peptides and graphene that are further enhanced by strong π-π stacking between the aromatic residues of extracted Aβ peptides and the graphene surface. Atomic force microscopy images confirm these predictions by demonstrating that mature amyloid fibrils can be cut into pieces and cleared by graphene oxides. Thioflavin fluorescence assays further illustrate the detailed dynamic processes by which graphene induces inhibition of monomer aggregation and clearance of mature amyloid fibrils, respectively. Cell viability and ROS assays indicate that graphene oxide can indeed mitigate cytotoxicity of Aβ peptide amyloids. Our findings provide new insights into the underlying molecular mechanisms that define graphene-amyloid interaction and suggest that further research on nanotherapies for Alzheimer's and other protein aggregation-related diseases is warranted.

  13. Lipidome of atherosclerotic plaques from hypercholesterolemic rabbits.

    Science.gov (United States)

    Bojic, Lazar A; McLaren, David G; Shah, Vinit; Previs, Stephen F; Johns, Douglas G; Castro-Perez, Jose M

    2014-12-15

    The cellular, macromolecular and neutral lipid composition of the atherosclerotic plaque has been extensively characterized. However, a comprehensive lipidomic analysis of the major lipid classes within atherosclerotic lesions has not been reported. The objective of this study was to produce a detailed framework of the lipids that comprise the atherosclerotic lesion of a widely used pre-clinical model of plaque progression. Male New Zealand White rabbits were administered regular chow supplemented with 0.5% cholesterol (HC) for 12 weeks to induce hypercholesterolemia and atherosclerosis. Our lipidomic analyses of plaques isolated from rabbits fed the HC diet, using ultra-performance liquid chromatography (UPLC) and high-resolution mass spectrometry, detected most of the major lipid classes including: Cholesteryl esters, triacylglycerols, phosphatidylcholines, sphingomyelins, diacylglycerols, fatty acids, phosphatidylserines, lysophosphatidylcholines, ceramides, phosphatidylglycerols, phosphatidylinositols and phosphatidylethanolamines. Given that cholesteryl esters, triacylglycerols and phosphatidylcholines comprise greater than 75% of total plasma lipids, we directed particular attention towards the qualitative and quantitative assessment of the fatty acid composition of these lipids. We additionally found that sphingomyelins were relatively abundant lipid class within lesions, and compared the abundance of sphingomyelins to their precursor phosphatidylcholines. The studies presented here are the first approach to a comprehensive characterization of the atherosclerotic plaque lipidome.

  14. Lipidome of Atherosclerotic Plaques from Hypercholesterolemic Rabbits

    Directory of Open Access Journals (Sweden)

    Lazar A. Bojic

    2014-12-01

    Full Text Available The cellular, macromolecular and neutral lipid composition of the atherosclerotic plaque has been extensively characterized. However, a comprehensive lipidomic analysis of the major lipid classes within atherosclerotic lesions has not been reported. The objective of this study was to produce a detailed framework of the lipids that comprise the atherosclerotic lesion of a widely used pre-clinical model of plaque progression. Male New Zealand White rabbits were administered regular chow supplemented with 0.5% cholesterol (HC for 12 weeks to induce hypercholesterolemia and atherosclerosis. Our lipidomic analyses of plaques isolated from rabbits fed the HC diet, using ultra-performance liquid chromatography (UPLC and high-resolution mass spectrometry, detected most of the major lipid classes including: Cholesteryl esters, triacylglycerols, phosphatidylcholines, sphingomyelins, diacylglycerols, fatty acids, phosphatidylserines, lysophosphatidylcholines, ceramides, phosphatidylglycerols, phosphatidylinositols and phosphatidylethanolamines. Given that cholesteryl esters, triacylglycerols and phosphatidylcholines comprise greater than 75% of total plasma lipids, we directed particular attention towards the qualitative and quantitative assessment of the fatty acid composition of these lipids. We additionally found that sphingomyelins were relatively abundant lipid class within lesions, and compared the abundance of sphingomyelins to their precursor phosphatidylcholines. The studies presented here are the first approach to a comprehensive characterization of the atherosclerotic plaque lipidome.

  15. Association between Randall's Plaque and Calcifying Nanoparticles

    Science.gov (United States)

    Citfcioglu, Neva; Vejdani, Kaveh; Lee, Olivia; Mathew, Grace; Aho, Katja M.; Kajander, Olavi; McKay, David S.; Jones, Jeffrey A.; Feiveson, Alan H.; Stoller, Marshall L.

    2007-01-01

    Randall initially described calcified subepithelial papillary plaques, which he hypothesized as nidi for kidney stone formation. The discovery of calcifying nanoparticles (CNP) in many calcifying processes of human tissues has raised another hypothesis about their possible involvement in urinary stone formation. This research is the first attempt to investigate the potential association of these two hypotheses. We collected renal papilla and blood samples from 17 human patients who had undergone laparoscopic nephrectomy due to neoplasia. Immunohistochemical staining (IHS) was applied on the tissue samples using monoclonal antibody 8D10 (mAb) against CNP. Homogenized papillary tissues and serum samples were cultured for CNP. Scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDS) analysis were performed on fixed papillary samples. Randall's plaques were visible on gross inspection in 11 out of 17 collected samples. IHS was positive for CNP antigen in 8 of these 11 visually positive samples, but in only 1 of the remaining 6 samples. SEM revealed spherical apatite formations in 14 samples, all of which had calcium and phosphate peaks detected by EDS analysis. From this study, there was some evidence of a link between the presence of Randall's plaques and the detection of CNP, also referred to as nanobacteria. Although causality was not demonstrated, these results suggest that further studies with negative control samples should be made to explore the etiology of Randall's plaque formation, thus leading to a better understanding of the pathogenesis of stone formation.

  16. Plaque rupture in humans and mice

    DEFF Research Database (Denmark)

    Schwartz, Stephen M; Galis, Zorina S; Rosenfeld, Michael E;

    2007-01-01

    Despite the many studies of murine atherosclerosis, we do not yet know the relevance of the natural history of this model to the final events precipitated by plaque disruption of human atherosclerotic lesions. The literature has become particularly confused because of the common use of terms such...

  17. Mathematical models for atherosclerotic plaque evolution

    NARCIS (Netherlands)

    Bulelzai, M.A.K.

    2013-01-01

    Atherosclerosis is a disease in which low density lipoproteins (LDL) accumulate in the arterial wall due to an inflammatory response, which is triggered by the oxidation of LDL molecules that are already present in the arterial wall. Progression of atherosclerotic plaques involves many components wh

  18. Adalimumab: A Review in Chronic Plaque Psoriasis.

    Science.gov (United States)

    Burness, Celeste B; McKeage, Kate

    2015-12-01

    Adalimumab (Humira(®)) is a fully human monoclonal antibody against tumour necrosis factor (TNF), formulated for subcutaneous administration. It is well established in the treatment of adults with moderate-to-severe chronic plaque psoriasis and has recently received approval in the EU for the treatment of severe chronic plaque psoriasis in children and adolescents from 4 years of age. In a phase III trial in paediatric patients, a significantly greater proportion of patients receiving adalimumab 0.8 mg/kg (to a maximum of 40 mg) every other week (eow) achieved a ≥75 % improvement from baseline in Psoriasis Area and Severity Index than those receiving methotrexate after 16 weeks of treatment. In adults, well-designed randomized clinical trials demonstrated that adalimumab 40 mg eow effectively reduced the signs and symptoms of psoriasis and improved dermatology-specific and general measures of health-related quality of life, with these benefits sustained during long-term treatment. Adalimumab was generally well tolerated, compared with placebo or methotrexate, during clinical trials in paediatric and adult patients with chronic plaque psoriasis. Thus, adalimumab remains an important treatment strategy in adults with moderate-to-severe chronic plaque psoriasis and provides a promising new systemic treatment option for children and adolescents from 4 years of age with severe psoriasis.

  19. Infliximab for the treatment of plaque psoriasis

    Directory of Open Access Journals (Sweden)

    Jennifer S Gall

    2008-03-01

    Full Text Available Jennifer S Gall, Robert E KalbState University of New York at Buffalo, School of Medicine and Biomedical Sciences, Department of Dermatology, NY, USAAbstract: Infliximab is a monoclonal antibody that targets tumor necrosis factor-α (TNFα. It is used in the treatment of a number of inflammatory disorders including severe plaque psoriasis. TNFα is thought to have a major role in psoriasis by promoting an inflammatory infiltrate into the skin and inducing keratinocyte proliferation and preventing keratinocyte apoptosis, which directly contributes to the characteristic plaque skin lesions. Based on four randomized, placebo-controlled, double-blind clinical trials and nine open-label uncontrolled trials of the use of infliximab in plaque psoriasis, it was found that infliximab is a highly efficacious, rapid, sustainable, and relatively safe therapy. Yet as with any biologic, caution is recommended in its use as infusion reactions, lupus-like syndromes, infections, malignancies including lymphomas, as well as other rare events have been reported.Keywords: infliximab, psoriasis, plaque

  20. Large plaque parapsoriasis in a child

    Directory of Open Access Journals (Sweden)

    Das Jayanta

    2005-01-01

    Full Text Available A case of large plaque parapsoriasis with extensive skin lesions is presented for its unusual clinical features. The controversial issue of its nosological position is discussed as it has a considerable impact on the management of such cases.

  1. Ex vivo coronary atherosclerotic plaque characterization with multi-detector-row CT

    International Nuclear Information System (INIS)

    Multi-detector-row CT angiography (CTA) is a new technology that allows for non-invasive investigation of coronary atherosclerosis in patients. The relation between the morphology of atherosclerotic plaques assessed by CTA and histopathology is unknown. We investigated 11 human cadaver heart specimens. A mixture of methylcellulose and CT contrast media was injected into the coronary arteries to achieve in-vivo-like contrast enhancement within the coronary artery lumen. The morphologic pattern of atherosclerotic lesions found on CTA images and the tissue attenuation of non-calcified plaques were determined. After CTA imaging, atherosclerotic lesions in the coronary arteries were macroscopically identified and characterized histopathologically according to American Heart Association criteria. A total of 50 and 40 lesions were found macroscopically and by CTA, respectively. Thirty-three lesions could have been compared directly. The sensitivity of CTA compared with macroscopic detection of atheromas, fibroatheromas, fibrocalcified, and calcified lesions was 73, 70, 86, and 100%, respectively. The mean CT attenuation of predominantly lipid-rich and fibrous-rich plaques was significantly different (47±9 and 104±28 HU, respectively; p<0.01). Atherosclerotic coronary plaques detected by CTA may represent different stages of coronary atherosclerosis. The tissue attenuation of non-calcified plaques may allow for assessment of their predominant component. (orig.)

  2. Inflamed psoriatic plaques: Drug toxicity or disease exacerbation?

    Directory of Open Access Journals (Sweden)

    Nidhi Jindal

    2013-01-01

    Full Text Available We are presenting a case of Methotrexate treated stable plaque psoriasis, in whom inflamed psoriatic plaques of drug toxicity were misdiagnosed as disease exacerbation. Erosive psoriatic plaques were present in the absence of biochemical or hematological derangements. Ulceration of psoriatic plaques in the presence of disturbed hematological profile is well described as a harbinger of methotrexate toxicity, but this kind of erosions in the absence of any systemic involvement is the first report of its kind.

  3. Characterization of Amyloid Cores in Prion Domains

    Science.gov (United States)

    Sant’Anna, Ricardo; Fernández, Maria Rosario; Batlle, Cristina; Navarro, Susanna; de Groot, Natalia S.; Serpell, Louise; Ventura, Salvador

    2016-01-01

    Amyloids consist of repetitions of a specific polypeptide chain in a regular cross-β-sheet conformation. Amyloid propensity is largely determined by the protein sequence, the aggregation process being nucleated by specific and short segments. Prions are special amyloids that become self-perpetuating after aggregation. Prions are responsible for neuropathology in mammals, but they can also be functional, as in yeast prions. The conversion of these last proteins to the prion state is driven by prion forming domains (PFDs), which are generally large, intrinsically disordered, enriched in glutamines/asparagines and depleted in hydrophobic residues. The self-assembly of PFDs has been thought to rely mostly on their particular amino acid composition, rather than on their sequence. Instead, we have recently proposed that specific amyloid-prone sequences within PFDs might be key to their prion behaviour. Here, we demonstrate experimentally the existence of these amyloid stretches inside the PFDs of the canonical Sup35, Swi1, Mot3 and Ure2 prions. These sequences self-assemble efficiently into highly ordered amyloid fibrils, that are functionally competent, being able to promote the PFD amyloid conversion in vitro and in vivo. Computational analyses indicate that these kind of amyloid stretches may act as typical nucleating signals in a number of different prion domains. PMID:27686217

  4. Tensile and compressive properties of fresh human carotid atherosclerotic plaques.

    LENUS (Irish Health Repository)

    Maher, Eoghan

    2009-12-11

    Accurate characterisation of the mechanical properties of human atherosclerotic plaque is important for our understanding of the role of vascular mechanics in the development and treatment of atherosclerosis. The majority of previous studies investigating the mechanical properties of human plaque are based on tests of plaque tissue removed following autopsy. This study aims to characterise the mechanical behaviour of fresh human carotid plaques removed during endarterectomy and tested within 2h. A total of 50 radial compressive and 17 circumferential tensile uniaxial tests were performed on samples taken from 14 carotid plaques. The clinical classification of each plaque, as determined by duplex ultrasound is also reported. Plaques were classified as calcified, mixed or echolucent. Experimental data indicated that plaques were highly inhomogeneous; with variations seen in the mechanical properties of plaque obtained from individual donors and between donors. The mean behaviour of samples for each classification indicated that calcified plaques had the stiffest response, while echolucent plaques were the least stiff. Results also indicated that there may be a difference in behaviour of samples taken from different anatomical locations (common, internal and external carotid), however the large variability indicates that more testing is needed to reach significant conclusions. This work represents a step towards a better understanding of the in vivo mechanical behaviour of human atherosclerotic plaque.

  5. Three-dimensional carotid ultrasound plaque texture predicts vascular events

    DEFF Research Database (Denmark)

    van Engelen, Arna; Wannarong, Thapat; Parraga, Grace;

    2014-01-01

    carotid plaque volume and 376 measures of plaque texture. Patients were followed up to 5 years (median [range], 3.12 [0.77-4.66]) for myocardial infarction, transient ischemic attack, and stroke. Sparse Cox regression was used to select the most predictive plaque texture measurements in independent...

  6. Glial fibrillary acidic protein isoform expression in plaque related astrogliosis in Alzheimer's disease.

    Science.gov (United States)

    Kamphuis, Willem; Middeldorp, Jinte; Kooijman, Lieneke; Sluijs, Jacqueline A; Kooi, Evert-Jan; Moeton, Martina; Freriks, Michel; Mizee, Mark R; Hol, Elly M

    2014-03-01

    In Alzheimer's disease (AD), amyloid plaques are surrounded by reactive astrocytes with an increased expression of intermediate filaments including glial fibrillary acidic protein (GFAP). Different GFAP isoforms have been identified that are differentially expressed by specific subpopulations of astrocytes and that impose different properties to the intermediate filament network. We studied transcript levels and protein expression patterns of all known GFAP isoforms in human hippocampal AD tissue at different stages of the disease. Ten different transcripts for GFAP isoforms were detected at different abundancies. Transcript levels of most isoforms increased with AD progression. GFAPδ-immunopositive astrocytes were observed in subgranular zone, hilus, and stratum-lacunosum-moleculare. GFAPδ-positive cells also stained for GFAPα. In AD donors, astrocytes near plaques displayed increased staining of both GFAPα and GFAPδ. The reading-frame-shifted isoform, GFAP(+1), staining was confined to a subset of astrocytes with long processes, and their number increased in the course of AD. In conclusion, the various GFAP isoforms show differential transcript levels and are upregulated in a concerted manner in AD. The GFAP(+1) isoform defines a unique subset of astrocytes, with numbers increasing with AD progression. These data indicate the need for future exploration of underlying mechanisms concerning the functions of GFAPδ and GFAP(+1) isoforms in astrocytes and their possible role in AD pathology.

  7. Amyloid fibrils compared to peptide nanotubes.

    Science.gov (United States)

    Zganec, Matjaž; Zerovnik, Eva

    2014-09-01

    Prefibrillar oligomeric states and amyloid fibrils of amyloid-forming proteins qualify as nanoparticles. We aim to predict what biophysical and biochemical properties they could share in common with better researched peptide nanotubes. We first describe what is known of amyloid fibrils and prefibrillar aggregates (oligomers and protofibrils): their structure, mechanisms of formation and putative mechanism of cytotoxicity. In distinction from other neuronal fibrillar constituents, amyloid fibrils are believed to cause pathology, however, some can also be functional. Second, we give a review of known biophysical properties of peptide nanotubes. Finally, we compare properties of these two macromolecular states side by side and discuss which measurements that have already been done with peptide nanotubes could be done with amyloid fibrils as well.

  8. Association between amylin and amyloid-β peptides in plasma in the context of apolipoprotein E4 allele.

    Directory of Open Access Journals (Sweden)

    Wei Qiao Qiu

    Full Text Available Amylin, a pancreatic peptide that readily crosses the blood brain barrier (BBB, and amyloid-beta peptide (Aβ, the main component of amyloid plaques and a major component of Alzheimer's disease (AD pathology in the brain, share several features. These include having similar β-sheet secondary structures, binding to the same receptor, and being degraded by the same protease. Thus, amylin may be associated with Aβ, but the nature of their relationship remains unclear. In this study, we used human samples to study the relationship between plasma amylin and Aβ in the context of the apolipoprotein E alleles (ApoE. We found that concentrations of Aβ1-42 (P<0.0001 and Aβ1-40 (P<0.0001 increased with each quartile increase of amylin. Using multivariate regression analysis, the study sample showed that plasma amylin was associated with Aβ1-42 (β = +0.149, SE = 0.025, P<0.0001 and Aβ1-40 (β = +0.034, SE = 0.016, P = 0.04 as an outcome after adjusting for age, gender, ethnicity, ApoE4, BMI, diabetes, stroke, kidney function and lipid profile. This positive association between amylin and Aβ1-42 in plasma was found regardless of the ApoE genotype. In contrast, the relationship between amylin and Aβ1-40 in plasma seen in ApoE4 non-carriers disappeared in the presence of ApoE4. Using AD mouse models, our recent study demonstrates that intraperitoneal (i.p. injection of synthetic amylin enhances the removal of Aβ from the brain into blood, thus resulting in increased blood levels of both amylin and Aβ. The positive association between amylin and Aβ, especially Aβ1-42, in human blood samples is probably relevant to the findings in the AD mouse models. The presence of ApoE4 may attenuate amylin's capacity to remove Aβ, especially Aβ1-40, from the AD brain.

  9. General amyloid inhibitors? A critical examination of the inhibition of IAPP amyloid formation by inositol stereoisomers.

    Directory of Open Access Journals (Sweden)

    Hui Wang

    Full Text Available Islet amyloid polypeptide (IAPP or amylin forms amyloid deposits in the islets of Langerhans; a process that is believed to contribute to the progression of type 2 diabetes and to the failure of islet transplants. An emerging theme in amyloid research is the hypothesis that the toxic species produced during amyloid formation by different polypeptides share common features and exert their effects by common mechanisms. If correct, this suggests that inhibitors of amyloid formation by one polypeptide might be effective against other amyloidogenic sequences. IAPP and Aβ, the peptide responsible for amyloid formation in Alzheimer's disease, are particularly interesting in this regard as they are both natively unfolded in their monomeric states and share some common characteristics. Comparatively little effort has been expended on the design of IAPP amyloid inhibitors, thus it is natural to inquire if Aβ inhibitors are effective against IAPP, especially since no IAPP inhibitors have been clinically approved. A range of compounds inhibit Aβ amyloid formation, including various stereoisomers of inositol. Myo-, scyllo-, and epi-inositol have been shown to induce conformational changes in Aβ and prevent Aβ amyloid fibril formation by stabilizing non-fibrillar β-sheet structures. We investigate the ability of inositol stereoisomers to inhibit amyloid formation by IAPP. The compounds do not induce a conformational change in IAPP and are ineffective inhibitors of IAPP amyloid formation, although some do lead to modest apparent changes in IAPP amyloid fibril morphology. Thus not all classes of Aβ inhibitors are effective against IAPP. This work provides a basis of comparison to work on polyphenol based inhibitors of IAPP amyloid formation and helps provide clues as to the features which render them effective. The study also helps provide information for further efforts in rational inhibitor design.

  10. Binding of ACE-inhibitors to in vitro and patient-derived amyloid-β fibril models

    Science.gov (United States)

    Bhavaraju, Manikanthan; Phillips, Malachi; Bowman, Deborah; Aceves-Hernandez, Juan M.; Hansmann, Ulrich H. E.

    2016-01-01

    Currently, no drugs exist that can prevent or reverse Alzheimer's disease, a neurodegenerative disease associated with the presence, in the brain, of plaques that are composed of β-amyloid (Aβ) peptides. Recent studies suggest that angiotensin-converting enzyme (ACE) inhibitors, a set of drugs used to treat hypertension, may inhibit amyloid formation in vitro. In the present study, we investigate through computer simulations the binding of ACE inhibitors to patient-derived Aβ fibrils and contrast it with that of ACE inhibitors binding to in vitro generated fibrils. The binding affinities of the ACE inhibitors are compared with that of Congo red, a dye that is used to identify amyloid structures and that is known to be a weak inhibitor of Aβ aggregation. We find that ACE inhibitors have a lower binding affinity to the patient-derived fibrils than to in vitro generated ones. For patient-derived fibrils, their binding affinities are even lower than that of Congo red. Our observations raise doubts on the hypothesis that these drugs inhibit fibril formation in Alzheimer patients by interacting directly with the amyloids.

  11. The contrasting effect of macromolecular crowding on amyloid fibril formation.

    Directory of Open Access Journals (Sweden)

    Qian Ma

    Full Text Available BACKGROUND: Amyloid fibrils associated with neurodegenerative diseases can be considered biologically relevant failures of cellular quality control mechanisms. It is known that in vivo human Tau protein, human prion protein, and human copper, zinc superoxide dismutase (SOD1 have the tendency to form fibril deposits in a variety of tissues and they are associated with different neurodegenerative diseases, while rabbit prion protein and hen egg white lysozyme do not readily form fibrils and are unlikely to cause neurodegenerative diseases. In this study, we have investigated the contrasting effect of macromolecular crowding on fibril formation of different proteins. METHODOLOGY/PRINCIPAL FINDINGS: As revealed by assays based on thioflavin T binding and turbidity, human Tau fragments, when phosphorylated by glycogen synthase kinase-3β, do not form filaments in the absence of a crowding agent but do form fibrils in the presence of a crowding agent, and the presence of a strong crowding agent dramatically promotes amyloid fibril formation of human prion protein and its two pathogenic mutants E196K and D178N. Such an enhancing effect of macromolecular crowding on fibril formation is also observed for a pathological human SOD1 mutant A4V. On the other hand, rabbit prion protein and hen lysozyme do not form amyloid fibrils when a crowding agent at 300 g/l is used but do form fibrils in the absence of a crowding agent. Furthermore, aggregation of these two proteins is remarkably inhibited by Ficoll 70 and dextran 70 at 200 g/l. CONCLUSIONS/SIGNIFICANCE: We suggest that proteins associated with neurodegenerative diseases are more likely to form amyloid fibrils under crowded conditions than in dilute solutions. By contrast, some of the proteins that are not neurodegenerative disease-associated are unlikely to misfold in crowded physiological environments. A possible explanation for the contrasting effect of macromolecular crowding on these two sets of

  12. High-resolution analytical imaging and electron holography of magnetite particles in amyloid cores of Alzheimer’s disease

    Science.gov (United States)

    Plascencia-Villa, Germán; Ponce, Arturo; Collingwood, Joanna F.; Arellano-Jiménez, M. Josefina; Zhu, Xiongwei; Rogers, Jack T.; Betancourt, Israel; José-Yacamán, Miguel; Perry, George

    2016-04-01

    Abnormal accumulation of brain metals is a key feature of Alzheimer’s disease (AD). Formation of amyloidplaque cores (APC) is related to interactions with biometals, especially Fe, Cu and Zn, but their particular structural associations and roles remain unclear. Using an integrative set of advanced transmission electron microscopy (TEM) techniques, including spherical aberration-corrected scanning transmission electron microscopy (Cs-STEM), nano-beam electron diffraction, electron holography and analytical spectroscopy techniques (EDX and EELS), we demonstrate that Fe in APC is present as iron oxide (Fe3O4) magnetite nanoparticles. Here we show that Fe was accumulated primarily as nanostructured particles within APC, whereas Cu and Zn were distributed through the amyloid fibers. Remarkably, these highly organized crystalline magnetite nanostructures directly bound into fibrillar Aβ showed characteristic superparamagnetic responses with saturated magnetization with circular contours, as observed for the first time by off-axis electron holography of nanometer scale particles.

  13. Crude caffeine reduces memory impairment and amyloid β(1-42) levels in an Alzheimer's mouse model.

    Science.gov (United States)

    Chu, Yi-Fang; Chang, Wen-Han; Black, Richard M; Liu, Jia-Ren; Sompol, Pradoldej; Chen, Yumin; Wei, Huilin; Zhao, Qiuyan; Cheng, Irene H

    2012-12-01

    Alzheimer's disease (AD), a chronic neurodegenerative disorder associated with the abnormal accumulations of amyloid β (Aβ) peptide and oxidative stress in the brain, is the most common form of dementia among the elderly. Crude caffeine (CC), a major by-product of the decaffeination of coffee, has potent hydrophilic antioxidant activity and may reduce inflammatory processes. Here, we showed that CC and pure caffeine intake had beneficial effects in a mouse model of AD. Administration of CC or pure caffeine for 2months partially prevented memory impairment in AD mice, with CC having greater effects than pure caffeine. Furthermore, consumption of CC, but not pure caffeine, reduced the Aβ(1-42) levels and the number of amyloid plaques in the hippocampus. Moreover, CC and caffeine protected primary neurons from Aβ-induced cell death and suppressed Aβ-induced caspase-3 activity. Our data indicate that CC may contain prophylactic agents against the cell death and the memory impairment in AD.

  14. Synthesis and biological evaluation of indole-chalcone derivatives as β-amyloid imaging probe.

    Science.gov (United States)

    Cui, Mengchao; Ono, Masahiro; Kimura, Hiroyuki; Liu, Bo Li; Saji, Hideo

    2011-02-01

    A series of chaclone derivatives containing an indole moiety were evaluated in competitive binding assays with Aβ(1-42) aggregates versus [(125)I]IMPY. The affinity of these compounds ranged from 4.46 to >1008 nM, depending on the substitution on the phenyl ring. Fluorescent staining in vitro showed that one compound with a N,N-dimethylamino group intensely stained Aβ plaques within brain sections of AD transgenic mice. The radioiodinated probe [(125)I]-(E)-3-(1H-indol-5-yl)-1-(4-iodophenyl)prop-2-en-1-one, [(125)I]4, was prepared and autoradiography in sections of brain tissue from an animal model of AD showed that it labeled Aβ plaques specifically. However, experiments with normal mice indicated that [(125)I]4 exhibited a low uptake into the brain in vivo (0.41% ID/g at 2 min). Additional chemical modifications of this indole-chalcone structure may lead to more useful imaging agents for detecting β-amyloid plaques in the brains of AD patients. PMID:21216142

  15. Amyloid domains in the cell nucleus controlled by nucleoskeletal protein lamin B1 reveal a new pathway of mercury neurotoxicity

    Directory of Open Access Journals (Sweden)

    Florian Arnhold

    2015-02-01

    Full Text Available Mercury (Hg is a bioaccumulating trace metal that globally circulates the atmosphere and waters in its elemental, inorganic and organic chemical forms. While Hg represents a notorious neurotoxicant, the underlying cellular pathways are insufficiently understood. We identify amyloid protein aggregation in the cell nucleus as a novel pathway of Hg-bio-interactions. By mass spectrometry of purified protein aggregates, a subset of spliceosomal components and nucleoskeletal protein lamin B1 were detected as constituent parts of an Hg-induced nuclear aggregome network. The aggregome network was located by confocal imaging of amyloid-specific antibodies and dyes to amyloid cores within splicing-speckles that additionally recruit components of the ubiquitin-proteasome system. Hg significantly enhances global proteasomal activity in the nucleus, suggesting that formation of amyloid speckles plays a role in maintenance of protein homeostasis. RNAi knock down showed that lamin B1 for its part regulates amyloid speckle formation and thus likewise participates in nuclear protein homeostasis. As the Hg-induced cascade of interactions between the nucleoskeleton and protein homeostasis reduces neuronal signalling, amyloid fibrillation in the cell nucleus is introduced as a feature of Hg-neurotoxicity that opens new avenues of future research. Similar to protein aggregation events in the cytoplasm that are controlled by the cytoskeleton, amyloid fibrillation of nuclear proteins may be driven by the nucleoskeleton.

  16. In vivo amyloid-β imaging in the APPPS1-21 transgenic mouse model with a 89Zr- labeled monoclonal antibody.

    Directory of Open Access Journals (Sweden)

    Ann-Marie eWaldron

    2016-03-01

    Full Text Available Introduction: The accumulation of amyloid-β is a pathological hallmark of Alzheimer’s disease and is a target for molecular imaging probes to aid in diagnosis and disease monitoring. This study evaluated the feasibility of using a radiolabeled monoclonal anti-amyloid-β antibody (JRF/AβN/25 to non-invasively assess amyloid-β burden in aged transgenic mice (APPPS1-21 with μPET imaging.Methods: We investigated the antibody JRF/AβN/25 that binds to full-length Aβ. JRF/AβN/25 was radiolabeled with a [89Zr]-desferal chelate and intravenously injected into 12-13 month aged APPPS1-21 mice and their wild-type (WT controls. Mice underwent in vivo μPET imaging at 2, 4 and 7 days post injection and were sacrificed at the end of each time point to assess brain penetrance, plaque labeling, biodistribution and tracer stability. To confirm imaging specificity we also evaluated brain uptake of a non-amyloid targeting [89Zr]-labeled antibody (Trastuzumab as a negative control, additionally we performed a competitive blocking study with non-radiolabeled Df-Bz-JRF/AβN/25 and finally we assessed the possible confounding effects of blood retention. Results: Voxel-wise analysis of μPET data demonstrated significant [89Zr]-Df-Bz-JRF/AβN/25 retention in APPPS1-21 mice at all time points investigated. With ex vivo measures of radioactivity, significantly higher retention of [89Zr]-Df-Bz-JRF/AβN/25 was found at 4 and 7 day pi in APPPS1-21 mice. Despite the observed genotypic differences, comparisons with immunohistochemistry revealed that in vivo plaque labeling was low. Furthermore, pre-treatment with Df-Bz-JRF/AβN/25 only partially blocked [89Zr]-Df-Bz-JRF/AβN/25 uptake indicative of a high contribution of non-specific binding. Conclusion: Amyloid plaques were detected in vivo with a radiolabeled monoclonal anti-amyloid antibody. The low brain penetrance of the antibodies in addition to non-specific binding prevented an accurate estimation of plaque

  17. Reliability and discriminatory power of methods for dental plaque quantification

    Directory of Open Access Journals (Sweden)

    Daniela Prócida Raggio

    2010-04-01

    Full Text Available OBJECTIVE: This in situ study evaluated the discriminatory power and reliability of methods of dental plaque quantification and the relationship between visual indices (VI and fluorescence camera (FC to detect plaque. MATERIAL AND METHODS: Six volunteers used palatal appliances with six bovine enamel blocks presenting different stages of plaque accumulation. The presence of plaque with and without disclosing was assessed using VI. Images were obtained with FC and digital camera in both conditions. The area covered by plaque was assessed. Examinations were done by two independent examiners. Data were analyzed by Kruskal-Wallis and Kappa tests to compare different conditions of samples and to assess the inter-examiner reproducibility. RESULTS: Some methods presented adequate reproducibility. The Turesky index and the assessment of area covered by disclosed plaque in the FC images presented the highest discriminatory powers. CONCLUSION: The Turesky index and images with FC with disclosing present good reliability and discriminatory power in quantifying dental plaque.

  18. Oculocutaneous albinism complicated with an ulcerated plaque

    Directory of Open Access Journals (Sweden)

    Lokanatha Keshavalu

    2013-04-01

    Full Text Available A 32-year-old male with a history of albinism and farmer by occupation presented with an ulcerated plaque on the right wrist. The patient had light eyes, hair, and skin. Physical examination showed extensive photodamage. A skin biopsy specimen from the plaque revealed a well-differentiated squamous-cell carcinoma. Wide surgical excision was done. The most common types of oculocutaneous albinism (OCA, OCA 1 and OCA 2, are autosomal recessive disorders of pigmentation that commonly affect the skin, hair and eyes. Photodamage and skin cancers plague patients with albinism. Albinos face a myriad of social and medical issues. Importance of photoprotection, skin cancer surveillance and treatment has been stressed upon in this report.

  19. Helicobacter pylori in Dental Plaque and Saliva

    OpenAIRE

    Kim, Nayoung; Lim, Seon Hee; Lee, Kye Heui; You, Jun Young; Kim, Jung Mogg; Lee, Na Rae; Jung, Hyun Chae; Song, In Sung; Kim, Chung Yong

    2000-01-01

    Background About half of the world population is infected with H. pylori, but the transmission and the source of this infection are still unclear. Recently, dental plaque (DP) and saliva have been implicated as possible sources of H. pylori infection. This study was done to investigate the detection rates of H. pylori in the DP and saliva by use of PCR depending on H. pylori infection state of gastric mucosa. Methods In 46 subjects, gastric H. pylori colonization was evaluated with CLO test, ...

  20. Characterization of cDNA encoding a human sperm membrane protein related to A4 amyloid protein.

    OpenAIRE

    Yan, Y C; Bai, Y.(Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, China); Wang, L.F.; Miao, S Y; Koide, S S

    1990-01-01

    A rat testis lambda gt11 cDNA library was screened with a monoclonal antibody raised against a human sperm membrane protein designated YWK-II. A clone was found with a cDNA insert composed of 1837 base pairs that contained an open reading frame coding for 191 amino acid residues. The deduced polypeptide contained a segment with high homology to the transmembrane-cytoplasmic domains of the A4 amyloid protein found in brain plaques of Alzheimer disease patients. A sequence of basic amino acid r...

  1. Hacking the Code of Amyloid Formation

    Science.gov (United States)

    Pastor, M Teresa; Esteras-Chopo, Alexandra

    2007-01-01

    Many research efforts in the last years have been directed towards understanding the factors determining protein misfolding and amyloid formation. Protein stability and amino acid composition have been identified as the two major factors in vitro. The research of our group has been focused on understanding the relationship between amino acid sequence and amyloid formation. Our approach has been the design of simple model systems that reproduce the biophysical properties of natural amyloids. An amyloid sequence pattern was extracted that can be used to detect amyloidogenic hexapeptide stretches in proteins. We have added evidence supporting that these amyloidogenic stretches can trigger amyloid formation by nonamyloidogenic proteins. Some experimental results in other amyloid proteins will be analyzed under the conclusions obtained in these studies. Our conclusions together with evidences from other groups suggest that amyloid formation is the result of the interplay between a decrease of protein stability, and the presence of highly amyloidogenic regions in proteins. As many of these results have been obtained in vitro, the challenge for the next years will be to demonstrate their validity in in vivo systems. PMID:19164912

  2. Retroperitoneal liposarcoma associated with small plaque parapsoriasis

    Directory of Open Access Journals (Sweden)

    Polichetti Paolo

    2007-07-01

    Full Text Available Abstract Background Extremely rare cases of paraneoplastic syndromes or ectopic production of proteins associated with liposarcoma are reported in literature. Production of Granulocyte-Colony Stimulating Factor, alpha-fetoprotein, paraneoplastic pemphigus and leucocytosis, Acrokeratosis paraneoplastica (Bazex's syndrome are reported. The present report describes a case of retroperitoneal liposarcoma associated with small plaque parapsoriasis. Our search in the English literature of such a kind of association did not reveal any case reported. Case presentation A 74 year male patient was admitted to our hospital because of the presence of an abdominal mass in right iliac fossa. He also complained of a two-year history of psoriasiform eruptions. The CT scan showed a retroperitoneal pelvic mass. Therefore surgical resection of the tumor was performed. After surgery, the skin eruptions disappeared completely in seven days and so a diagnosis of parapsoriasis syndrome was done. Conclusion Parallel disappearing of skin eruptions after surgery, typical clinical picture and not specific histology of the cutaneous lesions suggest the diagnosis of small plaque parapsoriasis. Therefore we propose to add Small Plaque Parapsoriasis to the list of paraneoplastic syndromes associated to liposarcoma.

  3. Optimization of 125I ophthalmic plaque brachytherapy

    International Nuclear Information System (INIS)

    Episcleral plaques containing 125I sources are often used in the treatment of ocular melanoma. Within four years post-treatment, however, the majority of patients experience some visual loss due to radiation retinopathy. The high incidence of late complications suggests that careful treatment optimization may lead to improved outcome. The goal of optimization would be to reduce the magnitude of vision-limiting complications without compromising tumor control. We have developed a three-dimensional computer model for ophthalmic plaque therapy which permits us to explore the potential of various optimization strategies. One simple strategy which shows promise is to maximize the ratio of dose to the tumor apex (T) compared to dose to the macula (M). By modifying the parameters of source location, activity distribution, source orientation, and shielding we find that the calculated T:M ratio can be varied by a factor of 2 for a common plaque design and posterior tumor location. Margins and dose to the tumor volume remain essentially unchanged

  4. Relationship between interleukin-18 levels and characterization of atherosclerotic plaque and percutaneous coronary intervention

    Institute of Scientific and Technical Information of China (English)

    Weihua Li; Kaimin Lin; Lei Gao; Rong Wu; Qiang Xie; Yongjun Guo; Shuhui Dai

    2008-01-01

    Background lnterleuldn-18(IL- 18) plays a key role in the development,progression and outcome of coronary artery disease and its complications.However,its variability relation to the characterization of atherosclerotic plaque and percutaneous coronary intervention are still unknown.Methods Fifty four patients with coronary artery disease [22 patients with stable angina (SA) and 32 patients with acute coronary syndrome (ACS)] were enrolled in this study.All patients underwent percutaneous coronary intervention (PCI).The stability of the plaques at the criminal vessels was assessed with analogical IVUS.Serum IL-18 levels were measured at the time points of 5 rain before PCI,and Oh,6h,24h and lmonth after PCI in all patients.Results ACS group consisted mainly of lipidic unstable plaques while SA group of fibrous stable plaques.Moreover,compared with those in SA group,eccentricity index (EI) and remodeling index (RI) were significantly higher in ACS group.Positive remodeling was seen in ACS group while negative or no remodeling in SA group.Further,serum IL-18 levels were significantly elevated in patients with ACS than those in SA group before PCI,increased at Oh,6h,24h after PCI (P<0.05)and were not significant different at 1 month after PCI from those before PCI.Conclusions There is significant difference in the composition and structural characteristics of atherosclerotic plaques between ACS and UA groups.PCI triggersd and enhances the inflammatory response in a short time.Serum levels of IL- 18 are the predictors of progression of unstable plaque in atherosclerosis.Post-operative complications of PCI might be reduced by inhibiting IL- 18.(J Geriatr Cardiol 2008;5:21-24)

  5. Alprostadil liposome microsphere preparation stabilizes vascular plaques and inhibits intra-plaque inflammation

    Institute of Scientific and Technical Information of China (English)

    CHEN Li; CHENG Wen-li; WANG Yong; KE Yuan-nan; FAN Shu-ying; PAN Lin; GUO Yan-ru; LI Hong; GUO Jian

    2012-01-01

    Background Vulnerable plaques play an important role in the onset of sudden cardiac events and strokes.How to stabilize vulnerable plaques is still a challenge to medical science.Alprostadil is a biologically active substance with strong activity on vessel.Our study assessed the stabilizing effects of an alprostadil liposome microsphere preparation (ALMP) on vulnerable plaques in the brachiocephalic artery of apolipoprotein E (Apo E) knockout mice.Methods Seventy-two male Apo E-knockout mice were fed a high-fat diet beginning at eight weeks of age.At week 17,they were divided randomly into groups for treatment with a high dose (3.6 μg · kg-1 · d-1) or low dose (1.8 μg · kg-1 · d-1) of an ALMP,or 0.2 ml/d normal saline (control group).The drug was administered using a micro-capsule pump.Twenty weeks after drug administration,pathological changes in the vulnerable plaques within the brachiocephalic artery were assessed,and levels of anti-mouse monocyte/macrophage monoclonal antibody (MOMA-2) and superoxide anions in the plaques were detected using immunofluorescence.The soluble intercellular adhesion molecule-1 (ICAM-1) expression was measured by ELISA,and the expression of matrix metalloproteinase-9 (MMP-9) and CD40 mRNA was measured using RT-PCR.Thrombospindin-1 (TSP-1) expression was detected using Western blotting.Results Compared with the control group,ALMP treatment significantly reduced the plaque area in the brachiocephalic artery (P <0.01),significantly lowered the contents of the lipid core (P <0.01),significantly reduced the number of ruptured fibrous caps (P <0.05),and increased the thickness of the fibrous cap and significantly reduced the incidence of intra-plaque hemorrhage (P <0.05).ALMP treatment significantly reduced the expression of MOMA-2,superoxide anion,MMP-9,ICAM-1 and CD40 in the plaques (P <0.01),decreased plasma ICAM-1 expression (P <0.01),and increased the expression of TSP-1.Conclusions Treatment with ALMP can stabilize

  6. Amyloid oligomer structure characterization from simulations: A general method

    Energy Technology Data Exchange (ETDEWEB)

    Nguyen, Phuong H., E-mail: phuong.nguyen@ibpc.fr [Laboratoire de Biochimie Théorique, UPR 9080, CNRS Université Denis Diderot, Sorbonne Paris Cité IBPC, 13 rue Pierre et Marie Curie, 75005 Paris (France); Li, Mai Suan [Institute of Physics, Polish Academy of Sciences, Al. Lotnikow 32/46, 02-668 Warsaw (Poland); Derreumaux, Philippe, E-mail: philippe.derreumaux@ibpc.fr [Laboratoire de Biochimie Théorique, UPR 9080, CNRS Université Denis Diderot, Sorbonne Paris Cité IBPC, 13 rue Pierre et Marie Curie, 75005 Paris (France); Institut Universitaire de France, 103 Bvd Saint-Germain, 75005 Paris (France)

    2014-03-07

    Amyloid oligomers and plaques are composed of multiple chemically identical proteins. Therefore, one of the first fundamental problems in the characterization of structures from simulations is the treatment of the degeneracy, i.e., the permutation of the molecules. Second, the intramolecular and intermolecular degrees of freedom of the various molecules must be taken into account. Currently, the well-known dihedral principal component analysis method only considers the intramolecular degrees of freedom, and other methods employing collective variables can only describe intermolecular degrees of freedom at the global level. With this in mind, we propose a general method that identifies all the structures accurately. The basis idea is that the intramolecular and intermolecular states are described in terms of combinations of single-molecule and double-molecule states, respectively, and the overall structures of oligomers are the product basis of the intramolecular and intermolecular states. This way, the degeneracy is automatically avoided. The method is illustrated on the conformational ensemble of the tetramer of the Alzheimer's peptide Aβ{sub 9−40}, resulting from two atomistic molecular dynamics simulations in explicit solvent, each of 200 ns, starting from two distinct structures.

  7. A binding-site barrier affects imaging efficiency of high affinity amyloid-reactive peptide radiotracers in vivo.

    Directory of Open Access Journals (Sweden)

    Jonathan S Wall

    Full Text Available Amyloid is a complex pathology associated with a growing number of diseases including Alzheimer's disease, type 2 diabetes, rheumatoid arthritis, and myeloma. The distribution and extent of amyloid deposition in body organs establishes the prognosis and can define treatment options; therefore, determining the amyloid load by using non-invasive molecular imaging is clinically important. We have identified a heparin-binding peptide designated p5 that, when radioiodinated, was capable of selectively imaging systemic visceral AA amyloidosis in a murine model of the disease. The p5 peptide was posited to bind effectively to amyloid deposits, relative to similarly charged polybasic heparin-reactive peptides, because it adopted a polar α helix secondary structure. We have now synthesized a variant, p5R, in which the 8 lysine amino acids of p5 have been replaced with arginine residues predisposing the peptide toward the α helical conformation in an effort to enhance the reactivity of the peptide with the amyloid substrate. The p5R peptide had higher affinity for amyloid and visualized AA amyloid in mice by using SPECT/CT imaging; however, the microdistribution, as evidenced in micro-autoradiographs, was dramatically altered relative to the p5 peptide due to its increased affinity and a resultant "binding site barrier" effect. These data suggest that radioiodinated peptide p5R may be optimal for the in vivo detection of discreet, perivascular amyloid, as found in the brain and pancreatic vasculature, by using molecular imaging techniques; however, peptide p5, due to its increased penetration, may yield more quantitative imaging of expansive tissue amyloid deposits.

  8. DBA/2J genetic background exacerbates spontaneous lethal seizures but lessens amyloid deposition in a mouse model of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Harriet M Jackson

    Full Text Available Alzheimer's disease (AD is a leading cause of dementia in the elderly and is characterized by amyloid plaques, neurofibrillary tangles (NFTs and neuronal dysfunction. Early onset AD (EOAD is commonly caused by mutations in amyloid precursor protein (APP or genes involved in the processing of APP including the presenilins (e.g. PSEN1 or PSEN2. In general, mouse models relevant to EOAD recapitulate amyloidosis, show only limited amounts of NFTs and neuronal cell dysfunction and low but significant levels of seizure susceptibility. To investigate the effect of genetic background on these phenotypes, we generated APPswe and PSEN1de9 transgenic mice on the seizure prone inbred strain background, DBA/2J. Previous studies show that the DBA/2J genetic background modifies plaque deposition in the presence of mutant APP but the impact of PSEN1de9 has not been tested. Our study shows that DBA/2J.APPswePSEN1de9 mice are significantly more prone to premature lethality, likely to due to lethal seizures, compared to B6.APPswePSEN1de9 mice-70% of DBA/2J.APPswePSEN1de9 mice die between 2-3 months of age. Of the DBA/2J.APPswePSEN1de9 mice that survived to 6 months of age, plaque deposition was greatly reduced compared to age-matched B6.APPswePSEN1de9 mice. The reduction in plaque deposition appears to be independent of microglia numbers, reactive astrocytosis and complement C5 activity.

  9. Intravascular probe for detection of vulnerable plaque

    Science.gov (United States)

    Patt, Bradley E.; Iwanczyk, Jan S.; MacDonald, Lawrence R.; Yamaguchi, Yuko; Tull, Carolyn R.; Janecek, Martin; Hoffman, Edward J.; Strauss, H. William; Tsugita, Ross; Ghazarossian, Vartan

    2001-12-01

    Coronary angiography is unable to define the status of the atheroma, and only measures the luminal dimensions of the blood vessel, without providing information about plaque content. Up to 70% of heart attacks are caused by minimally obstructive vulnerable plaques, which are too small to be detected adequately by angiography. We have developed an intravascular imaging detector to identify vulnerable coronary artery plaques. The detector works by sensing beta or conversion electron radiotracer emissions from plaque-binding radiotracers. The device overcomes the technical constraints of size, sensitivity and conformance to the intravascular environment. The detector at the distal end of the catheter uses six 7mm long by 0.5mm diameter scintillation fibers coupled to 1.5m long plastic fibers. The fibers are offset from each other longitudinally by 6mm and arranged spirally around a guide wire in the catheter. At the proximal end of the catheter the optical fibers are coupled to an interface box with a snap on connector. The interface box contains a position sensitive photomultiplier tube (PSPMT) to decode the individual fibers. The whole detector assembly fits into an 8-French (2.7 mm in diameter) catheter. The PSPMT image is further decoded with software to give a linear image, the total instantaneous count rate and an audio output whose tone corresponds to the count rate. The device was tested with F-18 and Tl-204 sources. Spectrometric response, spatial resolution, sensitivity and beta to background ratio were measured. System resolution is 6 mm and the sensitivity is >500 cps / micrometers Ci when the source is 1 mm from the detector. The beta to background ratio was 11.2 for F-18 measured on a single fiber. The current device will lead to a system allowing imaging of labeled vulnerable plaque in coronary arteries. This type of signature is expected to enable targeted and cost effective therapies to prevent acute coronary artery diseases such as: unstable angina

  10. Oxidative stress induces macroautophagy of amyloid beta-protein and ensuing apoptosis

    DEFF Research Database (Denmark)

    Zheng, Lin; Kågedal, Katarina; Dehvari, Nodi;

    2009-01-01

    There is increasing evidence for the toxicity of intracellular amyloid beta-protein (Abeta) to neurons and the involvement of lysosomes in this process in Alzheimer disease (AD). We have recently shown that oxidative stress, a recognized determinant of AD, enhances macroautophagy and leads to int...

  11. Amyloid Imaging in Aging and Dementia: Testing the Amyloid Hypothesis In Vivo

    Directory of Open Access Journals (Sweden)

    G. D. Rabinovici

    2009-01-01

    Full Text Available Amyloid imaging represents a major advance in neuroscience, enabling the detection and quantification of pathologic protein aggregations in the brain. In this review we survey current amyloid imaging techniques, focusing on positron emission tomography (PET with ^{11}carbon-labelled Pittsburgh Compound-B (11C-PIB, the most extensively studied and best validated tracer. PIB binds specifically to fibrillar beta-amyloid (Aβ deposits, and is a sensitive marker for Aβ pathology in cognitively normal older individuals and patients with mild cognitive impairment (MCI and Alzheimer’s disease (AD. PIB-PET provides us with a powerful tool to examine in vivo the relationship between amyloid deposition, clinical symptoms, and structural and functional brain changes in the continuum between normal aging and AD. Amyloid imaging studies support a model in which amyloid deposition is an early event on the path to dementia, beginning insidiously in cognitively normal individuals, and accompanied by subtle cognitive decline and functional and structural brain changes suggestive of incipient AD. As patients progress to dementia, clinical decline and neurodegeneration accelerate and proceed independently of amyloid accumulation. In the future, amyloid imaging is likely to supplement clinical evaluation in selecting patients for anti-amyloid therapies, while MRI and FDG-PET may be more appropriate markers of clinical progression.

  12. Effect of reader experience on variability, evaluation time and accuracy of coronary plaque detection with computed tomography coronary angiography

    Energy Technology Data Exchange (ETDEWEB)

    Saur, Stefan C.; Szekely, Gabor [ETH Zurich, Computer Vision Laboratory, Zurich (Switzerland); Alkadhi, Hatem [University Hospital Zurich, Institute of Diagnostic Radiology, Zurich (Switzerland); Massachusetts General Hospital and Harvard Medical School, Cardiac MR PET CT Group, Boston, MA (United States); Stolzmann, Paul; Baumueller, Stephan; Leschka, Sebastian; Scheffel, Hans; Desbiolles, Lotus [University Hospital Zurich, Institute of Diagnostic Radiology, Zurich (Switzerland); Fuchs, Thomas J. [ETH Zurich, Department of Computer Science, Zurich (Switzerland); Cattin, Philippe C. [ETH Zurich, Computer Vision Laboratory, Zurich (Switzerland); University of Basel, Medical Image Analysis Center, Basel (Switzerland)

    2010-07-15

    To assess the effect of reader experience on variability, evaluation time and accuracy in the detection of coronary artery plaques with computed tomography coronary angiography (CTCA). Three independent, blinded readers with three different experience levels twice labelled 50 retrospectively electrocardiography (ECG)-gated contrast-enhanced dual-source CTCA data sets (15 female, age 67.3 {+-} 10.4 years, range 46-86 years) indicating the presence or absence of coronary plaques. The evaluation times for the readings were recorded. Intra- and interobserver variability expressed as {kappa} statistics and sensitivity, specificity, and negative and positive predictive values were calculated for plaque detection, with a consensus reading of the three readers taken as the standard of reference. A bootstrap method was applied in the statistical analysis to account for clustering. Significant correlations were found between reader experience and, respectively, evaluation times (r = -0.59, p < 0.05) and intraobserver variability (r = 0.73, p < 0.05). The evaluation time significantly differed among the readers (p < 0.05). The observer variability for plaque detection, compared with the consensus, varied between {kappa} = 0.582 and {kappa} = 0.802. Variability of plaque detection was significantly smaller (p < 0.05) and more accurate (p < 0.05) for the most experienced reader. Reader experience significantly correlated with observer variability, evaluation time and accuracy of coronary plaque detection at CTCA. (orig.)

  13. The nitroxide radical TEMPOL prevents obesity, hyperlipidaemia, elevation of inflammatory cytokines, and modulates atherosclerotic plaque composition in apoE(-/-) mice

    DEFF Research Database (Denmark)

    Kim, Christine H. J.; Mitchell, James B.; Bursill, Christina A.;

    2015-01-01

    cholesterol, inflammatory cytokines and markers (interleukin-6, IL-6; monocyte-chemotactic protein, MCP-1; myeloperoxidase, MPO; serum amyloid A, SAA; adiponectin; leptin). Plaques in the aortic sinus were analysed for area, and content of collagen, lipid, macrophages and smooth muscle cells. RESULTS: High...... fat feeding resulted in marked increases in body mass and plasma lipid levels. Dietary TEMPOL decreased both parameters. In the high-fat-fed mice significant elevations in plasma lipid levels and the inflammatory markers IL-6, MCP-1, MPO, SAA were detected, along with an increase in leptin...

  14. Thrombosis and morphology of plaque rupture using optical coherence tomography

    Institute of Scientific and Technical Information of China (English)

    GUO Jun; CHEN Yun-dai; TIAN Feng; LIU Hong-bin; CHEN Lian; SUN Zhi-jun; REN Yi-hong

    2013-01-01

    Background Thrombosis following plaque rupture is the main cause of acute coronary syndrome,but not all plaque ruptures lead to thrombosis.There are limited in vivo data on the relationship between the morphology of ruptured plaque and thrombosis.Methods We used optical coherence tomography (OCT) to investigate the morphology of plaque rupture and its relation to coronary artery thrombosis in patients with coronary heart disease.Forty-two patients with coronary artery plaque rupture detected by OCT were divided into two groups (with or without thrombus) and the morphological characteristics of ruptured plaque,including fibrous cap thickness and broken cap site,were recorded.Results The fibrous cap of ruptured plaque with thrombus was significantly thinner compared to caps without thrombus ((57.00±17.00) μm vs.(96.00±48.00) μm; P=0.0076).Conclusions Plaque rupture associated with thrombosis occurs primarily in plaque covered by a thin fibrous cap.Thick fibrous caps are associated with greater stability of ruptured plaque.

  15. Loss of metal ions, disulfide reduction and mutations related to familial ALS promote formation of amyloid-like aggregates from superoxide dismutase.

    Directory of Open Access Journals (Sweden)

    Zeynep A Oztug Durer

    Full Text Available Mutations in the gene encoding Cu-Zn superoxide dismutase (SOD1 are one of the causes of familial amyotrophic lateral sclerosis (FALS. Fibrillar inclusions containing SOD1 and SOD1 inclusions that bind the amyloid-specific dye thioflavin S have been found in neurons of transgenic mice expressing mutant SOD1. Therefore, the formation of amyloid fibrils from human SOD1 was investigated. When agitated at acidic pH in the presence of low concentrations of guanidine or acetonitrile, metalated SOD1 formed fibrillar material which bound both thioflavin T and Congo red and had circular dichroism and infrared spectra characteristic of amyloid. While metalated SOD1 did not form amyloid-like aggregates at neutral pH, either removing metals from SOD1 with its intramolecular disulfide bond intact or reducing the intramolecular disulfide bond of metalated SOD1 was sufficient to promote formation of these aggregates. SOD1 formed amyloid-like aggregates both with and without intermolecular disulfide bonds, depending on the incubation conditions, and a mutant SOD1 lacking free sulfhydryl groups (AS-SOD1 formed amyloid-like aggregates at neutral pH under reducing conditions. ALS mutations enhanced the ability of disulfide-reduced SOD1 to form amyloid-like aggregates, and apo-AS-SOD1 formed amyloid-like aggregates at pH 7 only when an ALS mutation was also present. These results indicate that some mutations related to ALS promote formation of amyloid-like aggregates by facilitating the loss of metals and/or by making the intramolecular disulfide bond more susceptible to reduction, thus allowing the conversion of SOD1 to a form that aggregates to form resembling amyloid. Furthermore, the occurrence of amyloid-like aggregates per se does not depend on forming intermolecular disulfide bonds, and multiple forms of such aggregates can be produced from SOD1.

  16. Small heat shock proteins potentiate amyloid dissolution by protein disaggregases from yeast and humans.

    Directory of Open Access Journals (Sweden)

    Martin L Duennwald

    Full Text Available How small heat shock proteins (sHsps might empower proteostasis networks to control beneficial prions or disassemble pathological amyloid is unknown. Here, we establish that yeast sHsps, Hsp26 and Hsp42, inhibit prionogenesis by the [PSI+] prion protein, Sup35, via distinct and synergistic mechanisms. Hsp42 prevents conformational rearrangements within molten oligomers that enable de novo prionogenesis and collaborates with Hsp70 to attenuate self-templating. By contrast, Hsp26 inhibits self-templating upon binding assembled prions. sHsp binding destabilizes Sup35 prions and promotes their disaggregation by Hsp104, Hsp70, and Hsp40. In yeast, Hsp26 or Hsp42 overexpression prevents [PSI+] induction, cures [PSI+], and potentiates [PSI+]-curing by Hsp104 overexpression. In vitro, sHsps enhance Hsp104-catalyzed disaggregation of pathological amyloid forms of α-synuclein and polyglutamine. Unexpectedly, in the absence of Hsp104, sHsps promote an unprecedented, gradual depolymerization of Sup35 prions by Hsp110, Hsp70, and Hsp40. This unanticipated amyloid-depolymerase activity is conserved from yeast to humans, which lack Hsp104 orthologues. A human sHsp, HspB5, stimulates depolymerization of α-synuclein amyloid by human Hsp110, Hsp70, and Hsp40. Thus, we elucidate a heretofore-unrecognized human amyloid-depolymerase system that could have applications in various neurodegenerative disorders.

  17. The role of mutated amyloid beta 1-42 stimulating dendritic cells in a PDAPP transgenic mouse

    Directory of Open Access Journals (Sweden)

    LI Jia-lin

    2012-06-01

    Full Text Available Background Amyloid plaque is one of the pathological hallmarks of Alzheimer's disease (AD. Anti-beta-amyloid (Aβ immunotherapy is effective in removing brain Aβ, but has shown to be associated with detrimental effects. To avoid severe adverse effects such as meningoencephalitis induced by amyloid beta vaccine with adjuvant, and take advantage of amyloid beta antibody's therapeutic effect on Alzheimer's disease sufficiently, our group has developed a new Alzheimer vaccine with mutated amyloid beta 1-42 peptide stimulating dendritic cells (DC. Our previous work has confirmed that DC vaccine can induce adequate anti-amyloid beta antibody in PDAPP Tg mice safely and efficiently. The DC vaccine can improve impaired learning and memory in the Alzheimer's animal model, and did not cause microvasculitis, microhemorrhage or meningoencephalitis in the animal model. However, the exact mechanism of immunotherapy which reduces Aβ deposition remains unknown. In this report, we studied the mechanism of the vaccine, thinking that this may have implications for better understanding of the pathogenesis of Alzheimer's disease. Methods A new Alzheimer vaccine with mutated amyloid beta 1-42 peptide stimulating DC which were obtained from C57/B6 mouse bone marrow was developed. Amyloid beta with Freund's adjuvant was inoculated at the same time to act as positive control. After the treatment was done, the samples of brains were collected, fixed, cut. Immunohistochemical staining was performed to observe the expression of the nuclear hormone liver X receptor (LXR, membrane-bound protein tyrosine phosphatase (CD45, the ATP-binding cassette family of active transporters (ABCA1, receptor for advanced glycation end products (RAGE, β-site APP-cleaving enzyme (BACE and Aβ in mouse brain tissue. Semi-quantitative analysis was used to defect CA1, CA2, CA3, DG, Rad in hippocampus region and positive neuron in cortex region. Results Aβ was significantly reduced in the

  18. Genetics Home Reference: hereditary cerebral amyloid angiopathy

    Science.gov (United States)

    ... prognosis of a genetic condition? Genetic and Rare Diseases Information Center Frequency The prevalence of hereditary cerebral amyloid angiopathy is unknown. The Dutch type is the most common, with over 200 ...

  19. Amyloid myopathy presenting with respiratory failure.

    OpenAIRE

    Ashe, J.; Borel, C O; Hart, G.; Humphrey, R L; Derrick, D A; Kuncl, R W

    1992-01-01

    Amyloidosis is a rare cause of myopathy. Its prominent or presenting feature may be respiratory failure. Physiological measurement of transdiaphragmatic pressure and biopsy specimens of muscle show the pathological mechanism to be diaphragm weakness due to amyloid infiltration of the diaphragm rather than parenchymal lung involvement. Thus amyloid myopathy even without the typical macroglossia and muscle pseudohypertrophy should be considered as one of the neurological causes of respiratory f...

  20. Molecular mechanisms of amyloid self-regulation

    OpenAIRE

    Landreh, Michael

    2012-01-01

    Amyloid is associated with both pathological protein deposits and the formation of functional protein structures. Therefore, several strategies have evolved to control the formation or inhibition of amyloid in vivo. In this thesis, three separate systems were investigated in which amyloidogenic protein segments are coupled to regulatory elements that prevent or promote fibrillation. We describe the molecular mechanism for how (a) a propeptide segment prevents the uncontrolled a...

  1. Islet Amyloid Polypeptide: Structure, Function, and Pathophysiology

    Directory of Open Access Journals (Sweden)

    Rehana Akter

    2016-01-01

    Full Text Available The hormone islet amyloid polypeptide (IAPP, or amylin plays a role in glucose homeostasis but aggregates to form islet amyloid in type-2 diabetes. Islet amyloid formation contributes to β-cell dysfunction and death in the disease and to the failure of islet transplants. Recent work suggests a role for IAPP aggregation in cardiovascular complications of type-2 diabetes and hints at a possible role in type-1 diabetes. The mechanisms of IAPP amyloid formation in vivo or in vitro are not understood and the mechanisms of IAPP induced β-cell death are not fully defined. Activation of the inflammasome, defects in autophagy, ER stress, generation of reactive oxygen species, membrane disruption, and receptor mediated mechanisms have all been proposed to play a role. Open questions in the field include the relative importance of the various mechanisms of β-cell death, the relevance of reductionist biophysical studies to the situation in vivo, the molecular mechanism of amyloid formation in vitro and in vivo, the factors which trigger amyloid formation in type-2 diabetes, the potential role of IAPP in type-1 diabetes, the development of clinically relevant inhibitors of islet amyloidosis toxicity, and the design of soluble, bioactive variants of IAPP for use as adjuncts to insulin therapy.

  2. Hybrid Amyloid Membranes for Continuous Flow Catalysis.

    Science.gov (United States)

    Bolisetty, Sreenath; Arcari, Mario; Adamcik, Jozef; Mezzenga, Raffaele

    2015-12-29

    Amyloid fibrils are promising nanomaterials for technological applications such as biosensors, tissue engineering, drug delivery, and optoelectronics. Here we show that amyloid-metal nanoparticle hybrids can be used both as efficient active materials for wet catalysis and as membranes for continuous flow catalysis applications. Initially, amyloid fibrils generated in vitro from the nontoxic β-lactoglobulin protein act as templates for the synthesis of gold and palladium metal nanoparticles from salt precursors. The resulting hybrids possess catalytic features as demonstrated by evaluating their activity in a model catalytic reaction in water, e.g., the reduction of 4-nitrophenol into 4-aminophenol, with the rate constant of the reduction increasing with the concentration of amyloid-nanoparticle hybrids. Importantly, the same nanoparticles adsorbed onto fibrils surface show improved catalytic efficiency compared to the same unattached particles, pointing at the important role played by the amyloid fibril templates. Then, filter membranes are prepared from the metal nanoparticle-decorated amyloid fibrils by vacuum filtration. The resulting membranes serve as efficient flow catalysis active materials, with a complete catalytic conversion achieved within a single flow passage of a feeding solution through the membrane.

  3. 18FDG PET and ultrasound echolucency in carotid artery plaques

    DEFF Research Database (Denmark)

    Graebe, Martin; Pedersen, Sune F; Højgaard, Liselotte;

    2010-01-01

    for ultrasound and PET imaging. Plaque standardized gray scale medians (GSM) were measured in longitudinal ultrasound images to quantitate echolucency, and GSM values were compared with FDG PET uptake quantified by maximum standardized uptake values (SUV). Symptomatic plaques were compared with contralateral...... carotid artery plaques considered asymptomatic, and in 17 symptomatic patients, endarterectomized plaque specimens were analyzed for CD68 expression. RESULTS: There was a negative correlation between GSM and FDG SUV (r = -0.56, p ... plaques ranged from high to low inflammatory activity, as depicted with PET. Quantitative FDG SUV differentiated asymptomatic from symptomatic plaques, whereas GSM values did not. There was a positive correlation between CD68 expression and FDG uptake (r = 0.50, p = 0.04). CONCLUSIONS: Our results...

  4. Oral biofilm models for mechanical plaque removal.

    Science.gov (United States)

    Verkaik, Martinus J; Busscher, Henk J; Rustema-Abbing, Minie; Slomp, Anje M; Abbas, Frank; van der Mei, Henny C

    2010-08-01

    In vitro plaque removal studies require biofilm models that resemble in vivo dental plaque. Here, we compare contact and non-contact removal of single and dual-species biofilms as well as of biofilms grown from human whole saliva in vitro using different biofilm models. Bacteria were adhered to a salivary pellicle for 2 h or grown after adhesion for 16 h, after which, their removal was evaluated. In a contact mode, no differences were observed between the manual, rotating, or sonic brushing; and removal was on average 39%, 84%, and 95% for Streptococcus mutans, Streptococcus oralis, and Actinomyces naeslundii, respectively, and 90% and 54% for the dual- and multi-species biofilms, respectively. However, in a non-contact mode, rotating and sonic brushes still removed considerable numbers of bacteria (24-40%), while the manual brush as a control (5-11%) did not. Single A. naeslundii and dual-species (A. naeslundii and S. oralis) biofilms were more difficult to remove after 16 h growth than after 2 h adhesion (on average, 62% and 93% for 16- and 2-h-old biofilms, respectively), while in contrast, biofilms grown from whole saliva were easier to remove (97% after 16 h and 54% after 2 h of growth). Considering the strong adhesion of dual-species biofilms and their easier more reproducible growth compared with biofilms grown from whole saliva, dual-species biofilms of A. naeslundii and S. oralis are suggested to be preferred for use in mechanical plaque removal studies in vitro. PMID:19565279

  5. Reproducibility of high-resolution MRI for the middle cerebral artery plaque at 3 T

    International Nuclear Information System (INIS)

    Purpose: To assess the reproducibility of HR-MRI for the identification of MCA atherosclerotic plaque components and quantification of stenosis. Materials and methods: Seventy-three consecutive subjects who initially had ischemic stroke or asymptomatic MCA stenosis (>50%) were enrolled in the study. All subjects were scanned using 3.0 T MRI. Two independent readers reviewed all images and one reader reevaluated all images four weeks later. The tissue components of plaques were analyzed qualitatively and the vessels were quantitative measured. Results: HR-MRI displayed the artery wall and lumen clearly. The intra-observer reproducibility was excellent for the identification of plaques (kappa [κ] = 0.96; 95% CI: 0.83–1.04) and contrast enhancement (κ = 0.89; 0.78–0.95); it was substantial for intra-plaque hemorrhage (κ = 0.79; 0.57–0.96) and the fibrous cap (κ = 0.65; 0.42–0.86). The inter-observer reproducibility was excellent for plaques (κ = 0.92; 0.73–1.06), substantial for contrast enhancement (κ = 0.80; 0.65–0.93), intra-plaque hemorrhage (κ = 0.68; 0.47–0.92) and moderate for the fibrous cap (κ = 0.58; 0.44–0.79). Both intra-observer and inter-observer reproducibility were excellent for quantitative vessel, lumen and wall measurements with intraclass correlation coefficients ranging from 0.91 to 0.97 and 0.87 to 0.96, respectively. However, vessel and wall areas and the intervals defined by the Bland–Altman plots were wide in comparison to the mean. Conclusions: The identification of MCA atherosclerotic plaque components and the quantification of vessel and lumen measurements are reproducible. The reproducibility is overall acceptable. HR-MRI may provide a useful tool for clinical risk evaluation in MCA atherosclerosis

  6. Reproducibility of high-resolution MRI for the middle cerebral artery plaque at 3 T

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Wan-Qun [Department of Radiology, Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangzhou, Guangdong 510080 (China); Huang, Biao, E-mail: cjr.huangbiao@vip.163.com [Department of Radiology, Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangzhou, Guangdong 510080 (China); Liu, Xin-Tong [Department of Neurology, Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangzhou, Guangdong 510080 (China); Liu, Hong-Jun; Li, Pei-Jun [Department of Radiology, Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangzhou, Guangdong 510080 (China); Zhu, Wen-Zhen, E-mail: zhuwenzhen@hotmail.com [Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030 (China)

    2014-01-15

    Purpose: To assess the reproducibility of HR-MRI for the identification of MCA atherosclerotic plaque components and quantification of stenosis. Materials and methods: Seventy-three consecutive subjects who initially had ischemic stroke or asymptomatic MCA stenosis (>50%) were enrolled in the study. All subjects were scanned using 3.0 T MRI. Two independent readers reviewed all images and one reader reevaluated all images four weeks later. The tissue components of plaques were analyzed qualitatively and the vessels were quantitative measured. Results: HR-MRI displayed the artery wall and lumen clearly. The intra-observer reproducibility was excellent for the identification of plaques (kappa [κ] = 0.96; 95% CI: 0.83–1.04) and contrast enhancement (κ = 0.89; 0.78–0.95); it was substantial for intra-plaque hemorrhage (κ = 0.79; 0.57–0.96) and the fibrous cap (κ = 0.65; 0.42–0.86). The inter-observer reproducibility was excellent for plaques (κ = 0.92; 0.73–1.06), substantial for contrast enhancement (κ = 0.80; 0.65–0.93), intra-plaque hemorrhage (κ = 0.68; 0.47–0.92) and moderate for the fibrous cap (κ = 0.58; 0.44–0.79). Both intra-observer and inter-observer reproducibility were excellent for quantitative vessel, lumen and wall measurements with intraclass correlation coefficients ranging from 0.91 to 0.97 and 0.87 to 0.96, respectively. However, vessel and wall areas and the intervals defined by the Bland–Altman plots were wide in comparison to the mean. Conclusions: The identification of MCA atherosclerotic plaque components and the quantification of vessel and lumen measurements are reproducible. The reproducibility is overall acceptable. HR-MRI may provide a useful tool for clinical risk evaluation in MCA atherosclerosis.

  7. Development of a novel plaque reduction neutralisation test for hantavirus infection

    Directory of Open Access Journals (Sweden)

    Michelly de Pádua

    2015-08-01

    Full Text Available In the Americas, hantaviruses cause severe cardiopulmonary syndrome (HCPS with a high fatality rate. Hantavirus infection is commonly diagnosed using serologic techniques and reverse transcription-polymerase chain reaction. This paper presents a novel plaque reduction neutralisation test (PRNT for detecting antibodies to Brazilian hantavirus. Using PRNT, plaque detection was enhanced by adding 0.6% of dimethyl sulfoxide into the overlay culture medium of the infected cells. This procedure facilitated clear visualisation of small plaques under the microscope and provided for easy and accurate plaque counting. The sera from 37 HCPS patients from the city of Ribeirão Preto, Brazil was evaluated for the Rio Mamoré virus (RIOMV using PRNT. Six samples exhibited neutralising antibodies; these antibodies exhibited a low titre. The low level of seropositive samples may be due to fewer cross-reactions between two different hantavirus species; the patients were likely infected by Araraquara virus (a virus that has not been isolated and RIOMV was used for the test. This assay offers a new approach to evaluating and measuring neutralising antibodies produced during hantavirus infections and it can be adapted to other hantaviruses, including viruses that will be isolated in the future.

  8. Prophylaxis for infective endocarditis: antibiotic sensitivity of dental plaque.

    OpenAIRE

    MacFarlane, T W; McGowan, D A; Hunter, K.; MacKenzie, D

    1983-01-01

    The antibiotic sensitivity pattern of bacteria isolated from bacteraemia after dental extraction was compared with that of bacteria isolated from dental plaque samples from the same patient. The results supported the current practice of using penicillin and erythromycin empirically for prophylaxis. The prediction of the most appropriate antibiotic for prophylaxis using dental plaque samples was most accurate when the minimum inhibitory concentration (MIC) of plaque isolates were used. It appe...

  9. Helicobacter pylori in the dental plaque of healthy Saudis

    OpenAIRE

    Contractor Qais; Tahir Mohammed; Naseem Shahzad; Ahmad Shamweel

    1998-01-01

    The objective of this study is to determine the presence of Helicobacter pylori in the dental plaque of healthy Saudis and its relation to dental care. One hundred randomly selected healthy Saudis attending the dental clinic were assessed for oral hygiene and periodontal disease by dental examination. Information about the use of toothpaste, chewing stick, smoking and dentures was obtained. Samples of dental plaque were collected after scoring it according to the plaque index. Presence of H. ...

  10. Dosimetric Benefit of a New Ophthalmic Radiation Plaque

    Energy Technology Data Exchange (ETDEWEB)

    Marwaha, Gaurav, E-mail: marwahg2@ccf.org [Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, Ohio (United States); Cleveland Clinic Foundation, Cleveland, Ohio (United States); Wilkinson, Allan [Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, Ohio (United States); Cleveland Clinic Foundation, Cleveland, Ohio (United States); Bena, James [Department of Quantitative Health Sciences, Cleveland Clinic Foundation, Cleveland, Ohio (United States); Cleveland Clinic Foundation, Cleveland, Ohio (United States); Macklis, Roger [Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, Ohio (United States); Cleveland Clinic Foundation, Cleveland, Ohio (United States); Singh, Arun D. [Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, Ohio (United States); Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio (United States); Cleveland Clinic Foundation, Cleveland, Ohio (United States)

    2012-12-01

    Purpose: To determine whether the computed dosimetry of a new ophthalmic plaque, EP917, when compared with the standard Collaborative Ocular Melanoma Study (COMS) plaques, could reduce radiation exposure to vision critical structures of the eye. Methods and Materials: One hundred consecutive patients with uveal melanoma treated with COMS radiation plaques between 2007 and 2010 were included in this study. These treatment plans were generated with the use of Bebig Plaque Simulator treatment-planning software, both for COMS plaques and for EP917 plaques using I-125. Dose distributions were calculated for a prescription of 85 Gy to the tumor apex. Doses to the optic disc, opposite retina, lens, and macula were obtained, and differences between the 2 groups were analyzed by standard parametric methods. Results: When compared with the COMS plaques, the EP917 plaques used fewer radiation seeds by an average difference of 1.94 (P<.001; 95% confidence interval [CI], -2.8 to -1.06) and required less total strength of radiation sources by an average of 17.74 U (air kerma units) (P<.001; 95% CI, -20.16 to -15.32). The total radiation doses delivered to the optic disc, opposite retina, and macula were significantly less by 4.57 Gy, 0.50 Gy, and 11.18 Gy, respectively, with the EP917 plaques vs the COMS plaques. Conclusion: EP917 plaques deliver less overall radiation exposure to critical vision structures than COMS treatment plaques while still delivering the same total therapeutic dose to the tumor.

  11. Dosimetric Benefit of a New Ophthalmic Radiation Plaque

    International Nuclear Information System (INIS)

    Purpose: To determine whether the computed dosimetry of a new ophthalmic plaque, EP917, when compared with the standard Collaborative Ocular Melanoma Study (COMS) plaques, could reduce radiation exposure to vision critical structures of the eye. Methods and Materials: One hundred consecutive patients with uveal melanoma treated with COMS radiation plaques between 2007 and 2010 were included in this study. These treatment plans were generated with the use of Bebig Plaque Simulator treatment-planning software, both for COMS plaques and for EP917 plaques using I-125. Dose distributions were calculated for a prescription of 85 Gy to the tumor apex. Doses to the optic disc, opposite retina, lens, and macula were obtained, and differences between the 2 groups were analyzed by standard parametric methods. Results: When compared with the COMS plaques, the EP917 plaques used fewer radiation seeds by an average difference of 1.94 (P<.001; 95% confidence interval [CI], −2.8 to −1.06) and required less total strength of radiation sources by an average of 17.74 U (air kerma units) (P<.001; 95% CI, −20.16 to −15.32). The total radiation doses delivered to the optic disc, opposite retina, and macula were significantly less by 4.57 Gy, 0.50 Gy, and 11.18 Gy, respectively, with the EP917 plaques vs the COMS plaques. Conclusion: EP917 plaques deliver less overall radiation exposure to critical vision structures than COMS treatment plaques while still delivering the same total therapeutic dose to the tumor.

  12. Fatal transmissible amyloid encephalopathy: a new type of prion disease associated with lack of prion protein membrane anchoring.

    Directory of Open Access Journals (Sweden)

    Bruce Chesebro

    2010-03-01

    Full Text Available Prion diseases are fatal neurodegenerative diseases of humans and animals characterized by gray matter spongiosis and accumulation of aggregated, misfolded, protease-resistant prion protein (PrPres. PrPres can be deposited in brain in an amyloid-form and/or non-amyloid form, and is derived from host-encoded protease-sensitive PrP (PrPsen, a protein normally anchored to the plasma membrane by glycosylphosphatidylinositol (GPI. Previously, using heterozygous transgenic mice expressing only anchorless PrP, we found that PrP anchoring to the cell membrane was required for typical clinical scrapie. However, in the present experiments, using homozygous transgenic mice expressing two-fold more anchorless PrP, scrapie infection induced a new fatal disease with unique clinical signs and altered neuropathology, compared to non-transgenic mice expressing only anchored PrP. Brain tissue of transgenic mice had high amounts of infectivity, and histopathology showed dense amyloid PrPres plaque deposits without gray matter spongiosis. In contrast, infected non-transgenic mice had diffuse non-amyloid PrPres deposits with significant gray matter spongiosis. Brain graft studies suggested that anchored PrPsen expression was required for gray matter spongiosis during prion infection. Furthermore, electron and light microscopic studies in infected transgenic mice demonstrated several pathogenic processes not seen in typical prion disease, including cerebral amyloid angiopathy and ultrastructural alterations in perivascular neuropil. These findings were similar to certain human familial prion diseases as well as to non-prion human neurodegenerative diseases, such as Alzheimer's disease.

  13. Amyloid β-sheet mimics that antagonize protein aggregation and reduce amyloid toxicity

    Science.gov (United States)

    Cheng, Pin-Nan; Liu, Cong; Zhao, Minglei; Eisenberg, David; Nowick, James S.

    2012-11-01

    The amyloid protein aggregation associated with diseases such as Alzheimer's, Parkinson's and type II diabetes (among many others) features a bewildering variety of β-sheet-rich structures in transition from native proteins to ordered oligomers and fibres. The variation in the amino-acid sequences of the β-structures presents a challenge to developing a model system of β-sheets for the study of various amyloid aggregates. Here, we introduce a family of robust β-sheet macrocycles that can serve as a platform to display a variety of heptapeptide sequences from different amyloid proteins. We have tailored these amyloid β-sheet mimics (ABSMs) to antagonize the aggregation of various amyloid proteins, thereby reducing the toxicity of amyloid aggregates. We describe the structures and inhibitory properties of ABSMs containing amyloidogenic peptides from the amyloid-β peptide associated with Alzheimer's disease, β2-microglobulin associated with dialysis-related amyloidosis, α-synuclein associated with Parkinson's disease, islet amyloid polypeptide associated with type II diabetes, human and yeast prion proteins, and Tau, which forms neurofibrillary tangles.

  14. Plaque biofilms: the effect of chemical environment on natural human plaque biofilm architecture.

    Science.gov (United States)

    Robinson, C; Strafford, S; Rees, G; Brookes, S J; Kirkham, J; Shore, R C; Watson, P S; Wood, S

    2006-11-01

    The architecture of microbial biofilms especially the outer regions have an important influence on the interaction between biofilm and local environment particularly on the flux of materials into and out of biofilm compartments and as a consequence, biofilm metabolic behaviour. In the case of dental plaque biofilms, architecture will determine access of nutrients including acidogenic substrates and therapeutic materials to the microbial biomass and to the underlying tooth surface. Manipulation of this architecture may offer a means of altering mass transfer into the whole biofilm and biomass and raises the possibility of improving access of therapeutics. Plaque biofilms formed in vivo on human enamel were subjected to a number of different chemical conditions while under observation by confocal laser scanning microscopy in reflection mode. In this way the outer 50-100 microm or so of the biofilms was examined. Density and distribution of biomass were recorded as degree of reflectance. The amount and density of biofilm biomass increased from the plaque saliva interface towards the interior. Plaque biofilms were robust and little affected by mechanical manipulation, high ionic strength or low pH (2.5). Detergent (SLS), however, often appeared to either remove biomass and/or dramatically reduce its density.

  15. Association of Streptococcus with Plaque Type of Psoriasis

    Directory of Open Access Journals (Sweden)

    Mohammad Akram Hossain

    2015-05-01

    Full Text Available Background: Guttate psoriasis has a well-known association with streptococcal throat infections, but the effects of these infections in patients with chronic plaque type of psoriasis remains to be evaluated. In Bangladesh several studies were done on psoriasis but no data about association between streptococcal throat infection and plaque type psoriasis are available so far. Considering the co-morbidities of psoriasis patients, it might be justifiable to find out the events that provoke the initiation or exacerbation of psoriatic disease process. Objective: To observe the association of streptococcus with plaque type of psoriasis. Materials and Methods: This observational study was conducted in the department of Dermatology and Venereology, Bangabandhu Sheikh Mujib Medical University, Dhaka. Forty seven patients clinically and histopathologically diagnosed as having plaque psoriasis were selected as cases and patients with skin diseases other than psoriasis were selected as controls. Results: In this study majority of subjects (55% were diagnosed as chronic plaque psoriasis. Among the subjects with guttate flare of chronic plaque psoriasis 64.2% gave a positive history of sore throat. ASO titer was raised (>200 IU/mL in 28 (59.5% patients of chronic plaque psoriasis and 7 (17.9% patients of non-psoriatic respondents. The difference between two groups was significant (p0.05. Conclusion: This study shows that streptococcal throat infections are associated with plaque psoriasis and early treatment of throat infections may be beneficial for plaque type of psoriasis patients.

  16. The Role of the 14–20 Domain of the Islet Amyloid Polypeptide in Amyloid Formation

    Directory of Open Access Journals (Sweden)

    Sharon Gilead

    2008-01-01

    Full Text Available The molecular mechanism of amyloid formation by the islet amyloid polypeptide (IAPP has been intensively studied since its identification in the late 1980s. The IAPP(20–29 region is considered to be the central amyloidogenic module of the polypeptide. This assumption is mainly based on the amyloidogenic properties of the region and on the large sequence diversity within this region between the human and mouse IAPP, as the mouse IAPP does not form amyloids. A few years ago, another region within IAPP was identified that seems to be at least as important as IAPP(20–29 in facilitation of molecular recognition that leads to amyloid formation. Here, we reinforce our and others' previous findings by analyzing supporting evidence from the recent literature. Moreover, we provide new proofs to our hypothesis by comparing between the amyloidogenic properties of the two regions derived from the IAPP of cats, which is also known to form amyloid fibrils.

  17. Islet amyloid polypeptide-induced membrane leakage involves uptake of lipids by forming amyloid fibers.

    Science.gov (United States)

    Sparr, Emma; Engel, Maarten F M; Sakharov, Dmitri V; Sprong, Mariette; Jacobs, Jet; de Kruijff, Ben; Höppener, Jo W M; Killian, J Antoinette

    2004-11-01

    Fibril formation of islet amyloid polypeptide (IAPP) is associated with cell death of the insulin-producing pancreatic beta-cells in patients with Type 2 Diabetes Mellitus. A likely cause for the cytotoxicity of human IAPP is that it destroys the barrier properties of the cell membrane. Here, we show by fluorescence confocal microscopy on lipid vesicles that the process of hIAPP amyloid formation is accompanied by a loss of barrier function, whereby lipids are extracted from the membrane and taken up in the forming amyloid deposits. No membrane interaction was observed when preformed fibrils were used. It is proposed that lipid uptake from the cell membrane is responsible for amyloid-induced membrane damage and that this represents a general mechanism underlying the cytotoxicity of amyloid forming proteins. PMID:15527771

  18. Effect of Chlorhexidine with Fluoride Mouthrinse on Plaque Accumulation, Plaque pH - A Double Blind Parallel Randomized Clinical Trial

    Science.gov (United States)

    Saha, Sabyasachi; Singh, Sanjay

    2016-01-01

    Introduction Mouthwashes are important means used in chemical control of dental plaque. There is strong evidence suggestive of better effectiveness, when fluoride is added to chlorhexidine mouthwash. Aim To assess the anti-plaque efficacy of Chlorhexidine combined with Fluoride mouthwash and to measure its impact on plaque accumulation and on plaque pH. Materials and Methods Initially 100 subjects were screened. A double blind, parallel randomized clinical trial was conducted on 30 subjects after applying inclusion and exclusion criteria. Other independent variables were matched before randomly allocating them in three groups: Group A-Chlorhexidine as positive control, Group B-Chlorhexidine + Fluoride as test group and Group C- Distilled water as negative control. Oral prophylaxis of participants was done before onset of the study. Plaque pH was assessed before and immediately after rinsing at 0, 5 and 10 minutes interval and after 7 days with digital pH electrode (pHepR pH meter, Hanna Instruments R10285) and accumulation of plaque was recorded by Turesky et al., modification of Quigley Hein Plaque Index (1970). ANOVA test was used for statistical analysis. Results Although there was a statistically significant reduction in mean plaque scores from baseline to seven days in both Groups A and B, Group B showed better anti-plaque efficacy . Almost equal drop in plaque pH was seen for both the groups at 5 and 10 minutes. Conclusion Better anti-plaque efficacy was observed in Group B (Chlorhexidine and Fluoride combination) with minimum variation of plaque pH.

  19. Concept of Remission in Chronic Plaque Psoriasis.

    Science.gov (United States)

    Gisondi, Paolo; Di Mercurio, Marco; Idolazzi, Luca; Girolomoni, Giampiero

    2015-11-01

    Psoriasis is a lifelong chronic inflammatory disease affecting 2-3% of the worldwide population. Current understanding of the pathogenesis of psoriasis assigns central importance to an interaction between acquired and innate immunity. The disease is characterized by a series of linked cellular changes in the skin, including hyperplasia of epidermal keratinocytes, angiogenesis, and infiltration of T lymphocytes, neutrophils, and other types of leukocytes in the affected skin. Plaque psoriasis is the most common clinical form and is characterized by red and scaly plaques generally localized at extensor sites such as elbows and knees. Major determinants of psoriasis severity include the extent of skin involvement; localization in highly affected areas such as scalp, palms, and soles; pruritus; presence of comorbidities including psoriatic arthritis; and impairment on quality of life. About one-third of patients have moderate to severe psoriasis defined as PASI (Psoriasis Area and Severity Index) and/or Dermatology Life Quality Index>10, and/or affected body surface area>10%. The optimal treatment goal is to safely achieve complete or almost complete skin clearance. Treatments available are various and they are chosen according to disease features, comorbidities, and patient characteristics and priorities. Topical treatments including corticosteroids and Vitamin D analogs are reserved for mild disease. Phototherapy, cyclosporine, methotrexate, acitretin, or biologics such as tumor necrosis factor-α antagonists and ustekinumab are reserved for the moderate to severe forms.

  20. Contemporary treatment of amyloid heart disease.

    Science.gov (United States)

    Palecek, Tomas; Fikrle, Michal; Nemecek, Eduard; Bauerova, Lenka; Kuchynka, Petr; Louch, William E; Spicka, Ivan; Rysava, Romana

    2015-01-01

    The amyloidoses represent a group of diseases characterized by extracellular deposition of abnormal protein, amyloid, which is formed by insoluble extracellular fibrils in β-pleated sheets. Although cardiac involvement may occur in all types of amyloidoses, clinically relevant amyloid cardiomyopathy is a typical feature of AL amyloidosis and transthyretin-related amyloidoses. Congestive heart failure represents the commonest manifestation of amyloid heart disease. Noninvasive imaging techniques, especially echocardiography and cardiac magnetic resonance, play a major role in the diagnosis of amyloid cardiomyopathy; however, histological confirmation and exact typing of amyloid deposits is necessary whether in extracardiac location or directly in the myocardium. Early diagnosis of amyloid heart disease is of utmost importance as the presence and especially the severity of cardiac involvement generally drives the prognosis of affected subjects and plays a major role in determining the intensity of specific treatment, namely in AL amyloidosis. The management of patients with amyloid heart disease is complex. Loop diuretics together with aldosterone antagonists represent the basis for influencing signs of congestion. In AL amyloidosis, high-dose chemotherapy followed by autologous stem cell transplantation is generally considered to be a front-line treatment option, if the disease is diagnosed at its early stage. The combination of mephalan with dexamethasone has been the standard therapy for severely affected individuals; however, the combinations with several novel agents including immunomodulatory drugs and bortezomibe have been tested in clinical trials with promising results. New therapeutic substances with the potential to slow or even stop the progression of transthyretin-related amyloidosis are also extensively studied. PMID:25483951

  1. Oligomer stability of Amyloid- β (A β) 25-35: A Dissipative Particle Dynamics study

    Science.gov (United States)

    Pivkin, Igor; Peter, Emanuel

    Alzheimer's disease is strongly associated with an accumulation of Amyloid- β (A β) peptide plaques in the human brain. A β is a 43 residues long intrinsically disordered peptide and has a strong tendency to form aggregates. Evidence accumulates that A β acts toxic to the neurons in the brain through the formation of small soluble oligomers. A β 25-35 is the smallest fragment of A β which still retains its toxicity and its ability to form extended fibrils. In this talk we will present the results from simulations of aggregation of up to 100 A β 25-35 peptides using a novel polarizable coarse-grained protein model in combination with Dissipative Particle Dynamics.

  2. Amyloid-β probes: Review of structure–activity and brain-kinetics relationships

    Directory of Open Access Journals (Sweden)

    Todd J. Eckroat

    2013-05-01

    Full Text Available The number of people suffering from Alzheimer’s disease (AD is expected to increase dramatically in the coming years, placing a huge burden on society. Current treatments for AD leave much to be desired, and numerous research efforts around the globe are focused on developing improved therapeutics. In addition, current diagnostic tools for AD rely largely on subjective cognitive assessment rather than on identification of pathophysiological changes associated with disease onset and progression. These facts have led to numerous efforts to develop chemical probes to detect pathophysiological hallmarks of AD, such as amyloidplaques, for diagnosis and monitoring of therapeutic efficacy. This review provides a survey of chemical probes developed to date for AD with emphasis on synthetic methodologies and structure–activity relationships with regards to affinity for target and brain kinetics. Several probes discussed herein show particularly promising results and will be of immense value moving forward in the fight against AD.

  3. Recent Development of Bifunctional Small Molecules to Study Metal-Amyloid-β Species in Alzheimer's Disease.

    Science.gov (United States)

    Braymer, Joseph J; Detoma, Alaina S; Choi, Jung-Suk; Ko, Kristin S; Lim, Mi Hee

    2010-12-08

    Alzheimer's disease (AD) is a multifactorial neurodegenerative disease related to the deposition of aggregated amyloid-β (Aβ) peptides in the brain. It has been proposed that metal ion dyshomeostasis and miscompartmentalization contribute to AD progression, especially as metal ions (e.g., Cu(II) and Zn(II)) found in Aβ plaques of the diseased brain can bind to Aβ and be linked to aggregation and neurotoxicity. The role of metal ions in AD pathogenesis, however, is uncertain. To accelerate understanding in this area and contribute to therapeutic development, recent efforts to devise suitable chemical reagents that can target metal ions associated with Aβ have been made using rational structure-based design that combines two functions (metal chelation and Aβ interaction) in the same molecule. This paper presents bifunctional compounds developed by two different design strategies (linkage or incorporation) and discusses progress in their applications as chemical tools and/or potential therapeutics.

  4. Destruction of amyloid fibrils by graphene through penetration and extraction of peptides

    Science.gov (United States)

    Yang, Zaixing; Ge, Cuicui; Liu, Jiajia; Chong, Yu; Gu, Zonglin; Jimenez-Cruz, Camilo A.; Chai, Zhifang; Zhou, Ruhong

    2015-11-01

    Current therapies for Alzheimer's disease (AD) can provide a moderate symptomatic reduction or delay progression at various stages of the disease, but such treatments ultimately do not arrest the advancement of AD. As such, novel approaches for AD treatment and prevention are urgently needed. We here provide both experimental and computational evidence that pristine graphene and graphene-oxide nanosheets can inhibit Aβ peptide monomer fibrillation and clear mature amyloid fibrils, thus impacting the central molecular superstructures correlated with AD pathogenesis. Our molecular dynamics simulations for the first time reveal that graphene nanosheets can penetrate and extract a large number of peptides from pre-formed amyloid fibrils; these effects seem to be related to exceptionally strong dispersion interactions between peptides and graphene that are further enhanced by strong π-π stacking between the aromatic residues of extracted Aβ peptides and the graphene surface. Atomic force microscopy images confirm these predictions by demonstrating that mature amyloid fibrils can be cut into pieces and cleared by graphene oxides. Thioflavin fluorescence assays further illustrate the detailed dynamic processes by which graphene induces inhibition of monomer aggregation and clearance of mature amyloid fibrils, respectively. Cell viability and ROS assays indicate that graphene oxide can indeed mitigate cytotoxicity of Aβ peptide amyloids. Our findings provide new insights into the underlying molecular mechanisms that define graphene-amyloid interaction and suggest that further research on nanotherapies for Alzheimer's and other protein aggregation-related diseases is warranted.Current therapies for Alzheimer's disease (AD) can provide a moderate symptomatic reduction or delay progression at various stages of the disease, but such treatments ultimately do not arrest the advancement of AD. As such, novel approaches for AD treatment and prevention are urgently needed. We

  5. Synthesis of fluorescent-maghemite nanoparticles as multimodal imaging agents for amyloid-beta fibrils detection and removal by a magnetic field.

    Science.gov (United States)

    Skaat, Hadas; Margel, Shlomo

    2009-09-01

    Early diagnosis in Alzheimer's disease (AD), before the onset of marked clinical symptoms, is critical in preventing the irreversible neuronal damage that eventually leads to dementia and ultimately death. Therefore, there is an urgent need for in vivo imaging agents, which are valuable as specific biomarkers to demonstrate the location and density of amyloid plaques in the living human brain. The present manuscript describes a novel method for selective marking of Abeta(40) fibrils by non-fluorescent gamma-Fe(2)O(3) and fluorescent-magnetic gamma-Fe(2)O(3)-rhodamine or gamma-Fe(2)O(3)-Congo red nanoparticles, and the complete removal of the magnetized fibrils from the aqueous continuous phase by a magnetic field. These fluorescent-maghemite nanoparticles as multimodal imaging agents have a great advantage due to the combination of the magnetic and fluorescence imaging into one nanostructured system. This hybrid system, which selectively marks Abeta(40) fibrils, might enable the early detection of plaques using both MRI and fluorescence microscopy, and therefore may be applied in in vivo AD diagnosis studies. These fluorescent-magnetic nanoparticles may also be useful as selective biomarkers to detect the location and the removal of other amyloid plaques derived from different amyloidogenic proteins that lead to neurodegenerative diseases, e.g., Parkinson's, Huntington's, mad cow, and prion diseases. PMID:19559008

  6. Genetic divergence of Chikungunya virus plaque variants from the Comoros Island (2005).

    Science.gov (United States)

    Wasonga, Caroline; Inoue, Shingo; Rumberia, Cecilia; Michuki, George; Kimotho, James; Ongus, Juliette R; Sang, Rosemary; Musila, Lillian

    2015-12-01

    Chikungunya virus (CHIKV) from a human sample collected during the 2005 Chikungunya outbreak in the Comoros Island, showed distinct and reproducible large (L2) and small (S7) plaques which were characterized in this study. The parent strain and plaque variants were analysed by in vitro growth kinetics in different cell lines and their genetic similarity assessed by whole genome sequencing, comparative sequence alignment and phylogenetic analysis. In vitro growth kinetic assays showed similar growth patterns of both plaque variants in Vero cells but higher viral titres of S7 compared to L2 in C6/36 cells. Amino acids (AA) alignments of the CHIKV plaque variants and S27 African prototype strain, showed 30 AA changes in the non-structural proteins (nsP) and 22 AA changes in the structural proteins. Between L2 and S7, only two AAs differences were observed. A missense substitution (C642Y) of L2 in the nsP2, involving a conservative AA substitution and a nonsense substitution (R524X) of S7 in the nsP3, which has been shown to enhance O'nyong-nyong virus infectivity and dissemination in Anopheles mosquitoes. The phenotypic difference observed in plaque size could be attributed to one of these AA substitutions. Phylogenetic analysis showed that the parent strain and its variants clustered closely together with each other and with Indian Ocean CHIKV strains indicating circulation of isolates with close evolutionary relatedness in the same outbreak. These observations pave way for important functional studies to understand the significance of the identified genetic changes in virulence and viral transmission in mosquito and mammalian hosts.

  7. The proteome response to amyloid protein expression in vivo.

    Directory of Open Access Journals (Sweden)

    Ricardo A Gomes

    Full Text Available Protein misfolding disorders such as Alzheimer, Parkinson and transthyretin amyloidosis are characterized by the formation of protein amyloid deposits. Although the nature and location of the aggregated proteins varies between different diseases, they all share similar molecular pathways of protein unfolding, aggregation and amyloid deposition. Most effects of these proteins are likely to occur at the proteome level, a virtually unexplored reality. To investigate the effects of an amyloid protein expression on the cellular proteome, we created a yeast expression system using human transthyretin (TTR as a model amyloidogenic protein. We used Saccharomyces cerevisiae, a living test tube, to express native TTR (non-amyloidogenic and the amyloidogenic TTR variant L55P, the later forming aggregates when expressed in yeast. Differential proteome changes were quantitatively analyzed by 2D-differential in gel electrophoresis (2D-DIGE. We show that the expression of the amyloidogenic TTR-L55P causes a metabolic shift towards energy production, increased superoxide dismutase expression as well as of several molecular chaperones involved in protein refolding. Among these chaperones, members of the HSP70 family and the peptidyl-prolyl-cis-trans isomerase (PPIase were identified. The latter is highly relevant considering that it was previously found to be a TTR interacting partner in the plasma of ATTR patients but not in healthy or asymptomatic subjects. The small ubiquitin-like modifier (SUMO expression is also increased. Our findings suggest that refolding and degradation pathways are activated, causing an increased demand of energetic resources, thus the metabolic shift. Additionally, oxidative stress appears to be a consequence of the amyloidogenic process, posing an enhanced threat to cell survival.

  8. Extrahepatic production of acute phase serum amyloid A

    OpenAIRE

    Upragarin, N.; Landman, W.J.M.; Gaastra, W; Gruys, E.

    2005-01-01

    Amyloidosis is a group of diseases characterized by the extracellular deposition of protein that contains non-branching, straight fibrils on electron microscopy (amyloid fibrils) that have a high content of ß-pleated sheet conformation. Various biochemically distinct proteins can undergo transformation into amyloid fibrils. The precursor protein of amyloid protein A (AA) is the acute phase protein serum amyloid A (SAA). The concentration of SAA in plasma increa...

  9. STIMULATED PLATELETS RELEASE AMYLOID β–PROTEIN PRECURSOR

    OpenAIRE

    Cole, Gregory M.; Galasko, Douglas; Shapiro, I. Paul; Saitoh, Tsunao

    1990-01-01

    Human platelets can be stimulated by thrombin or ionomycin to secrete soluble truncated amyloid β–protein precursor and particulate membrane fragments which contain C-terminal and N-terminal immunoreactive amyloid β–protein precursor. This suggests a possible circulating source of β–protein in serum which may play a role in the formation of amyloid deposits. The release of soluble amyloid β-protein precursor could be involved in normal platelet physiology.

  10. Appropriate Use Criteria for Amyloid PET

    Science.gov (United States)

    Johnson, Keith A.; Minoshima, Satoshi; Bohnen, Nicolaas I.; Donohoe, Kevin J.; Foster, Norman L.; Herscovitch, Peter; Karlawish, Jason H.; Rowe, Christopher C.; Carrillo, Maria C.; Hartley, Dean M.; Hedrick, Saima; Mitchell, Kristi; Pappas, Virginia; Thies, William H.

    2013-01-01

    Positron Emission Tomography (PET) of brain amyloid-beta is a technology that is becoming more available, but its clinical utility in medical practice requires careful definition. In order to provide guidance to dementia care practitioners, patients and caregivers, the Alzheimer Association and the Society of Nuclear Medicine and Molecular Imaging convened the Amyloid Imaging Taskforce (AIT). The AIT considered a broad range of specific clinical scenarios in which amyloid PET could potentially be appropriately used. Peer-reviewed, published literature was searched to ascertain available evidence relevant to these scenarios, and the AIT developed a consensus of expert opinion. While empirical evidence of impact on clinical outcomes is not yet available, a set of specific Appropriate Use Criteria (AUC) were agreed upon that define the types of patients and clinical circumstances in which amyloid PET could be used. Both appropriate and inappropriate uses were considered and formulated, and are reported and discussed here. Because both dementia care and amyloid PET technology are in active development, these AUC will require periodic reassessment. Future research directions are also outlined, including diagnostic utility and patient-centered outcomes. PMID:23360977

  11. A comparative study on plaque vulnerability using constitutive equations.

    Science.gov (United States)

    Karimi, A; Navidbakhsh, M; Faghihi, S

    2014-03-01

    Atherosclerosis is the most serious and common form of cardiovascular disease in which plaque builds up inside the arteries. Peak plaque stress is considered as the main reason for plaque rupture, which results in heart attack and stroke. In the current research, the finite element method is used to anticipate plaque vulnerability, using human samples. A total of 23 healthy and atherosclerotic human coronary arteries (14 healthy and 9 atherosclerotic) were removed within 5 h postmortem. The samples were mounted on a uniaxial tensile test machine and the obtained mechanical properties were used in finite element models. The peak plaque stresses for the Ogden hyperelastic model were compared to the Mooney-Rivlin and Neo-Hookean outcomes. The results indicated that hypocellular plaque in all three models has the highest stress values compared to the cellular and calcified ones and, as a result, is quite prone to rupture. The calcified plaque type, in contrast, has the lowest stress values and remains stable. The results can be used in plaque vulnerability prediction and have clinical implications for interventions and surgeries such as balloon-angioplasty, cardiopulmonary bypass and stenting.

  12. New low-viscosity overlay medium for viral plaque assays

    Directory of Open Access Journals (Sweden)

    Garten Wolfgang

    2006-08-01

    Full Text Available Abstract Background Plaque assays in cell culture monolayers under solid or semisolid overlay media are commonly used for quantification of viruses and antiviral substances. To overcome the pitfalls of known overlays, we tested suspensions of microcrystalline cellulose Avicel RC/CL™ as overlay media in the plaque and plaque-inhibition assay of influenza viruses. Results Significantly larger plaques were formed under Avicel-containing media, as compared to agar and methylcellulose (MC overlay media. The plaque size increased with decreasing Avicel concentration, but even very diluted Avicel overlays (0.3% ensured formation of localized plaques. Due to their low viscosity, Avicel overlays were easier to use than methylcellulose overlays, especially in the 96-well culture plates. Furthermore, Avicel overlay could be applied without prior removal of the virus inoculum thus facilitating the assay and reducing chances of cross-contamination. Using neuraminidase inhibitor oseltamivir carboxylate, we demonstrated applicability of the Avicel-based plaque reduction assay for testing of antiviral substances. Conclusion Plaque assay under Avicel-containing overlay media is easier, faster and more sensitive than assays under agar- and methylcellulose overlays. The assay can be readily performed in a 96-well plate format and seems particularly suitable for high-throughput virus titrations, serological studies and experiments on viral drug sensitivity. It may also facilitate work with highly pathogenic agents performed under hampered conditions of bio-safety labs.

  13. Carotid plaque, intima-media thickness, and incident aortic stenosis

    DEFF Research Database (Denmark)

    Martinsson, Andreas; Östling, Gerd; Persson, Margaretha;

    2014-01-01

    OBJECTIVE: Aortic stenosis (AS) shares risk factors with atherosclerotic vascular disease. Carotid intima-media thickness (IMT) and plaque may reflect the cumulative damage from exposure to different atherosclerotic risk factors. We examined the relationship of carotid IMT and plaque with inciden...

  14. [Effect of Root Iron Plaque on Norfloxacin Uptake by Rice].

    Science.gov (United States)

    Ma, Wei; Bao, Yan-yu

    2015-06-01

    In anaerobic condition, release of oxygen by roots to rhyzosphere caused the formation of red plaque of iron oxides or hydroxides on the root surface of rice. The effect of iron plaque on norfloxacin uptake was investigated with solution culture in greenhouse, and the results are showed in the following. The content of iron plaque increased with the increase of Fe2+ concentration in medium. After the addition of norfloxacin in nutrient solution, the content of iron plaques on the root surface decreased to different degree, and the reduction of iron plaques was increasing with the increase of norfloxacin mass concentration. Significant relationships were found between the iron plaques and norfloxacin on the root surface, and the correlation coefficients were 0.959 (norfloxacin mass concentration was 10 mg x L(-1)) and 0.987 (norfloxacin mass concentration was 50 mg x L(-1)), respectively, however, the norfloxacin contents in roots and shoots had no significant correlation with the iron plaques. After addition of different mass concentrations of norfloxacin, the quality distribution percentages of norfloxacin on the root surface and in roots and shoots were 87.7%-97.6%, 0.8%-4.8%, 1.5%-7.5%, respectively, the norfloxacin content on the root surface was far greater than those in roots and shoots. It was therefore concluded that iron plaque on roots was a norfloxacin reservoir for rice plant but had no significant effect on the transfer of norfloxacin to roots and shoots of the rice plant.

  15. Directional spatial frequency analysis of lipid distribution in atherosclerotic plaque

    Science.gov (United States)

    Korn, Clyde; Reese, Eric; Shi, Lingyan; Alfano, Robert; Russell, Stewart

    2016-04-01

    Atherosclerosis is characterized by the growth of fibrous plaques due to the retention of cholesterol and lipids within the artery wall, which can lead to vessel occlusion and cardiac events. One way to evaluate arterial disease is to quantify the amount of lipid present in these plaques, since a higher disease burden is characterized by a higher concentration of lipid. Although therapeutic stimulation of reverse cholesterol transport to reduce cholesterol deposits in plaque has not produced significant results, this may be due to current image analysis methods which use averaging techniques to calculate the total amount of lipid in the plaque without regard to spatial distribution, thereby discarding information that may have significance in marking response to therapy. Here we use Directional Fourier Spatial Frequency (DFSF) analysis to generate a characteristic spatial frequency spectrum for atherosclerotic plaques from C57 Black 6 mice both treated and untreated with a cholesterol scavenging nanoparticle. We then use the Cauchy product of these spectra to classify the images with a support vector machine (SVM). Our results indicate that treated plaque can be distinguished from untreated plaque using this method, where no difference is seen using the spatial averaging method. This work has the potential to increase the effectiveness of current in-vivo methods of plaque detection that also use averaging methods, such as laser speckle imaging and Raman spectroscopy.

  16. The novel amyloid-beta peptide aptamer inhibits intracellular amyloid-beta peptide toxicity

    Institute of Scientific and Technical Information of China (English)

    Xu Wang; Yi Yang; Mingyue Jia; Chi Ma; Mingyu Wang; Lihe Che; Yu Yang; Jiang Wu

    2013-01-01

    Amyloid β peptide binding alcohol dehydrogenase (ABAD) decoy peptide (DP) can competitively antagonize binding of amyloid β peptide to ABAD and inhibit the cytotoxic effects of amyloid β peptide. Based on peptide aptamers, the present study inserted ABAD-DP into the disulfide bond of human thioredoxin (TRX) using molecular cloning technique to construct a fusion gene that can express the TRX1-ABAD-DP-TRX2 aptamer. Moreover, adeno-associated virus was used to allow its stable expression. Immunofluorescent staining revealed the co-expression of the transduced fusion gene TRX1-ABAD-DP-TRX2 and amyloid β peptide in NIH-3T3 cells, indicating that the TRX1-ABAD-DP-TRX2 aptamer can bind amyloid β peptide within cells. In addition, cell morphology and MTT results suggested that TRX1-ABAD-DP-TRX2 attenuated amyloid β peptide-induced SH-SY5Y cell injury and improved cell viability. These findings confirmed the possibility of constructing TRX-based peptide aptamer using ABAD-DP. Moreover, TRX1-ABAD-DP-TRX2 inhibited the cytotoxic effect of amyloid β peptide.

  17. Cholinergic degeneration is associated with increased plaque deposition and cognitive impairment in APPswe/PS1dE9 mice

    DEFF Research Database (Denmark)

    Laursen, Bettina; Mørk, Arne; Plath, Niels;

    2013-01-01

    Cholinergic dysfunction and deposition of plaques containing amyloid ß-peptides (Aß) are two of the characteristics of Alzheimer's disease. Here, we combine APPswe/PS1dE9 (APP/PS1) mice with the cholinergic immunotoxin mu p75-saporin (SAP) to integrate partial basal forebrain cholinergic degenera......Cholinergic dysfunction and deposition of plaques containing amyloid ß-peptides (Aß) are two of the characteristics of Alzheimer's disease. Here, we combine APPswe/PS1dE9 (APP/PS1) mice with the cholinergic immunotoxin mu p75-saporin (SAP) to integrate partial basal forebrain cholinergic...... degeneration and the neuropathology of APP/PS1 mice. By 6 months of age, APP/PS1 mice and wild type littermates (Wt) received intracerebroventricular injection of 0.6 µg SAP (lesion) or PBS (sham). Two months following surgery, APP/PS1 mice treated with SAP were significantly impaired compared to sham treated...... APP/PS1 mice in a behavioural paradigm addressing working memory. Conversely, the performance of Wt mice was unaffected by SAP treatment. Choline acetyltransferase activity was reduced in the hippocampus and frontal cortex following SAP treatment. The selective effect of a mild SAP lesion in APP/PS1...

  18. Surface Binding of TOTAPOL Assists Structural Investigations of Amyloid Fibrils by Dynamic Nuclear Polarization NMR Spectroscopy.

    Science.gov (United States)

    Nagaraj, Madhu; Franks, Trent W; Saeidpour, Siavash; Schubeis, Tobias; Oschkinat, Hartmut; Ritter, Christiane; van Rossum, Barth-Jan

    2016-07-15

    Dynamic nuclear polarization (DNP) NMR can enhance sensitivity but often comes at the price of a substantial loss of resolution. Two major factors affect spectral quality: low-temperature heterogeneous line broadening and paramagnetic relaxation enhancement (PRE) effects. Investigations by NMR spectroscopy, isothermal titration calorimetry (ITC), and EPR revealed a new substantial affinity of TOTAPOL to amyloid surfaces, very similar to that shown by the fluorescent dye thioflavin-T (ThT). As a consequence, DNP spectra with remarkably good resolution and still reasonable enhancement could be obtained at very low TOTAPOL concentrations, typically 400 times lower than commonly employed. These spectra yielded several long-range constraints that were difficult to obtain without DNP. Our findings open up new strategies for structural studies with DNP NMR spectroscopy on amyloids that can bind the biradical with affinity similar to that shown towards ThT. PMID:27147408

  19. Imaging Modalities to Identity Inflammation in an Atherosclerotic Plaque

    International Nuclear Information System (INIS)

    Atherosclerosis is a chronic, progressive, multifocal arterial wall disease caused by local and systemic inflammation responsible for major cardiovascular complications such as myocardial infarction and stroke. With the recent understanding that vulnerable plaque erosion and rupture, with subsequent thrombosis, rather than luminal stenosis, is the underlying cause of acute ischemic events, there has been a shift of focus to understand the mechanisms that make an atherosclerotic plaque unstable or vulnerable to rupture. The presence of inflammation in the atherosclerotic plaque has been considered as one of the initial events which convert a stable plaque into an unstable and vulnerable plaque. This paper systemically reviews the noninvasive and invasive imaging modalities that are currently available to detect this inflammatory process, at least in the intermediate stages, and discusses the ongoing studies that will help us to better understand and identify it at the molecular level

  20. Spectroscopy to improve identification of vulnerable plaques in cardiovascular disease.

    Science.gov (United States)

    Bruggink, Janneke L M; Meerwaldt, Robbert; van Dam, Gooitzen M; Lefrandt, Joop D; Slart, Riemer H J A; Tio, René A; Smit, Andries J; Zeebregts, Clark J

    2010-01-01

    Many apparent healthy persons die from cardiovascular disease, despite major advances in prevention and treatment of cardiovascular disease. Traditional cardiovascular risk factors are able to predict cardiovascular events in the long run, but fail to assess current disease activity or nearby cardiovascular events. There is a clear relation between the occurrence of cardiovascular events and the presence of so-called vulnerable plaques. These vulnerable plaques are characterized by active inflammation, a thin cap and a large lipid pool. Spectroscopy is an optical imaging technique which depicts the interaction between light and tissues, and thereby shows the biochemical composition of tissues. In recent years, impressive advances have been made in spectroscopy technology and intravascular spectroscopy is able to assess the composition of plaques of interest and thereby to identify and actually quantify plaque vulnerability. This review summarizes the current evidence for spectroscopy as a measure of plaque vulnerability and discusses the potential role of intravascular spectroscopic imaging techniques.

  1. High shear stress induces atherosclerotic vulnerable plaque formation through angiogenesis.

    Science.gov (United States)

    Wang, Yi; Qiu, Juhui; Luo, Shisui; Xie, Xiang; Zheng, Yiming; Zhang, Kang; Ye, Zhiyi; Liu, Wanqian; Gregersen, Hans; Wang, Guixue

    2016-12-01

    Rupture of atherosclerotic plaques causing thrombosis is the main cause of acute coronary syndrome and ischemic strokes. Inhibition of thrombosis is one of the important tasks developing biomedical materials such as intravascular stents and vascular grafts. Shear stress (SS) influences the formation and development of atherosclerosis. The current review focuses on the vulnerable plaques observed in the high shear stress (HSS) regions, which localizes at the proximal region of the plaque intruding into the lumen. The vascular outward remodelling occurs in the HSS region for vascular compensation and that angiogenesis is a critical factor for HSS which induces atherosclerotic vulnerable plaque formation. These results greatly challenge the established belief that low shear stress is important for expansive remodelling, which provides a new perspective for preventing the transition of stable plaques to high-risk atherosclerotic lesions. PMID:27482467

  2. Imaging Modalities to Identity Inflammation in an Atherosclerotic Plaque

    Directory of Open Access Journals (Sweden)

    Sunny Goel

    2015-01-01

    Full Text Available Atherosclerosis is a chronic, progressive, multifocal arterial wall disease caused by local and systemic inflammation responsible for major cardiovascular complications such as myocardial infarction and stroke. With the recent understanding that vulnerable plaque erosion and rupture, with subsequent thrombosis, rather than luminal stenosis, is the underlying cause of acute ischemic events, there has been a shift of focus to understand the mechanisms that make an atherosclerotic plaque unstable or vulnerable to rupture. The presence of inflammation in the atherosclerotic plaque has been considered as one of the initial events which convert a stable plaque into an unstable and vulnerable plaque. This paper systemically reviews the noninvasive and invasive imaging modalities that are currently available to detect this inflammatory process, at least in the intermediate stages, and discusses the ongoing studies that will help us to better understand and identify it at the molecular level.

  3. Explosive character of the atheroma plaques ablation

    International Nuclear Information System (INIS)

    At the present time, ischemia (heart disease) is a main cause of the death in the world; a promising method for its treatment is the use of the technology of the laser light of raised power for the ablation of the atherosclerosis plaques. In this paper, the thermodynamic processes will be studied at the beginning and during atheroma ablation using Nd-YAG (10-50 w) and Argon (4-10 w) lasers of a theoretical point of view. The spatial distribution of the temperature during the ablation has been modelated by the method of finite volumes. The manifestation of the raised temperature of the tissue at the threshold of the ablation, which describes the explosive nature of the ablation by laser (popcorn effect), is observed and discussed. The results indicate the quantitative differences in the ablation behavior between the two used lasers, which can have important clinical implications particularly in the reduction of thermal damages to surrounding normal tissue. (author)

  4. Imaging Atherosclerotic Plaque Calcification: Translating Biology.

    Science.gov (United States)

    Bailey, Grant; Meadows, Judith; Morrison, Alan R

    2016-08-01

    Calcification of atherosclerotic lesions was long thought to be an age - related, passive process, but increasingly data has revealed that atherosclerotic calcification is a more active process, involving complex signaling pathways and bone-like genetic programs. Initially, imaging of atherosclerotic calcification was limited to gross assessment of calcium burden, which is associated with total atherosclerotic burden and risk of cardiovascular mortality and of all cause mortality. More recently, sophisticated molecular imaging studies of the various processes involved in calcification have begun to elucidate information about plaque calcium composition and consequent vulnerability to rupture, leading to hard cardiovascular events like myocardial infarction. As such, there has been renewed interest in imaging calcification to advance risk assessment accuracy in an evolving era of precision medicine. Here we summarize recent advances in our understanding of the biologic process of atherosclerotic calcification as well as some of the molecular imaging tools used to assess it. PMID:27339750

  5. The high-risk plaque initiative

    DEFF Research Database (Denmark)

    Falk, Erling; Sillesen, Henrik; Muntendam, Pieter;

    2011-01-01

    have been initiated, including the BioImage Study in which novel approaches are tested in a typical health plan population. Asymptomatic at-risk individuals were enrolled, including a survey-only group (n = 865), a group undergoing traditional risk factor scoring (n = 718), and a group in which all......The High-Risk Plaque (HRP) Initiative is a research and development effort to advance the understanding, recognition, and management of asymptomatic individuals at risk for a near-term atherothrombotic event such as myocardial infarction or stroke. Clinical studies using the newest technologies...... were assessed for both risk factors and subclinical atherosclerosis (n = 6104). The latter two groups underwent baseline examination in a dedicated mobile facility equipped with advanced imaging tools suitable for noninvasive screening for subclinical atherosclerosis (coronary artery calcium...

  6. Estrogen stimulates release of secreted amyloid precursor protein from primary rat cortical neurons via protein kinase C pathway

    Institute of Scientific and Technical Information of China (English)

    Sun ZHANG; Ying HUANG; Yi-chun ZHU; Tai YAO

    2005-01-01

    Aim: To investigate the mechanism of the action of estrogen, which stimulates the release of secreted amyloid precursor protein α (sAPPα) and decreases the gen eration of amyloid-β protein (Aβ), a dominant component in senile plaques in the brains of Alzheimer's disease patients. Methods: Experiments were carried out inprimary rat cortical neurons, and Western blot was used to detect sAPPα in aculture medium and the total amount of cellular amyloid precursor protein (APP) in neurons. Results: 17β-Estradiol (but not 17α-estradiol) and β-estradiol 6-(Ocarboxymethyl) oxime: BSA increased the secretion of sAPPα and this effect was blocked by protein kinase C (PKC) inhibitor calphostin C, but not by the classical estrogen receptor antagonist ICI 182,780. Meanwhile, 17β-estradiol did not alter the synthesis of cellular APP. Conclusion: The effect of 17β-estradiol on sAPPα secretion is likely mediated through the membrane binding sites, and needs molecular configuration specificity of the ligand. Furthermore, the action of the PKC dependent pathway might be involved in estrogen-induced sAPPα secretion.

  7. A setup for simultaneous measurement of infrared spectra and light scattering signals: Watching amyloid fibrils grow from intact proteins

    Energy Technology Data Exchange (ETDEWEB)

    Li, Yang; Maurer, Jürgen; Roth, Andreas; Vogel, Vitali; Winter, Ernst; Mäntele, Werner, E-mail: maentele@biophysik.uni-frankfurt.de [Institut für Biophysik, Goethe-Universität Frankfurt am Main, Max-von Laue-Straße 1, D-60438 Frankfurt am Main (Germany)

    2014-08-15

    A setup for the simultaneous measurement of mid-infrared spectra and static light scattering is described that can be used for the analysis of the formation of nanoscale and microscopic aggregates from smaller molecules to biopolymers. It can be easily integrated into sample chambers of infrared spectrometers or combined with laser beams from tunable infrared lasers. Here, its use for the analysis of the formation of amyloid fibrils from intact proteins is demonstrated. The formation of amyloid fibrils or plaques from proteins is a widespread and pathogenetic relevant process, and a number of diseases are caused and correlated with the deposition of amyloid fibrils in cells and tissues. The molecular mechanisms of these transformations, however, are still unclear. We report here the simultaneous measurement of infrared spectra and static light scattering for the analysis of fibril formation from egg-white lysozyme. The transformation of the native form into non-native forms rich in β-sheet structure is measured by analysis of the amide I spectral region in the infrared spectra, which is sensitive for local structures. At the same time, light scattering signals at forward direction as well as the forward/backward ratio, which are sensitive for the number of scattering centers and their approximate sizes, respectively, are collected for the analysis of fibril growth. Thermodynamic and kinetic parameters as well as mechanistic information are deduced from the combination of the two complementary techniques.

  8. Determining the Effect of Aluminum Oxide Nanoparticles on the Aggregation of Amyloid-Beta in Transgenic Caenorhabditis elegans

    Science.gov (United States)

    Patel, Suhag; Matticks, John; Howell, Carina

    2014-03-01

    The cause of Alzheimer's disease has been linked partially to genetic factors but the predicted environmental components have yet to be determined. In Alzheimer's, accumulation of amyloid-beta protein in the brain forms plaques resulting in neurodegeneration and loss of mental functions. It has been postulated that aluminum influences the aggregation of amyloid-beta. To test this hypothesis, transgenic Caenorhabditis elegans, CL2120, was used as a model organism to observe neurodegeneration in nematodes exposed to aluminum oxide nanoparticles. Behavioral testing, fluorescent staining, and fluorescence microscopy were used to test the effects of aggregation of amyloid-beta in the nervous systems of effected nematodes exposed to aluminum oxide nanoparticles. Energy-dispersive x-ray spectroscopy was used to quantify the total concentration of aluminum oxide that the worms were exposed to during the experiment. Exposure of transgenic and wild type worms to a concentration of 4 mg mL-1 aluminum oxide showed a decrease in the sinusoidal motion, as well as an infirmity of transgenic worms when compared to control worms. These results support the hypothesis that aluminum may play a role in neurodegeneration in C. elegans, and may influence and increase the progression of Alzheimer's disease. This work was supported by National Science Foundation grants DUE-1058829, DMR-0923047 DUE-0806660 and Lock Haven FPDC grants.

  9. Elevation in sphingomyelin synthase activity is associated with increases in amyloid-beta peptide generation.

    Directory of Open Access Journals (Sweden)

    Jen-Hsiang T Hsiao

    Full Text Available A pathological hallmark of Alzheimer's disease (AD is the presence of amyloid-beta peptide (Aβ plaques in the brain. Aβ is derived from a sequential proteolysis of the transmenbrane amyloid precursor protein (APP, a process which is dependent on the distribution of lipids present in the plasma membrane. Sphingomyelin is a major membrane lipid, however its role in APP processing is unclear. Here, we assessed the expression of sphingomyelin synthase (SGMS1; the gene responsible for sphingomyelin synthesis in human brain and found that it was significantly elevated in the hippocampus of AD brains, but not in the cerebellum. Secondly, we assessed the impact of altering SGMS activity on Aβ generation. Inhibition of SGMS activity significantly reduced the level of Aβ in a dose- and time dependent manner. The decrease in Aβ level occurred without changes in APP expression or cell viability. These results when put together indicate that SGMS activity impacts on APP processing to produce Aβ and it could be a contributing factor in Aβ pathology associated with AD.

  10. Comparative pathobiology of β-amyloid and the unique susceptibility of humans to Alzheimer's disease.

    Science.gov (United States)

    Rosen, Rebecca F; Tomidokoro, Yasushi; Farberg, Aaron S; Dooyema, Jeromy; Ciliax, Brian; Preuss, Todd M; Neubert, Thomas A; Ghiso, Jorge A; LeVine, Harry; Walker, Lary C

    2016-08-01

    The misfolding and accumulation of the protein fragment β-amyloid (Aβ) is an early and essential event in the pathogenesis of Alzheimer's disease (AD). Despite close biological similarities among primates, humans appear to be uniquely susceptible to the profound neurodegeneration and dementia that characterize AD, even though nonhuman primates deposit copious Aβ in senile plaques and cerebral amyloid-β angiopathy as they grow old. Because the amino acid sequence of Aβ is identical in all primates studied to date, we asked whether differences in the properties of aggregated Aβ might underlie the vulnerability of humans and the resistance of other primates to AD. In a comparison of aged squirrel monkeys (Saimiri sciureus) and humans with AD, immunochemical and mass spectrometric analyses indicate that the populations of Aβ fragments are largely similar in the 2 species. In addition, Aβ-rich brain extracts from the brains of aged squirrel monkeys and AD patients similarly seed the deposition of Aβ in a transgenic mouse model. However, the epitope exposure of aggregated Aβ differs in sodium dodecyl sulfate-stable oligomeric Aβ from the 2 species. In addition, the high-affinity binding of (3)H Pittsburgh Compound B to Aβ is significantly diminished in tissue extracts from squirrel monkeys compared with AD patients. These findings support the hypothesis that differences in the pathobiology of aggregated Aβ among primates are linked to post-translational attributes of the misfolded protein, such as molecular conformation and/or the involvement of species-specific cofactors. PMID:27318146

  11. Relation between plaque type, plaque thickness, blood shear stress, and plaque stress in coronary arteries assessed by X-ray Angiography and Intravascular Ultrasound

    OpenAIRE

    Balocco, Simone; Gatta, Carlo; Alberti, Marina; Carrillo, Xavier; Rigla, Juan; Radeva, Petia

    2012-01-01

    Purpose: Atheromatic plaque progression is affected, among others phenomena, by biomechanical, biochemical, and physiological factors. In this paper, the authors introduce a novel framework able to provide both morphological (vessel radius, plaque thickness, and type) and biomechanical (wall shear stress and Von Mises stress) indices of coronary arteries. Methods: First, the approach reconstructs the three-dimensional morphology of the vessel from intravascular ultrasound(IVUS) and Angiograph...

  12. Automated coronary CT angiography plaque-lumen segmentation

    Science.gov (United States)

    Cline, Harvey E.; Krishnan, Karthik; Napel, Sandy; Rubin, Geoffrey D.; Turner, Wesley D.; Avila, Ricardo S.

    2009-02-01

    We are investigating the feasibility of a computer-aided detection (CAD) system to assist radiologists in diagnosing coronary artery disease in ECG gated cardiac multi-detector CT scans having calcified plaque. Coronary artery stenosis analysis is challenging if calcified plaque or the iodinated blood pool hides viable lumen. The research described herein provides an improved presentation to the radiologist by removing obscuring calcified plaque and blood pool. The algorithm derives a Gaussian estimate of the point spread function (PSF) of the scanner responsible for plaque blooming by fitting measured CTA image profiles. An initial estimate of the extent of calcified plaque is obtained from the image evidence using a simple threshold. The Gaussian PSF estimate is then convolved with the initial plaque estimate to obtain an estimate of the extent of the blooming artifact and this plaque blooming image is subtracted from the CT image to obtain an image largely free of obscuring plaque. In a separate step, the obscuring blood pool is suppressed using morphological operations and adaptive region growing. After processing by our algorithm, we are able to project the segmented plaque-free lumen to form synthetic angiograms free from obstruction. We can also analyze the coronary arteries with vessel tracking and centerline extraction to produce cross sectional images for measuring lumen stenosis. As an additional aid to radiologists, we also produce plots of calcified plaque and lumen cross-sectional area along selected blood vessels. The method was validated using digital phantoms and actual patient data, including in one case, a validation against the results of a catheter angiogram.

  13. Neuropsychological Effects of Cerebral Amyloid Angiopathy.

    Science.gov (United States)

    Schrag, Matthew; Kirshner, Howard

    2016-08-01

    Cerebral amyloid angiopathy is a condition of the cerebral arterioles and to a lesser extent capillaries and veins, wherein beta-amyloid is deposited. In arterioles, this preferentially targets vascular smooth muscle cells and in the later stages undermines the stability of the vessel. This condition is frequently comorbid with Alzheimer's disease and its role in cognitive impairment and dementia is a topic of considerable recent research. This article reviews recent literature which confirms that CAA independently contributes to cognitive impairment by potentiating the neurodegeneration of Alzheimer's disease, by predisposing to microhemorrhagic and microischemic injury to the brain parenchyma, and by interfering with the autoregulation of CNS blood flow. In this review, we discuss the clinical presentation of cerebral amyloid angiopathy, with a focus on the neuropsychological manifestations of this vasculopathy. PMID:27357378

  14. Fibrillar dimer formation of islet amyloid polypeptides

    Energy Technology Data Exchange (ETDEWEB)

    Chiu, Chi-cheng [Univ. of Chicago, IL (United States); Argonne National Lab. (ANL), Argonne, IL (United States); de Pablo, Juan J. [Univ. of Chicago, IL (United States); Argonne National Lab. (ANL), Argonne, IL (United States)

    2015-05-08

    Amyloid deposits of human islet amyloid polypeptide (hIAPP), a 37-residue hormone co-produced with insulin, have been implicated in the development of type 2 diabetes. Residues 20 – 29 of hIAPP have been proposed to constitute the amyloidogenic core for the aggregation process, yet the segment is mostly unstructured in the mature fibril, according to solid-state NMR data. Here we use molecular simulations combined with bias-exchange metadynamics to characterize the conformational free energies of hIAPP fibrillar dimer and its derivative, pramlintide. We show that residues 20 – 29 are involved in an intermediate that exhibits transient β-sheets, consistent with recent experimental and simulation results. By comparing the aggregation of hIAPP and pramlintide, we illustrate the effects of proline residues on inhibition of the dimerization of IAPP. The mechanistic insights presented here could be useful for development of therapeutic inhibitors of hIAPP amyloid formation.

  15. Fibrillar dimer formation of islet amyloid polypeptides

    Science.gov (United States)

    Chiu, Chi-cheng; de Pablo, Juan J.

    2015-09-01

    Amyloid deposits of human islet amyloid polypeptide (hIAPP), a 37-residue hormone co-produced with insulin, have been implicated in the development of type 2 diabetes. Residues 20 - 29 of hIAPP have been proposed to constitute the amyloidogenic core for the aggregation process, yet the segment is mostly unstructured in the mature fibril, according to solid-state NMR data. Here we use molecular simulations combined with bias-exchange metadynamics to characterize the conformational free energies of hIAPP fibrillar dimer and its derivative, pramlintide. We show that residues 20 - 29 are involved in an intermediate that exhibits transient β-sheets, consistent with recent experimental and simulation results. By comparing the aggregation of hIAPP and pramlintide, we illustrate the effects of proline residues on inhibition of the dimerization of IAPP. The mechanistic insights presented here could be useful for development of therapeutic inhibitors of hIAPP amyloid formation.

  16. Real-time porphyrin detection in plaque and caries: a case study

    Science.gov (United States)

    Timoshchuk, Mari-Alina I.; Ridge, Jeremy S.; Rugg, Amanda L.; Nelson, Leonard Y.; Kim, Amy S.; Seibel, Eric J.

    2015-02-01

    An ultrathin scanning fiber endoscope, originally developed for cancer diagnosis, was used in a case study to locate plaque and caries. The imaging system incorporated software mitigation of background auto-fluorescence (AF). In conventional fluorescence imaging, varying AF across a tooth surface can mask low-level porphyrin signals. Laser-induced auto-fluorescence signals of dental tissue excited using a 405-nm laser typically produce fluorescence over a wavelength range extending from 440-nm to 750-nm. Anaerobic bacterial metabolism produces various porphyrin species (eg. protoporphyrin IX) that are located in carious enamel, dentin, gingivitis sites, and plaque. In our case study, these porphyrin deposits remained as long as one day after prophylaxis. Imaging the tooth surface using 405-nm excitation and subtracting the natural AF enhances the image contrast of low-level porphyrin deposits, which would otherwise be masked by the high background AF. In a case study, healthy tissues as well as sites of early and advanced caries formations were scanned for visual and quantitative signs of red fluorescence associated with porphyrin species using a background mitigation algorithm. Initial findings show increasing amplitudes of red fluorescence as caries severity increases from early to late stages. Sites of plaque accumulation also displayed red fluorescence similar to that found in carious dental tissue. The use of real-time background mitigation of natural dental AF can enhance the detection of low porphyrin concentrations that are indicators of early stage caries formation.

  17. Circulating Leukocyte and Carotid Atherosclerotic Plaque Telomere Length Interrelation, Association With Plaque Characteristics, and Restenosis After Endarterectomy

    NARCIS (Netherlands)

    Huzen, Jardi; Peeters, Wouter; de Boer, Rudolf A.; Moll, Frans L.; Wong, Liza S. M.; Codd, Veryan; de Kleijn, Dominique P. V.; de Smet, Bart J. G. L.; van Veldhuisen, Dirk J.; Samani, Nilesh J.; van Gilst, Wiek H.; Pasterkamp, Gerard; van der Harst, Pim

    2011-01-01

    Objective-Shorter leukocyte telomeres are associated with atherosclerosis and predict future heart disease. The goal of the present study was to determine whether leukocyte telomere length is related to atherosclerotic plaque telomere length and whether it is associated with plaque characteristics o

  18. Evidence for novel beta-sheet structures in Iowa mutant beta-amyloid fibrils.

    Science.gov (United States)

    Tycko, Robert; Sciarretta, Kimberly L; Orgel, Joseph P R O; Meredith, Stephen C

    2009-07-01

    Asp23-to-Asn mutation within the coding sequence of beta-amyloid, called the Iowa mutation, is associated with early onset, familial Alzheimer's disease and cerebral amyloid angiopathy, in which patients develop neuritic plaques and massive vascular deposition predominantly of the mutant peptide. We examined the mutant peptide, D23N-Abeta40, by electron microscopy, X-ray diffraction, and solid-state NMR spectroscopy. D23N-Abeta40 forms fibrils considerably faster than the wild-type peptide (k = 3.77 x 10(-3) min(-1) and 1.07 x 10(-4) min(-1) for D23N-Abeta40 and the wild-type peptide WT-Abeta40, respectively) and without a lag phase. Electron microscopy shows that D23N-Abeta40 forms fibrils with multiple morphologies. X-ray fiber diffraction shows a cross-beta pattern, with a sharp reflection at 4.7 A and a broad reflection at 9.4 A, which is notably smaller than the value for WT-Abeta40 fibrils (10.4 A). Solid-state NMR measurements indicate molecular level polymorphism of the fibrils, with only a minority of D23N-Abeta40 fibrils containing the in-register, parallel beta-sheet structure commonly found in WT-Abeta40 fibrils and most other amyloid fibrils. Antiparallel beta-sheet structures in the majority of fibrils are indicated by measurements of intermolecular distances through (13)C-(13)C and (15)N-(13)C dipole-dipole couplings. An intriguing possibility exists that there is a relationship between the aberrant structure of D23N-Abeta40 fibrils and the unusual vasculotropic clinical picture in these patients.

  19. Evidence for Novel [beta]-Sheet Structures in Iowa Mutant [beta]-Amyloid Fibrils

    Energy Technology Data Exchange (ETDEWEB)

    Tycko, Robert; Sciarretta, Kimberly L.; Orgel, Joseph P.R.O.; Meredith, Stephen C.; (IIT); (NIH); (UC)

    2009-07-24

    Asp23-to-Asn mutation within the coding sequence of {beta}-amyloid, called the Iowa mutation, is associated with early onset, familial Alzheimer's disease and cerebral amyloid angiopathy, in which patients develop neuritic plaques and massive vascular deposition predominantly of the mutant peptide. We examined the mutant peptide, D23N-A{beta}40, by electron microscopy, X-ray diffraction, and solid-state NMR spectroscopy. D23N-A{beta}40 forms fibrils considerably faster than the wild-type peptide (k = 3.77 x 10{sup -3} min{sup -1} and 1.07 x 10{sup -4} min{sup -1} for D23N-A{beta}40 and the wild-type peptide WT-A{beta}40, respectively) and without a lag phase. Electron microscopy shows that D23N-A{beta}40 forms fibrils with multiple morphologies. X-ray fiber diffraction shows a cross-{beta} pattern, with a sharp reflection at 4.7 {angstrom} and a broad reflection at 9.4 {angstrom}, which is notably smaller than the value for WT-A{beta}40 fibrils (10.4 {angstrom}). Solid-state NMR measurements indicate molecular level polymorphism of the fibrils, with only a minority of D23N-A{beta}40 fibrils containing the in-register, parallel {beta}-sheet structure commonly found in WT-A{beta}40 fibrils and most other amyloid fibrils. Antiparallel {beta}-sheet structures in the majority of fibrils are indicated by measurements of intermolecular distances through 13C-13C and 15N-13C dipole-dipole couplings. An intriguing possibility exists that there is a relationship between the aberrant structure of D23N-A{beta}40 fibrils and the unusual vasculotropic clinical picture in these patients.

  20. Structural and dynamic study of the transmembrane domain of the amyloid precursor protein.

    Science.gov (United States)

    Nadezhdin, K D; Bocharova, O V; Bocharov, E V; Arseniev, A S

    2011-01-01

    Alzheimer's disease affects people all over the world, regardless of nationality, gender or social status. An adequate study of the disease requires essential understanding of the molecular fundamentals of the pathogenesis. The amyloid β-peptide, which forms amyloid plaques in the brain of people with Alzheimer's disease, is the product of sequential cleavage of a single-span membrane amyloid precursor protein (APP). More than half of the APP mutations found to be associated with familial forms of Alzheimer's disease are located in its transmembrane domain. The pathogenic mutations presumably affect the structural-dynamic properties of the APP transmembrane domain by changing its conformational stability and/or lateral dimerization. In the present study, the structure and dynamics of the recombinant peptide corresponding to the APP fragment, Gln686-Lys726, which comprises the APP transmembrane domain with an adjacent N-terminal juxtamembrane sequence, were determined in the membrane mimetic environment composed of detergent micelles using NMR spectroscopy. The structure obtained in dodecylphosphocholine micelles consists of two α-helices: a short surface-associated juxtamembrane helix (Lys687-Asp694) and a long transmembrane helix (Gly700-Leu723), both connected via a mobile loop region. A minor bend of the transmembrane α-helix is observed near the paired residues Gly708-Gly709. A cholesterol-binding hydrophobic cavity is apparently formed under the loop region, where the juxtamembrane α-helix comes into contact with the membrane surface near the N-terminus of the transmembrane α-helix. PMID:22649674

  1. Amyloids or prions? That is the question.

    Science.gov (United States)

    Sabate, Raimon; Rousseau, Frederic; Schymkowitz, Joost; Batlle, Cristina; Ventura, Salvador

    2015-01-01

    Despite major efforts devoted to understanding the phenomenon of prion transmissibility, it is still poorly understood how this property is encoded in the amino acid sequence. In recent years, experimental data on yeast prion domains allow to start at least partially decrypting the sequence requirements of prion formation. These experiments illustrate the need for intrinsically disordered sequence regions enriched with a particularly high proportion of glutamine and asparagine. Bioinformatic analysis suggests that these regions strike a balance between sufficient amyloid nucleation propensity on the one hand and disorder on the other, which ensures availability of the amyloid prone regions but entropically prevents unwanted nucleation and facilitates brittleness required for propagation.

  2. Quenched Hydrogen Exchange NMR of Amyloid Fibrils.

    Science.gov (United States)

    Alexandrescu, Andrei T

    2016-01-01

    Amyloid fibrils are associated with a number of human diseases. These aggregatively misfolded intermolecular β-sheet assemblies constitute some of the most challenging targets in structural biology because to their complexity, size, and insolubility. Here, protocols and controls are described for experiments designed to study hydrogen-bonding in amyloid fibrils indirectly, by transferring information about amide proton occupancy in the fibrils to the dimethyl sulfoxide-denatured state. Since the denatured state is amenable to solution NMR spectroscopy, the method can provide residue-level-resolution data on hydrogen exchange for the monomers that make up the fibrils.

  3. Quantification of immunohistochemical findings of neurofibrillary tangles and senile plaques for a diagnosis of dementia in forensic autopsy cases.

    Science.gov (United States)

    Takayama, Mio; Kashiwagi, Masayuki; Matsusue, Aya; Waters, Brian; Hara, Kenji; Ikematsu, Natsuki; Kubo, Shin-Ichi

    2016-09-01

    We report the quantification of immunohistochemical findings for a diagnosis of dementia in autopsy cases among older decedents. Autopsy cases were selected with the following requirements: >65yo; no head injuries, thermal injuries, or heat stroke; no intracranial lesions; and within 48h of death. Among cases that met all requirements, 10 had a clinical diagnosis of dementia were included in dementia group. Non-dementia group consisted of 38 cases without any record of dementia. To compare these groups, immunohistochemically, beta-amyloid, tau protein, gephyrin, and IL-33 were examined in five regions. Quantitative analysis was performed by collecting with image data analyzed using analysis software. Image data on tau-immunopositive neurofibrillary tangles (NFT) and beta-amyloid-positive senile plaques (SP) were photographed. Criteria for dementia were made by counting and measuring NFT and SP from image data using software. Differences in SP and NFT were effective for discriminating between the two groups. These criteria may reveal the presence and progression of dementia. Total of tau-positive NFT in Ammon's horn (AH) may be useful for diagnosing dementia. When the total is more than 41 in approximately 6mm(2) of AH, the possibility of dementia is considered. Total of beta-amyloid-positive SP in the parahippocampal gyrus (PHG) may be useful for diagnosing dementia. When the total in approximately 5mm(2) of PHG is more than 47, the possibility of dementia is considered. Immunohistochemical staining may be more useful for obtaining image data for quantification than conventional staining techniques, such as Bielschowsky-Hirano's silver staining. PMID:27591545

  4. Analysis of Amyloid Precursor Protein Function in Drosophila melanogaster.

    Science.gov (United States)

    Cassar, Marlène; Kretzschmar, Doris

    2016-01-01

    The Amyloid precursor protein (APP) has mainly been investigated in connection with its role in Alzheimer's Disease (AD) due to its cleavage resulting in the production of the Aβ peptides that accumulate in the plaques characteristic for this disease. However, APP is an evolutionary conserved protein that is not only found in humans but also in many other species, including Drosophila, suggesting an important physiological function. Besides Aβ, several other fragments are produced by the cleavage of APP; large secreted fragments derived from the N-terminus and a small intracellular C-terminal fragment. Although these fragments have received much less attention than Aβ, a picture about their function is finally emerging. In contrast to mammals, which express three APP family members, Drosophila expresses only one APP protein called APP-like or APPL. Therefore APPL functions can be studied in flies without the complication that other APP family members may have redundant functions. Flies lacking APPL are viable but show defects in neuronal outgrowth in the central and peripheral nervous system (PNS) in addition to synaptic changes. Furthermore, APPL has been connected with axonal transport functions. In the adult nervous system, APPL, and more specifically its secreted fragments, can protect neurons from degeneration. APPL cleavage also prevents glial death. Lastly, APPL was found to be involved in behavioral deficits and in regulating sleep/activity patterns. This review, will describe the role of APPL in neuronal development and maintenance and briefly touch on its emerging function in circadian rhythms while an accompanying review will focus on its role in learning and memory formation. PMID:27507933

  5. PARP-1 modulates amyloid beta peptide-induced neuronal damage.

    Directory of Open Access Journals (Sweden)

    Sara Martire

    Full Text Available Amyloid beta peptide (Aβ causes neurodegeneration by several mechanisms including oxidative stress, which is known to induce DNA damage with the consequent activation of poly (ADP-ribose polymerase (PARP-1. To elucidate the role of PARP-1 in the neurodegenerative process, SH-SY5Y neuroblastoma cells were treated with Aβ25-35 fragment in the presence or absence of MC2050, a new PARP-1 inhibitor. Aβ25-35 induces an enhancement of PARP activity which is prevented by cell pre-treatment with MC2050. These data were confirmed by measuring PARP-1 activity in CHO cells transfected with amylod precursor protein and in vivo in brains specimens of TgCRND8 transgenic mice overproducing the amyloid peptide. Following Aβ25-35 exposure a significant increase in intracellular ROS was observed. These data were supported by the finding that Aβ25-35 induces DNA damage which in turn activates PARP-1. Challenge with Aβ25-35 is also able to activate NF-kB via PARP-1, as demonstrated by NF-kB impairment upon MC2050 treatment. Moreover, Aβ25-35 via PARP-1 induces a significant increase in the p53 protein level and a parallel decrease in the anti-apoptotic Bcl-2 protein. These overall data support the hypothesis of PARP-1 involvment in cellular responses induced by Aβ and hence a possible rationale for the implication of PARP-1 in neurodegeneration is discussed.

  6. Amyloid-β aggregation with gold nanoparticles on brain lipid bilayer.

    Science.gov (United States)

    Lee, Hyojin; Kim, Yuna; Park, Anna; Nam, Jwa-Min

    2014-05-14

    Understanding and manipulating amyloid-β (Aβ) aggregation provide key knowledge and means for the diagnosis and cure of Alzheimer's disease (AD) and the applications of Aβ-based aggregation systems. Here, we studied the formation of various Aβ aggregate structures with gold nanoparticles (AuNPs) and brain total lipid extract-based supported lipid bilayer (brain SLB). The roles of AuNPs and brain SLB in forming Aβ aggregates were studied in real time, and the structural details of Aβ aggregates were monitored and analyzed with the dark-field imaging of plasmonic AuNPs that allows for long-term in situ imaging of Aβ aggregates with great structural details without further labeling. It was shown that the fluid brain SLB platform provides the binding sites for Aβ and drives the fast and efficient formation of Aβ aggregate structures and, importantly, large Aβ plaque structures (>15 μm in diameter), a hallmark for AD, were formed without going through fibril structures when Aβ peptides were co-incubated with AuNPs on the brain SLB. The dark-field scattering and circular dichroism-correlation data suggest that AuNPs were heavily involved with Aβ aggregation on the brain SLB and less α-helix, less β-sheet and more random coil structures were found in large plaque-like Aβ aggregates.

  7. P-glycoprotein expression and amyloid accumulation in human aging and Alzheimer's disease: preliminary observations.

    Science.gov (United States)

    Chiu, Catherine; Miller, Miles C; Monahan, Renée; Osgood, Doreen P; Stopa, Edward G; Silverberg, Gerald D

    2015-09-01

    P-glycoprotein (P-gp), part of the blood-brain barrier, limits drug access to the brain and is the target for therapies designed to improve drug penetration. P-gp also extrudes brain amyloid-beta (Aβ). Accumulation of Aβ is a hallmark of Alzheimer's disease (AD). Aβ accumulates in normal aging and in AD primarily due to decreased Aβ clearance. This is a preliminary report on the relative protein and messenger RNA expression of P-gp in human brains, ages 20-100 years, including AD subjects. In these preliminary studies, cortical endothelial P-gp expression decreased in AD compared with controls (p P-gp expression in human aging are similar to aging rats. Microvessel P-gp messenger RNA remained unchanged with aging and AD. Aβ plaques were found in 42.8% of normal subjects (54.5% of those older than 50 years). A qualitative analysis showed that P-gp expression is lower than the group mean in subjects older than 75 years but increased if younger. Decreased P-gp expression may be related to Aβ plaques in aging and AD. Downregulating P-gp to allow pharmaceuticals into the central nervous system may increase Aβ accumulation.

  8. Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid β peptide.

    Science.gov (United States)

    Hashimoto, Tadafumi; Serrano-Pozo, Alberto; Hori, Yukiko; Adams, Kenneth W; Takeda, Shuko; Banerji, Adrian Olaf; Mitani, Akinori; Joyner, Daniel; Thyssen, Diana H; Bacskai, Brian J; Frosch, Matthew P; Spires-Jones, Tara L; Finn, Mary Beth; Holtzman, David M; Hyman, Bradley T

    2012-10-24

    Alzheimer's disease (AD) is the most common progressive neurodegenerative disorder causing dementia. Massive deposition of amyloid β peptide (Aβ) as senile plaques in the brain is the pathological hallmark of AD, but oligomeric, soluble forms of Aβ have been implicated as the synaptotoxic component. The apolipoprotein E ε 4 (apoE ε4) allele is known to be a genetic risk factor for developing AD. However, it is still unknown how apoE impacts the process of Aβ oligomerization. Here, we found that the level of Aβ oligomers in APOE ε4/ε4 AD patient brains is 2.7 times higher than those in APOE ε3/ε3 AD patient brains, matched for total plaque burden, suggesting that apoE4 impacts the metabolism of Aβ oligomers. To test this hypothesis, we examined the effect of apoE on Aβ oligomer formation. Using both synthetic Aβ and a split-luciferase method for monitoring Aβ oligomers, we observed that apoE increased the level of Aβ oligomers in an isoform-dependent manner (E2 apoE4, increases Aβ oligomers in the brain. Higher levels of Aβ oligomers in the brains of APOE ε4/ε4 carriers compared with APOE ε3/ε3 carriers may increase the loss of dendritic spines and accelerate memory impairments, leading to earlier cognitive decline in AD.

  9. Designed amyloid fibers as materials for selective carbon dioxide capture.

    Science.gov (United States)

    Li, Dan; Furukawa, Hiroyasu; Deng, Hexiang; Liu, Cong; Yaghi, Omar M; Eisenberg, David S

    2014-01-01

    New materials capable of binding carbon dioxide are essential for addressing climate change. Here, we demonstrate that amyloids, self-assembling protein fibers, are effective for selective carbon dioxide capture. Solid-state NMR proves that amyloid fibers containing alkylamine groups reversibly bind carbon dioxide via carbamate formation. Thermodynamic and kinetic capture-and-release tests show the carbamate formation rate is fast enough to capture carbon dioxide by dynamic separation, undiminished by the presence of water, in both a natural amyloid and designed amyloids having increased carbon dioxide capacity. Heating to 100 °C regenerates the material. These results demonstrate the potential of amyloid fibers for environmental carbon dioxide capture.

  10. Hydrogen peroxide is generated during the very early stages of aggregation of the amyloid peptides implicated in Alzheimer disease and familial British dementia.

    Science.gov (United States)

    Tabner, Brian J; El-Agnaf, Omar M A; Turnbull, Stuart; German, Matthew J; Paleologou, Katerina E; Hayashi, Yoshihito; Cooper, Leanne J; Fullwood, Nigel J; Allsop, David

    2005-10-28

    Alzheimer disease and familial British dementia are neurodegenerative diseases that are characterized by the presence of numerous amyloid plaques in the brain. These lesions contain fibrillar deposits of the beta-amyloid peptide (Abeta) and the British dementia peptide (ABri), respectively. Both peptides are toxic to cells in culture, and there is increasing evidence that early "soluble oligomers" are the toxic entity rather than mature amyloid fibrils. The molecular mechanisms responsible for this toxicity are not clear, but in the case of Abeta, one prominent hypothesis is that the peptide can induce oxidative damage via the formation of hydrogen peroxide. We have developed a reliable method, employing electron spin resonance spectroscopy in conjunction with the spin-trapping technique, to detect any hydrogen peroxide generated during the incubation of Abeta and other amyloidogenic peptides. Here, we monitored levels of hydrogen peroxide accumulation during different stages of aggregation of Abeta-(1-40) and ABri and found that in both cases it was generated as a short "burst" early on in the aggregation process. Ultrastructural studies with both peptides revealed that structures resembling "soluble oligomers" or "protofibrils" were present during this early phase of hydrogen peroxide formation. Mature amyloid fibrils derived from Abeta-(1-40) did not generate hydrogen peroxide. We conclude that hydrogen peroxide formation during the early stages of protein aggregation may be a common mechanism of cell death in these (and possibly other) neurodegenerative diseases.

  11. Safflower yellow reduces lipid peroxidation, neuropathology, tau phosphorylation and ameliorates amyloid β-induced impairment of learning and memory in rats.

    Science.gov (United States)

    Ma, Qin; Ruan, Ying-ying; Xu, Hui; Shi, Xiao-meng; Wang, Zhi-xiang; Hu, Yan-li

    2015-12-01

    Insoluble plaques of amyloid β proteins (Aβ) and neurofibrillary tangles of hyperphosphorylated tau are key markers for Alzheimer's disease (AD). Safflower yellow (SY) is one of traditional Chinese medicine extracted from safflower, which is suggested to have therapeutic potential for neurodegenerative disorders. However, whether SY can ameliorate impairment of learning and memory in AD model, and its causal mechanism are still unclear. Here, we applied different doses of SY intragastrically to Wistar rats injected with amyloid β (1-42) for 1 month. By the Morris water maze test, we found that treatment of SY significantly attenuated amyloid β (1-42)-induced impairment of memory in rats. Mechanistically, SY treatment increased the level of superoxidedismutase (SOD) and Glutathione peroxidase (GSH-Px), and decreased the level of malondialdehyde (MDA) and acetylcholinesterase (T-CHE) in brain tissues of AD rats. Pathological analysis also showed that SY treatment inhibited the morphological alteration of neurons and tau hyperphosphorylation induced by amyloid β (1-42)-injection in the cortex and hippocampus. Moreover, SY treatment inhibited CDK-5 and GSK-3 signaling pathways, which are upregulated in AD rats. Our data indicate that safflower yellow can serve as a therapeutic candidate for Alzheimer's disease.

  12. Presence of non-fibrillar amyloid beta protein in skin biopsies of Alzheimer's disease (AD), Down's syndrome and non-AD normal persons

    DEFF Research Database (Denmark)

    Wen, G Y; Wisniewski, H M; Blondal, H;

    1994-01-01

    -24 of synthetic amyloid beta protein (A beta), and 4G8-Fab (the antigen-binding fragment of 4G8 IgG, reactive only to amyloid plaque) was observed in the epidermis-dermis junction or the basement membrane of the epidermis and in some blood vessels of the biopsy skins of 13/18 (72%) AD, 9/10 (90%) DS, and 14....../38 (37%) non-AD control cases. The Fisher exact probability test revealed a significant difference (P = 0.0415 one-tailed) in immunoreactivity between AD and age-matched controls. There was also a significant difference (P = 0.0152 one-tailed; P = 0.0200 two-tailed) between DS and age-matched control...

  13. The Effect of Milk Constituents and Crowding Agents on Amyloid Fibril Formation by κ-Casein.

    Science.gov (United States)

    Liu, Jihua; Dehle, Francis C; Liu, Yanqin; Bahraminejad, Elmira; Ecroyd, Heath; Thorn, David C; Carver, John A

    2016-02-17

    When not incorporated into the casein micelle, κ-casein, a major milk protein, rapidly forms amyloid fibrils at physiological pH and temperature. In this study, the effects of milk components (calcium, lactose, lipids, and heparan sulfate) and crowding agents on reduced and carboxymethylated (RCM) κ-casein fibril formation was investigated using far-UV circular dichroism spectroscopy, thioflavin T binding assays, and transmission electron microscopy. Longer-chain phosphatidylcholine lipids, which form the lining of milk ducts and milk fat globules, enhanced RCM κ-casein fibril formation irrespective of whether the lipids were in a monomeric or micellar state, whereas shorter-chain phospholipids and triglycerides had little effect. Heparan sulfate, a component of the milk fat globule membrane and catalyst of amyloid deposition in extracellular tissue, had little effect on the kinetics of RCM κ-casein fibril formation. Major nutritional components such as calcium and lactose also had no significant effect. Macromolecular crowding enhances protein-protein interactions, but in contrast to other fibril-forming species, the extent of RCM κ-casein fibril formation was reduced by the presence of a variety of crowding agents. These data are consistent with a mechanism of κ-casein fibril formation in which the rate-determining step is dissociation from the oligomer to give the highly amyloidogenic monomer. We conclude that the interaction of κ-casein with membrane-associated phospholipids along its secretory pathway may contribute to the development of amyloid deposits in mammary tissue. However, the formation of spherical oligomers such as casein micelles is favored over amyloid fibrils in the crowded environment of milk, within which the occurrence of amyloid fibrils is low. PMID:26807595

  14. Dental plaque biofilm in oral health and disease.

    Science.gov (United States)

    Seneviratne, Chaminda Jayampath; Zhang, Cheng Fei; Samaranayake, Lakshman Perera

    2011-01-01

    Dental plaque is an archetypical biofilm composed of a complex microbial community. It is the aetiological agent for major dental diseases such as dental caries and periodontal disease. The clinical picture of these dental diseases is a net result of the cross-talk between the pathogenic dental plaque biofilm and the host tissue response. In the healthy state, both plaque biofilm and adjacent tissues maintain a delicate balance, establishing a harmonious relationship between the two. However, changes occur during the disease process that transform this 'healthy' dental plaque into a 'pathogenic' biofilm. Recent advances in molecular microbiology have improved the understanding of dental plaque biofilm and produced numerous clinical benefits. Therefore, it is imperative that clinicians keep abreast with these new developments in the field of dentistry. Better understanding of the molecular mechanisms behind dental diseases will facilitate the development of novel therapeutic strategies to establish a 'healthy dental plaque biofilm' by modulating both host and microbial factors. In this review, the present authors aim to summarise the current knowledge on dental plaque as a microbial biofilm and its properties in oral health and disease.

  15. Atherosclerotic Plaque Destabilization in Mice: A Comparative Study.

    Directory of Open Access Journals (Sweden)

    Helene Hartwig

    Full Text Available Atherosclerosis-associated diseases are the main cause of mortality and morbidity in western societies. The progression of atherosclerosis is a dynamic process evolving from early to advanced lesions that may become rupture-prone vulnerable plaques. Acute coronary syndromes are the clinical manifestation of life-threatening thrombotic events associated with high-risk vulnerable plaques. Hyperlipidemic mouse models have been extensively used in studying the mechanisms controlling initiation and progression of atherosclerosis. However, the understanding of mechanisms leading to atherosclerotic plaque destabilization has been hampered by the lack of proper animal models mimicking this process. Although various mouse models generate atherosclerotic plaques with histological features of human advanced lesions, a consensus model to study atherosclerotic plaque destabilization is still lacking. Hence, we studied the degree and features of plaque vulnerability in different mouse models of atherosclerotic plaque destabilization and find that the model based on the placement of a shear stress modifier in combination with hypercholesterolemia represent with high incidence the most human like lesions compared to the other models.

  16. Palladium-103 versus iodine-125 for ophthalmic plaque radiotherapy

    International Nuclear Information System (INIS)

    A dosimetry study compared the use of I-125 vs. Pd-103 radioactive seeds for ophthalmic plaque brachytherapy. Pd-103 seeds in ophthalmic plaques were used to treat 15 patients with intraocular malignant melanoma. Computer-aided simulations were performed to evaluate the intraocular dose distribution of I-125 versus Pd-103 ophthalmic plaques (delivering equivalent apex doses). Seven target points were selected. Starting at the outer scleral surface, four were located along the central axis of the plaque: the 1 mm point (the inner sclera), the 6 mm point, the tumors apex, and the opposite eye wall. They also evaluated the fovea, optic nerve, and the lens because they were considered to be critical structures. These studies demonstrated that the lower energy photons generated by Pd-103 seeds (average 21 KeV) in ophthalmic plaques were more rapidly absorbed in tissue than photons generated by I-125 (average 28 KeV). Therefore, during ophthalmic plaque radiotherapy, Pd-103 photons were found to be more rapidly absorbed within the tumor and less likely to reach most normal ocular structures. On average, the use of Pd-103 decreased the dose to the fovea by 5.7%, to the optic nerve by 8.4%, to the lens by 26%, and to the opposite eye wall by 38.4%. Pd-103 ophthalmic plaque brachytherapy resulted in slightly more irradiation of the tumor and less radiation to most normal ocular structures. 36 refs., 1 fig., 3 tabs

  17. Increased γ-secretase activity in idiopathic normal pressure hydrocephalus patients with β-amyloid pathology.

    Directory of Open Access Journals (Sweden)

    Tiina Laiterä

    Full Text Available The potential similarity between the brain pathology of idiopathic normal pressure hydrocephalus (iNPH and Alzheimer disease (AD is intriguing and thus further studies focusing on the underlying molecular mechanisms may offer valuable information for differential diagnostics and the development of treatments for iNPH. Here, we investigated β- and γ-secretase activities in relation to amyloid-β (Aβ pathology in the brain tissue samples collected from iNPH and AD patients. β- and γ-secretase activities were measured from the frontal cortical biopsies of 26 patients with suspected iNPH as well as post-mortem tissue samples from the inferior temporal cortex of 74 AD patients and eight subjects without neurofibrillary pathology. In iNPH samples with detectable Aβ plaques, γ-secretase activity was significantly increased (∼ 1.6-fold when compared to iNPH samples without Aβ plaques (p = 0.009. In the AD samples, statistically significant differences in the γ-secretase activity were not observed with respect to disease severity (mild, moderate and severe AD according to neurofibrillary pathology. Conversely, β-secretase activity was unaltered in iNPH samples with or without Aβ plaques, while it was significantly increased in relation to disease severity in the AD patients. These results show for the first time increased γ-secretase but not β-secretase activity in the biopsy samples from the frontal cortex of iNPH patients with AD-like Aβ pathology. Conversely, the opposite was observed in these secretase activities in AD patients with respect to neurofibrillary pathology. Despite the resemblances in the Aβ pathology, iNPH and AD patients appear to have marked differences in the cellular mechanisms responsible for the production of Aβ.

  18. Plaque Index in Multi-Bracket Fixed Appliances

    International Nuclear Information System (INIS)

    To compare the plaque index in patients receiving multi-bracket fixed orthodontic treatment for various factors like age, gender, socio-economic status, brushing practices, meal habits, types of brackets, types of ligations, use of mouthwash and duration of treatment. Study Design: Cross-sectional analytical study. Place and Duration of Study: Orthodontics Clinic, The Aga Khan University Hospital, from September to November 2011. Methodology: Socio-demographic and clinical modalities were defined and recorded for 131 patients having multi-bracket fixed appliances. The plaque index of subjects were recorded according to the Silness and Loe plaque index method. Independent sample t-test was used to see difference in plaque index in factors having two variables. One way ANOVA and Post-Hoc Tukey tests were used to see difference in plaque index in factors having three variables. Kappa statistics was used to assess inter examiner reliability. P-value 0.05 was taken to be significant. Results: The sample comprised of 37% males (n = 48) and 63% females (n = 83). The plaque index had statistically significant association with practice of brushing i.e., timing of brushing (p=0.001), method of brushing (p=0.08), type of ligatures (p=0.05) and frequency of visits (p=0.01). Conclusion: The plaque accumulation is significantly decreased in subjects who brush the teeth twice or more than twice a day and those who brush their teeth after breakfast. The use of interdental brush and stainless steel ligatures had significantly low plaque. Subjects presenting with more frequent appointments of short-period had significantly less plaque. (author)

  19. Inhibitory effects of β-ionone on amyloid fibril formation of β-lactoglobulin.

    Science.gov (United States)

    Ma, Baoliang; You, Xiong; Lu, Fujiao

    2014-03-01

    β-Lactoglobulin (β-LG) is the major constituent of whey food, which has been shown to interact with a wide range of aroma compounds. In the present work, a model aroma compound, β-ionone, is used to investigate the influence of aroma compounds on the urea-induced unfolding of β-LG at pH 7.0. β-Ionone is observed to enhance the stability of β-LG at pH 7.0. Moreover, the amyloid fibrils are observed when β-LG at pH 7.0 is incubated for 12-20 days at 37 °C in the presence of 3-5M urea. However, the formation of amyloid fibrils is inhibited when β-ionone is added into the samples and the inhibitory effects follow a concentration-dependent fashion. There is a clear correlation between Cm and lag time. The correlation demonstrates that protein stability affects the amyloid fibril formation of β-LG. The results highlight the critical role of protein stability and provide an approach to prevent the formation of amyloid fibrils in vitro. PMID:24325860

  20. Serum Amyloid A Induces Inflammation, Proliferation and Cell Death in Activated Hepatic Stellate Cells.

    Science.gov (United States)

    Siegmund, Sören V; Schlosser, Monika; Schildberg, Frank A; Seki, Ekihiro; De Minicis, Samuele; Uchinami, Hiroshi; Kuntzen, Christian; Knolle, Percy A; Strassburg, Christian P; Schwabe, Robert F

    2016-01-01

    Serum amyloid A (SAA) is an evolutionary highly conserved acute phase protein that is predominantly secreted by hepatocytes. However, its role in liver injury and fibrogenesis has not been elucidated so far. In this study, we determined the effects of SAA on hepatic stellate cells (HSCs), the main fibrogenic cell type of the liver. Serum amyloid A potently activated IκB kinase, c-Jun N-terminal kinase (JNK), Erk and Akt and enhanced NF-κB-dependent luciferase activity in primary human and rat HSCs. Serum amyloid A induced the transcription of MCP-1, RANTES and MMP9 in an NF-κB- and JNK-dependent manner. Blockade of NF-κB revealed cytotoxic effects of SAA in primary HSCs with signs of apoptosis such as caspase 3 and PARP cleavage and Annexin V staining. Serum amyloid A induced HSC proliferation, which depended on JNK, Erk and Akt activity. In primary hepatocytes, SAA also activated MAP kinases, but did not induce relevant cell death after NF-κB inhibition. In two models of hepatic fibrogenesis, CCl4 treatment and bile duct ligation, hepatic mRNA levels of SAA1 and SAA3 were strongly increased. In conclusion, SAA may modulate fibrogenic responses in the liver in a positive and negative fashion by inducing inflammation, proliferation and cell death in HSCs. PMID:26937641

  1. Fetzima (levomilnacipran), a drug for major depressive disorder as a dual inhibitor for human serotonin transporters and beta-site amyloid precursor protein cleaving enzyme-1.

    Science.gov (United States)

    Rizvi, Syed Mohd Danish; Shaikh, Sibhghatulla; Khan, Mahiuddin; Biswas, Deboshree; Hameed, Nida; Shakil, Shazi

    2014-01-01

    Pharmacological management of Major Depressive Disorder includes the use of serotonin reuptake inhibitors which targets serotonin transporters (SERT) to increase the synaptic concentrations of serotonin. Beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1) is responsible for amyloid β plaque formation. Hence it is an interesting target for Alzheimer's disease (AD) therapy. This study describes molecular interactions of a new Food and Drug Administration approved antidepressant drug named 'Fetzima' with BACE-1 and SERT. Fetzima is chemically known as levomilnacipran. The study has explored a possible link between the treatment of Depression and AD. 'Autodock 4.2' was used for docking study. The free energy of binding (ΔG) values for 'levomilnacipran-SERT' interaction and 'levomilnacipran-BACE1' interaction were found to be -7.47 and -8.25 kcal/mol, respectively. Levomilnacipran was found to interact with S438, known to be the most important amino acid residue of serotonin binding site of SERT during 'levomilnacipran-SERT' interaction. In the case of 'levomilnacipran-BACE1' interaction, levomilnacipran interacted with two very crucial aspartic acid residues of BACE-1, namely, D32 and D228. These residues are accountable for the cleavage of amyloid precursor protein and the subsequent formation of amyloid β plaques in AD brain. Hence, Fetzima (levomilnacipran) might act as a potent dual inhibitor of SERT and BACE-1 and expected to form the basis of a future dual therapy against depression and AD. It is an established fact that development of AD is associated with Major Depressive Disorder. Therefore, the design of new BACE-1 inhibitors based on antidepressant drug scaffolds would be particularly beneficial. PMID:25345508

  2. Modeling clustered activity increase in amyloid-beta positron emission tomographic images with statistical descriptors

    Directory of Open Access Journals (Sweden)

    Shokouhi S

    2015-04-01

    Full Text Available Sepideh Shokouhi,1 Baxter P Rogers,1 Hakmook Kang,2 Zhaohua Ding,1 Daniel O Claassen,3 John W Mckay,1 William R Riddle1On behalf of the Alzheimer’s Disease Neuroimaging Initiative1Department of Radiology and Radiological Sciences, Vanderbilt University Institute of Imaging Science, 2Department of Biostatistics, 3Department of Neurology, Vanderbilt University, Nashville, TN, USABackground: Amyloid-beta (Aβ imaging with positron emission tomography (PET holds promise for detecting the presence of Aβ plaques in the cortical gray matter. Many image analyses focus on regional average measurements of tracer activity distribution; however, considerable additional information is available in the images. Metrics that describe the statistical properties of images, such as the two-point correlation function (S2, have found wide applications in astronomy and materials science. S2 provides a detailed characterization of spatial patterns in images typically referred to as clustering or flocculence. The objective of this study was to translate the two-point correlation method into Aβ-PET of the human brain using 11C-Pittsburgh compound B (11C-PiB to characterize longitudinal changes in the tracer distribution that may reflect changes in Aβ plaque accumulation.Methods: We modified the conventional S2 metric, which is primarily used for binary images and formulated a weighted two-point correlation function (wS2 to describe nonbinary, real-valued PET images with a single statistical function. Using serial 11C-PiB scans, we calculated wS2 functions from two-dimensional PET images of different cortical regions as well as three-dimensional data from the whole brain. The area under the wS2 functions was calculated and compared with the mean/median of the standardized uptake value ratio (SUVR. For three-dimensional data, we compared the area under the wS2 curves with the subjects’ cerebrospinal fluid measures.Results: Overall, the longitudinal changes in wS2

  3. Effect of curcumin and Cu 2+/Zn 2+ ions on the fibrillar aggregates formed by the amyloid peptide and other peptides at the organic-aqueous interface

    Science.gov (United States)

    Sanghamitra, Nusrat J. M.; Varghese, Neenu; Rao, C. N. R.

    2010-08-01

    Characteristic features of a perilous neuro-degenerative disease such as the Alzhiemer's disease is fibrillar plaque formation by the amyloid (Aβ) peptide. We have modelled the formation and disintegration of fibrils by studying the aggregate structures formed by Aβ structural motif diphenylalanine as well as insulin and bovine serum albumin at the organic-aqueous interface. Even small concentrations of curcumin in the organic medium or Cu 2+ and Zn 2+ ions in the aqueous medium are found to break down the fibrillar structures.

  4. Computer assisted treatment planning for 125I ophthalmic plaque radiotherapy

    International Nuclear Information System (INIS)

    This paper describes a computer program for planning the treatment of ocular tumors with 125I plaques. The program permits the input of the tumor configuration into a model eye and facilitates the viewing of the relative geometry of the tumor and various eye structures in different perspectives. Custom-designed 125I plaques can be localized onto the globe, and dose distributions can be calculated and superimposed on the eye structures in any plane or on the inner eye surface. The program allows efficient evaluation of the plaque design in terms of radiation dose distribution relative to the tumor and critical structures

  5. Atherosclerotic plaque detection by confocal Brillouin and Raman microscopies

    Science.gov (United States)

    Meng, Zhaokai; Basagaoglu, Berkay; Yakovlev, Vladislav V.

    2015-02-01

    Atherosclerosis, the development of intraluminal plaque, is a fundamental pathology of cardiovascular system and remains the leading cause of morbidity and mortality worldwide. Biomechanical in nature, plaque rupture occurs when the mechanical properties of the plaque, related to the morphology and viscoelastic properties, are compromised, resulting in intraluminal thrombosis and reduction of coronary blood flow. In this report, we describe the first simultaneous application of confocal Brillouin and Raman microscopies to ex-vivo aortic wall samples. Such a non-invasive, high specific approach allows revealing a direct relationship between the biochemical and mechanical properties of atherosclerotic tissue.

  6. Thiocyanate supplementation decreases atherosclerotic plaque in mice expressing human myeloperoxidase

    DEFF Research Database (Denmark)

    Morgan, P E; Laura, R P; Maki, R A;

    2015-01-01

    appreciably altered. Serum MPO levels steadily increased in mice on the high-fat diet, however, comparison of SCN(-)-supplemented versus control mice showed no significant changes in MPO protein, cholesterol, or triglyceride levels; thiol levels were decreased in supplemented mice at one time-point. Plaque...... curve (AUC). Mean serum SCN(-) concentrations were elevated in the supplemented mice (200-320 μM) relative to controls (< 120 μM). Normalized aortic root plaque areas at sacrifice were 26% lower in the SCN(-)-supplemented mice compared with controls (P = 0.0417), but plaque morphology was not...

  7. Imaging of amyloid deposition in human brain using positron emission tomography and [{sup 18}F]FACT: comparison with [{sup 11}C]PIB

    Energy Technology Data Exchange (ETDEWEB)

    Ito, Hiroshi [National Institute of Radiological Sciences, Molecular Imaging Center, Chiba (Japan); National Institute of Radiological Sciences, Biophysics Program, Molecular Imaging Center, Chiba (Japan); Shinotoh, Hitoshi; Shimada, Hitoshi; Miyoshi, Michie; Takano, Harumasa; Takahashi, Hidehiko; Arakawa, Ryosuke; Kodaka, Fumitoshi; Ono, Maiko; Eguchi, Yoko; Higuchi, Makoto; Fukumura, Toshimitsu; Suhara, Tetsuya [National Institute of Radiological Sciences, Molecular Imaging Center, Chiba (Japan); Yanai, Kazuhiko; Okamura, Nobuyuki [Tohoku University School of Medicine, Department of Pharmacology, Sendai (Japan)

    2014-04-15

    The characteristic neuropathological changes in Alzheimer's disease (AD) are deposition of amyloid senile plaques and neurofibrillary tangles. The {sup 18}F-labeled amyloid tracer, [{sup 18}F]2-[(2-{(E)-2-[2-(dimethylamino)-1,3-thiazol-5-yl]vinyl}-1, 3-benzoxazol-6-yl)oxy ]-3-fluoropropan-1-ol (FACT), one of the benzoxazole derivatives, was recently developed. In the present study, deposition of amyloid senile plaques was measured by positron emission tomography (PET) with both [ {sup 11}C ]Pittsburgh compound B (PIB) and [ {sup 18}F ]FACT in the same subjects, and the regional uptakes of both radiotracers were directly compared. Two PET scans, one of each with [ {sup 11}C ]PIB and [ {sup 18}F ]FACT, were performed sequentially on six normal control subjects, two mild cognitive impairment (MCI) patients, and six AD patients. The standardized uptake value ratio of brain regions to the cerebellum was calculated with partial volume correction using magnetic resonance (MR) images to remove the effects of white matter accumulation. No significant differences in the cerebral cortical uptake were observed between normal control subjects and AD patients in [ {sup 18}F ]FACT studies without partial volume correction, while significant differences were observed in [ {sup 11}C ]PIB. After partial volume correction, the cerebral cortical uptake was significantly larger in AD patients than in normal control subjects for [ {sup 18}F ]FACT studies as well as [ {sup 11}C ]PIB. Relatively lower uptakes of [ {sup 11}C ]PIB in distribution were observed in the medial side of the temporal cortex and in the occipital cortex as compared with [ {sup 18}F ]FACT. Relatively higher uptake of [ {sup 11}C ]PIB in distribution was observed in the frontal and parietal cortices. Since [ {sup 18}F ]FACT might bind more preferentially to dense-cored amyloid deposition, regional differences in cerebral cortical uptake between [ {sup 11}C ]PIB and [ {sup 18}F ]FACT might be due to differences

  8. Bap: A New Type of Functional Amyloid.

    Science.gov (United States)

    Di Martino, Patrick

    2016-09-01

    Bacteria can build a biofilm matrix scaffold from exopolysaccharides or proteins, and DNA. In a recent report, Taglialegna and colleagues show that pathogenic Staphylococcus aureus produces a protein scaffold based on amyloid assembly of fragments from the biofilm-associated protein. Amyloidogenesis occurs in response to environmental signals.

  9. Calumenin interacts with serum amyloid P component

    DEFF Research Database (Denmark)

    Vorum, H; Jacobsen, Christian; Honoré, Bent

    2000-01-01

    with calumenin in the presence of Ca(2+). Amino acid sequencing identified this protein as serum amyloid P component (SAP). Furthermore, we verified and characterized the calumenin-SAP interaction by the surface plasmon resonance technique. The findings indicate that calumenin may participate...

  10. Bap: A New Type of Functional Amyloid.

    Science.gov (United States)

    Di Martino, Patrick

    2016-09-01

    Bacteria can build a biofilm matrix scaffold from exopolysaccharides or proteins, and DNA. In a recent report, Taglialegna and colleagues show that pathogenic Staphylococcus aureus produces a protein scaffold based on amyloid assembly of fragments from the biofilm-associated protein. Amyloidogenesis occurs in response to environmental signals. PMID:27451288

  11. Is amyloid A (AA) amyloidosis always secondary?

    OpenAIRE

    Maury, C P; Törnroth, T; Wegelius, O

    1985-01-01

    The case is reported of a patient with systemic AA amyloidosis associated with non-specific mesenteric lymphadenitis and chronic sideropenia. Renal, small bowel, and rectal biopsies showed amyloid deposits containing AA protein, as defined by potassium permanganate sensitivity and by reactivity with AA antiserum. Reversal of the nephrotic syndrome occurred during steroid-azathioprine therapy.

  12. Elevated mRNA-levels of gonadotropin-releasing hormone and its receptor in plaque-bearing Alzheimer's disease transgenic mice.

    Directory of Open Access Journals (Sweden)

    Syed Nuruddin

    Full Text Available Research on Alzheimer's disease (AD has indicated an association between hormones of the hypothalamic-pituitary-gonadal (HPG axis and cognitive senescence, indicating that post meno-/andropausal changes in HPG axis hormones are implicated in the neuropathology of AD. Studies of transgenic mice with AD pathologies have led to improved understanding of the pathophysiological processes underlying AD. The aims of this study were to explore whether mRNA-levels of gonadotropin-releasing hormone (Gnrh and its receptor (Gnrhr were changed in plaque-bearing Alzheimer's disease transgenic mice and to investigate whether these levels and amyloid plaque deposition were downregulated by treatment with a gonadotropin-releasing hormone analog (Gnrh-a; Leuprorelin acetate. The study was performed on mice carrying the Arctic and Swedish amyloid-β precursor protein (AβPP mutations (tgArcSwe. At 12 months of age, female tgArcSwe mice showed a twofold higher level of Gnrh mRNA and more than 1.5 higher level of Gnrhr mRNA than age matched controls. Male tgArcSwe mice showed the same pattern of changes, albeit more pronounced. In both sexes, Gnrh-a treatment caused significant down-regulation of Gnrh and Gnrhr mRNA expression. Immunohistochemistry combined with quantitative image analysis revealed no significant changes in the plaque load after Gnrh-a treatment in hippocampus and thalamus. However, plaque load in the cerebral cortex of treated females tended to be lower than in female vehicle-treated mice. The present study points to the involvement of hormonal changes in AD mice models and demonstrates that these changes can be effectively counteracted by pharmacological treatment. Although known to increase in normal aging, our study shows that Gnrh/Gnrhr mRNA expression increases much more dramatically in tgArcSwe mice. Treatment with Leuprorelin acetate successfully abolished the transgene specific effects on Gnrh/Gnrhr mRNA expression. The present experimental

  13. MRI plaque imaging reveals high-risk carotid plaques especially in diabetic patients irrespective of the degree of stenosis

    Directory of Open Access Journals (Sweden)

    Holzer K

    2010-11-01

    Full Text Available Abstract Background Plaque imaging based on magnetic resonance imaging (MRI represents a new modality for risk assessment in atherosclerosis. It allows classification of carotid plaques in high-risk and low-risk lesion types (I-VIII. Type 2 diabetes mellitus (DM 2 represents a known risk factor for atherosclerosis, but its specific influence on plaque vulnerability is not fully understood. This study investigates whether MRI-plaque imaging can reveal differences in carotid plaque features of diabetic patients compared to nondiabetics. Methods 191 patients with moderate to high-grade carotid artery stenosis were enrolled after written informed consent was obtained. Each patient underwent MRI-plaque imaging using a 1.5-T scanner with phased-array carotid coils. The carotid plaques were classified as lesion types I-VIII according to the MRI-modified AHA criteria. For 36 patients histology data was available. Results Eleven patients were excluded because of insufficient MR-image quality. DM 2 was diagnosed in 51 patients (28.3%. Concordance between histology and MRI-classification was 91.7% (33/36 and showed a Cohen's kappa value of 0.81 with a 95% CI of 0.98-1.15. MRI-defined high-risk lesion types were overrepresented in diabetic patients (n = 29; 56.8%. Multiple logistic regression analysis revealed association between DM 2 and MRI-defined high-risk lesion types (OR 2.59; 95% CI [1.15-5.81], independent of the degree of stenosis. Conclusion DM 2 seems to represent a predictor for the development of vulnerable carotid plaques irrespective of the degree of stenosis and other risk factors. MRI-plaque imaging represents a new tool for risk stratification of diabetic patients. See Commentary: http://www.biomedcentral.com/1741-7015/8/78/abstract

  14. Moderate-to-Severe Plaque Psoriasis

    Directory of Open Access Journals (Sweden)

    Rocío Prieto-Pérez

    2015-01-01

    Full Text Available Psoriasis is a chronic skin disease in which genetics play a major role. Although many genome-wide association studies have been performed in psoriasis, knowledge of the age at onset remains limited. Therefore, we analyzed 173 single-nucleotide polymorphisms in genes associated with psoriasis and other autoimmune diseases in patients with moderate-to-severe plaque psoriasis type I (early-onset, <40 years or type II (late-onset, ≥40 years and healthy controls. Moreover, we performed a comparison between patients with type I psoriasis and patients with type II psoriasis. Our comparison of a stratified population with type I psoriasis n=155 and healthy controls N=197 is the first to reveal a relationship between the CLMN, FBXL19, CCL4L, C17orf51, TYK2, IL13, SLC22A4, CDKAL1, and HLA-B/MICA genes. When we compared type I psoriasis with type II psoriasis N=36, we found a significant association between age at onset and the genes PSORS6, TNF-α, FCGR2A, TNFR1, CD226, HLA-C, TNFAIP3, and CCHCR1. Moreover, we replicated the association between rs12191877 (HLA-C and type I psoriasis and between type I and type II psoriasis. Our findings highlight the role of genetics in age of onset of psoriasis.

  15. Assessment of dental plaque by optoelectronic methods

    Science.gov (United States)

    Negrutiu, Meda-Lavinia; Sinescu, Cosmin; Bortun, Cristina Maria; Levai, Mihaela-Codrina; Topala, Florin Ionel; Crǎciunescu, Emanuela Lidia; Cojocariu, Andreea Codruta; Duma, Virgil Florin; Podoleanu, Adrian Gh.

    2016-03-01

    The formation of dental biofilm follows specific mechanisms of initial colonization on the surface, microcolony formation, development of organized three dimensional community structures, and detachment from the surface. The structure of the plaque biofilm might restrict the penetration of antimicrobial agents, while bacteria on a surface grow slowly and display a novel phenotype; the consequence of the latter is a reduced sensitivity to inhibitors. The aim of this study was to evaluate with different optoelectronic methods the morphological characteristics of the dental biofilm. The study was performed on samples from 25 patients aged between 18 and 35 years. The methods used in this study were Spectral Domain Optical Coherence Tomography (SD-OCT) working at 870 nm for in vivo evaluations and Scanning Electron Microscopy (SEM) for validations. For each patient a sample of dental biofilm was obtained directly from the vestibular surface of the teeth's. SD-OCT produced C- and B-scans that were used to generate three dimensional (3D) reconstructions of the sample. The results were compared with SEM evaluations. The biofilm network was dramatically destroyed after the professional dental cleaning. OCT noninvasive methods can act as a valuable tool for the 3D characterization of dental biofilms.

  16. Detecting microcalcifications in atherosclerotic plaques by a simple trichromic staining method for epoxy embedded carotid endarterectomies

    Science.gov (United States)

    Relucenti, M.; Heyn, R.; Petruzziello, L.; Pugliese, G.; Taurino, M.; Familiari, G.

    2010-01-01

    Atherosclerotic plaques have a high probability of undergoing rapid progression to stenosis, becoming responsible of acute coronary syndrome or stroke. Microcalcifications may act as enhancers of atherosclerotic plaque vulnerability. Considering that calcifications with a diameter smalller than 10 µm in paraffin embedded tissue are rather difficult to detect, our aim was to analyze microcalcifications on semithin sections from epoxy resin embedded samples of carotid endarterectomies using an original trichromic stain (methylene blue-azur B - basic fuchsine - alizarin red). We have compared samples stained either with our method, methylene blue-azur B alone or with Von Kossa staining, and methylene blue-azur B -basic fuchsine alone or with Von Kossa staining. Our method resulted to be simple and fast (ca. 2 min), it gives a sharp general contrast for all structures and allows to easy identify collagen and elastin. In addition, gray-green colour associated to intracellular lipid droplets evidences foam cells, which are particularly abundant in endarterectomies samples. Mast cells and their metachromatic granules are also well recognized. Calcifications over 0,5 µm are clearly recognizable. In conclusion, microcalcifications are clearly distinguished from the extracellular matrix in spite of their reduced dimensions. Methylene blue-azur B-basic fuchsine-alizarin red method is easy to use, reproducible, and is particularly suitable for the identification of microcalcifications in the morphological analysis of atherosclerotic plaques. PMID:20819772

  17. Detecting microcalcifications in atherosclerotic plaques by a simple trichromic staining method for epoxy embedded carotid endarterectomies

    Directory of Open Access Journals (Sweden)

    G. Familiari

    2010-09-01

    Full Text Available Atherosclerotic plaques have a high probability of undergoing rapid progression to stenosis, becoming responsible of acute coronary syndrome or stroke. Microcalcifications may act as enhancers of atherosclerotic plaque vulnerability. Considering that calcifications with a diameter smalller than 10 mm in paraffin embedded tissue are rather difficult to detect, our aim was to analyze microcalcifications on semithin sections from epoxy resin embedded samples of carotid endarterectomies using an original trichromic stain (methylene blue- azur B - basic fuchsine - alizarin red. We have compared samples stained either with our method, methylene blue-azur B alone or with Von Kossa staining, and methylene blue-azur B -basic fuchsine alone or with Von Kossa staining. Our method resulted to be simple and fast (ca. 2 min, it gives a sharp general contrast for all structures and allows to easy identify collagen and elastin. In addition, gray-green colour associated to intracellular lipid droplets evidences foam cells, which are particularly abundant in endarterectomies samples. Mast cells and their metachromatic granules are also well recognized. Calcifications over 0,5 mm are clearly recognizable. In conclusion, microcalcifications are clearly distinguished from the extracellular matrix in spite of their reduced dimensions. Methylene blue-azur B-basic fuchsine-alizarin red method is easy to use, reproducible, and is particularly suitable for the identification of microcalcifications in the morphological analysis of atherosclerotic plaques.

  18. Nucleus factory on cavitation bubble for amyloid β fibril.

    Science.gov (United States)

    Nakajima, Kichitaro; Ogi, Hirotsugu; Adachi, Kanta; Noi, Kentaro; Hirao, Masahiko; Yagi, Hisashi; Goto, Yuji

    2016-01-01

    Structural evolution from monomer to fibril of amyloid β peptide is related to pathogenic mechanism of Alzheimer disease, and its acceleration is a long-running problem in drug development. This study reveals that ultrasonic cavitation bubbles behave as catalysts for nucleation of the peptide: The nucleation reaction is highly dependent on frequency and pressure of acoustic wave, and we discover an optimum acoustical condition, at which the reaction-rate constant for nucleation is increased by three-orders-of magnitudes. A theoretical model is proposed for explaining highly frequency and pressure dependent nucleation reaction, where monomers are captured on the bubble surface during its growth and highly condensed by subsequent bubble collapse, so that they are transiently exposed to high temperatures. Thus, the dual effects of local condensation and local heating contribute to dramatically enhance the nucleation reaction. Our model consistently reproduces the frequency and pressure dependences, supporting its essential applicability. PMID:26912021

  19. Nucleus factory on cavitation bubble for amyloid β fibril

    Science.gov (United States)

    Nakajima, Kichitaro; Ogi, Hirotsugu; Adachi, Kanta; Noi, Kentaro; Hirao, Masahiko; Yagi, Hisashi; Goto, Yuji

    2016-02-01

    Structural evolution from monomer to fibril of amyloid β peptide is related to pathogenic mechanism of Alzheimer disease, and its acceleration is a long-running problem in drug development. This study reveals that ultrasonic cavitation bubbles behave as catalysts for nucleation of the peptide: The nucleation reaction is highly dependent on frequency and pressure of acoustic wave, and we discover an optimum acoustical condition, at which the reaction-rate constant for nucleation is increased by three-orders-of magnitudes. A theoretical model is proposed for explaining highly frequency and pressure dependent nucleation reaction, where monomers are captured on the bubble surface during its growth and highly condensed by subsequent bubble collapse, so that they are transiently exposed to high temperatures. Thus, the dual effects of local condensation and local heating contribute to dramatically enhance the nucleation reaction. Our model consistently reproduces the frequency and pressure dependences, supporting its essential applicability.

  20. Protective effects of Lingguizhugan decoction on amyloid-beta peptide (25-35)-induced cell injury: Anti-inflammatory effects☆

    OpenAIRE

    Xi, Feifei; Sang, Feng; Zhou, Chunxiang; Ling, Yun

    2012-01-01

    In the present study, a human neuroblastoma cell line (SH-SY5Y) and BV-2 microglia were treated with amyloid-β peptide (25–35), as a model of Alzheimer’s disease, to evaluate the protective effects of 10-3–10-8 g/mL Lingguizhugan decoction and to examine the underlying anti-inflammatory mechanism. Lingguizhugan decoction significantly enhanced the viability of SH-SY5Y cells with amyloid-β peptide-induced injury, and lowered levels of interleukin-1β, interleukin-6, tumor necrosis factor-α and ...

  1. Evidence for xylitol 5-P production in human dental plaque

    Energy Technology Data Exchange (ETDEWEB)

    Waaler, S.M. (Department of Preclinical Techniques and Material Sciences and Department of Pedodontics, Dental Faculty, University of Oslo, Oslo (Norway))

    1992-01-01

    The Turku sugar studies indicated that xylitol may possess a caries-therapeutic effect. More recent data show that xylotol exhibits a bacteriostatic activity on a wide range of bacteria based on uptake and expulsion of xylitol. Intracellular xylitol 5-P appears to be a key substance associated with inhibition of bacterial metabolism by xylitol. This has been shown in studies with pure strains of bacteria, mainly Streptococcus mutans. The aim of the present study was to examine if production of xylitol 5-P occurs in freshly collected dental plaque which is exposed to labeled xylitol. Plaque extracts were analyzed by thin-layer chromatography combined with autoradiography and high performance liquid chromatography. Strong indications were obtained that xylitol 5-P is readily produced by dental plaque. No other significant xylitol metabolites were identified. The bacteriostatic properties of xylitol in plaque are a mechanism which may well account for the caries-therapeutic effect of xylitol. (au).

  2. Evidence for xylitol 5-P production in human dental plaque

    International Nuclear Information System (INIS)

    The Turku sugar studies indicated that xylitol may possess a caries-therapeutic effect. More recent data show that xylotol exhibits a bacteriostatic activity on a wide range of bacteria based on uptake and expulsion of xylitol. Intracellular xylitol 5-P appears to be a key substance associated with inhibition of bacterial metabolism by xylitol. This has been shown in studies with pure strains of bacteria, mainly Streptococcus mutans. The aim of the present study was to examine if production of xylitol 5-P occurs in freshly collected dental plaque which is exposed to labeled xylitol. Plaque extracts were analyzed by thin-layer chromatography combined with autoradiography and high performance liquid chromatography. Strong indications were obtained that xylitol 5-P is readily produced by dental plaque. No other significant xylitol metabolites were identified. The bacteriostatic properties of xylitol in plaque are a mechanism which may well account for the caries-therapeutic effect of xylitol. (au)

  3. Coronary spasm, a pathogenic trigger of vulnerable plaque rupture

    Institute of Scientific and Technical Information of China (English)

    WANG Li-xin; L(U) Shu-zheng; ZHANG Wei-jun; SONG Xian-tao; CHEN Hui; ZHANG Li-jie

    2011-01-01

    Objective This coronary artery spasm review aimed to explore the most possible pathogenic trigger mechanism of vulnerable plaque rupture.Data sources Data used in this coronary artery spasm review were mainly from Medline and Pubmed in English.Study selection These reports from major review on coronary artery spasm.and these research included coronary artery conception,pathogenesis of spasm,mechanisms of plaque rupture,epidemiological evidence,clinical manifestation and the relationship between coronary artery spasm and vulnerable plaque rupture.Results Coronary artery spasm is somehow related to the presence of atherosclerotic intima disease in the coronary artery.However,chronic low-grade inflammation causes coronary vessel smooth muscle cell hypersensitivity,which can directely cause coronary artery spasm.Myocardial infarction and sudden cardiac death may be initiated by a sudden intense localized contraction of coronary artery smooth muscle.Conclusion Coronary artery spasm may be one trigger that can initiate and exacerbate vulnerable plaque rupture.

  4. Argonne National Laboratory research offers clues to Alzheimer's plaques

    CERN Multimedia

    2003-01-01

    Researchers from Argonne National Laboratory and the University of Chicago have developed methods to directly observe the structure and growth of microscopic filaments that form the characteristic plaques found in the brains of those with Alzheimer's Disease (1 page).

  5. Serum amyloid A inhibits osteoclast differentiation to maintain macrophage function.

    Science.gov (United States)

    Kim, Jiseon; Yang, Jihyun; Park, Ok-Jin; Kang, Seok-Seong; Yun, Cheol-Heui; Han, Seung Hyun

    2016-04-01

    Serum amyloid A is an acute phase protein that is elevated under inflammatory conditions. Additionally, the serum levels of serum amyloid A are associated with the progression of inflammatory arthritis; thus, serum amyloid A might be involved in the regulation of osteoclast differentiation. In the present study, we examined the effects of serum amyloid A on osteoclast differentiation and function. When bone marrow-derived macrophages, as osteoclast precursors, were stimulated with serum amyloid A in the presence of M-CSF and receptor activator of nuclear factor-κB ligand, osteoclast differentiation and its bone-resorption activity were substantially inhibited. TLR2 was important in the inhibitory effect of serum amyloid A on osteoclast differentiation, because serum amyloid A stimulated TLR2. The inhibitory effect was absent in bone marrow-derived macrophages obtained from TLR2-deficient mice. Furthermore, serum amyloid A inhibited the expression of c-Fos and nuclear factor of activated T cells c1, which are crucial transcription factors for osteoclast differentiation, but prevented downregulation of IFN regulatory factor-8, a negative regulator of osteoclast differentiation. In contrast, serum amyloid A sustained the endocytic capacity of bone marrow-derived macrophages and their ability to induce the proinflammatory cytokines, IL-6, IL-1β, and TNF-α. Taken together, these results suggest that serum amyloid A, when increased by inflammatory conditions, inhibits differentiation of macrophages to osteoclasts, likely to maintain macrophage function for host defense.

  6. A role for amyloid in cell aggregation and biofilm formation.

    Directory of Open Access Journals (Sweden)

    Melissa C Garcia

    Full Text Available Cell adhesion molecules in Saccharomyces cerevisiae and Candida albicans contain amyloid-forming sequences that are highly conserved. We have now used site-specific mutagenesis and specific peptide perturbants to explore amyloid-dependent activity in the Candida albicans adhesin Als5p. A V326N substitution in the amyloid-forming region conserved secondary structure and ligand binding, but abrogated formation of amyloid fibrils in soluble Als5p and reduced cell surface thioflavin T fluorescence. When displayed on the cell surface, Als5p with this substitution prevented formation of adhesion nanodomains and formation of large cellular aggregates and model biofilms. In addition, amyloid nanodomains were regulated by exogenous peptides. An amyloid-forming homologous peptide rescued aggregation and biofilm activity of Als5p(V326N cells, and V326N substitution peptide inhibited aggregation and biofilm activity in Als5p(WT cells. Therefore, specific site mutation, inhibition by anti-amyloid peturbants, and sequence-specificity of pro-amyloid and anti-amyloid peptides showed that amyloid formation is essential for nanodomain formation and activation.

  7. Gene expression and 18FDG uptake in atherosclerotic carotid plaques

    DEFF Research Database (Denmark)

    Pedersen, Sune Folke; Græbe, Martin; Hag, Anne Mette Fisker;

    2010-01-01

    ) and an additional ipsilateral internal carotid artery stenosis of greater than 60% were recruited. FDG uptake in the carotids was determined by PET/computed tomography and expressed as mean and maximal standardized uptake values (SUVmean and SUVmax). The atherosclerotic plaques were subsequently recovered...... as SUVmax (R=0.30, Puptake. We suggest that FDG uptake is a composite indicator of macrophage load, overall inflammatory activity and collagenolytic plaque...

  8. Acid production in dental plaque after exposure to probiotic bacteria

    OpenAIRE

    Keller Mette K; Twetman Svante

    2012-01-01

    Abstract Background The increasing interest in probiotic lactobacilli in health maintenance has raised the question of potential risks. One possible side effect could be an increased acidogenicity in dental plaque. The aim of this study was to investigate the effect of probiotic lactobacilli on plaque lactic acid (LA) production in vitro and in vivo. Methods In the first part (A), suspensions of two lactobacilli strains (L. reuteri DSM 17938, L. plantarum 299v) were added to suspensions of su...

  9. Prevalence of Periodontal Pathogens in Dental Plaque of Children

    OpenAIRE

    Gafan, Gavin P.; Lucas, Victoria S.; Roberts, Graham J.; Petrie, Aviva; Wilson, Michael; David A. Spratt

    2004-01-01

    Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans, and Tannerella forsythensis have been implicated as the main etiological agents of periodontal disease. The purpose of this work was to estimate the prevalence of these organisms in plaque from children without gingivitis (group 1; n = 65) and from those with gingivitis (group 2; n = 53). Extracted DNA from plaque was subjected to two rounds of PCR targeting the 16S rRNA gene using both universal primers and species-specific prim...

  10. An interactive treatment planning system for ophthalmic plaque radiotherapy

    International Nuclear Information System (INIS)

    Brachytherapy using removable episcleral plaques containing sealed radioisotope sources is being studied as an alternative to enucleation in the treatment of choroidal melanoma and other tumors of the eye. Encouraging early results have been reported, but late complications which lead to loss of vision continue to be a problem. A randomized national study, the Collaborative Ocular Melanoma Study (COMS) is currently in progress to evaluate the procedure. The COMS specified isotope is 125I. Precise dosimetric calculations near the plaque may correlate strongly with complications and could also be used to optimize isotope loading patterns in the plaques. A microcomputer based treatment planning system has been developed for ophthalmic plaque brachytherapy. The program incorporates an interactive, 3-dimensional, solid-surface, color-graphic interface. The program currently supports 125I and 192Ir seeds which are treated as anisotropic line sources. Collimation effects related to plaque structure are accounted for, permitting detailed study of shielding effectiveness near the lip of a plaque. A dose distribution matrix may be calculated in any subregion of a transverse, sagittal, or coronal planar cross section of the eye, in any plane transecting the plaque and crossing the eye diametrically, or on a spherical surface within or surrounding the eye. Spherical surfaces may be displayed as 3-dimensional perspective projections or as funduscopic diagrams. Isodose contours are interpolated from the dose matrix. A pointer is also available to explicitly calculate and display dose at any location on the dosimetry surface. An interactive editing capability allows new plaque designs to be rapidly added to the system

  11. Insulin inhibits inflammation and promotes atherosclerotic plaque stability via PI3K-Akt pathway activation.

    Science.gov (United States)

    Yan, Hao; Ma, Ying; Li, Yan; Zheng, Xiaohui; Lv, Ping; Zhang, Yuan; Li, Jia; Ma, Meijuan; Zhang, Le; Li, Congye; Zhang, Rongqing; Gao, Feng; Wang, Haichang; Tao, Ling

    2016-02-01

    Toll-like receptor (TLR) 4 induced inflammation was reported to play an important role in atherosclerotic plaque stability. Recent studies indicated that insulin could inhibit inflammation by activating phosphatidylinositol 3-kinase-Akt-dependent (PI3K-Akt) signaling pathway. In the current study, we hypothesized that insulin would inhibit TLR4 induced inflammation via promoting PI3K-Akt activation, thus enhancing the stabilization of atherosclerotic plaques. In order to mimic the process of plaque formation, monocyte-macrophage lineage RAW264.7 were cultured and induced to form foam cells by oxidized LDL (ox-LDL). Oil red O staining results showed that insulin significantly restrained ox-LDL-induced foam cell formation. Analysis of inflammatory reaction during foam cell formation indicated that insulin significantly down-regulated the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-6 levels, inhibited TLR4, myeloid differentiation primary response gene (MyD) 88 and nuclear factor (NF)-κB. Further mechanism analysis showed that pretreating with the PI3K blocker, wortmannin dramatically dampened the insulin-induced up-regulation of pAkt expression. Additionally, blockade of PI3K-Akt signaling also dampened the immunosuppression effect brought by insulin. Following the construction of a rodent atherosclerosis model, pretreatment of insulin resulted in an evident decrease in lipid deposition of the blood vessel wall, serum levels of TNF-α and IL-6, and numbers of infiltrated macrophages and foam cells. Taken together, these results suggested that insulin might inhibit inflammation and promote atherosclerotic plaque stability via the PI3K-Akt pathway by targeting TLR4-MyD88-NF-κB signaling. Our findings may provide a potential target for the prevention of cardiovascular disease. PMID:26681144

  12. Serial changes of coronary atherosclerotic plaque: Assessment with 64-slice multi-detector computed tomography

    International Nuclear Information System (INIS)

    Evaluate the progression of coronary atherosclerotic plaque during follow-up, and its association with cardiovascular risk factors. Fifty-six atherosclerotic patients with plaque were enrolled in this retrospective study. Patient's plaque was detected on repeat 64-slice multidetector CT scans with a mean interval of 25 ± 10 months changes in calcified and non-calcified plaque volumes and cardiovascular risk factors were assessed over time. Absolute and relative changes in plaque volume were compared, and the association between rapid progression and cardiovascular risk factors was determined. Diameter of the stenosis, length, calcified and non-calcified lesion plaque volumes increased significantly on follow-up CT. Absolute and relative annual changes in plaque volumes were significantly greater in non-calcified plaque (median, 22.7 mm3, 90.4%) than in calcified plaque (median, 0.7 mm3, 0%). Obesity, smoking, hypertension, hypercholesterolemia, and low high-density lipoprotein were significant predictors of progression of non-calcified plaque. Progression of calcified plaque was not associated with any cardiovascular risk factors. Coronary plaque volume increased significantly on follow-up CT. The rate of progression is related to non-calcified plaque than to calcified plaque. Cardiovascular risk factors are independently associated with the rapid progression of non-calcified plaque volume, but not associated with the progression of calcified plaque.

  13. Serial changes of coronary atherosclerotic plaque: Assessment with 64-slice multi-detector computed tomography

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Eun Young; Kang, Doo Kyoung; Sun, Joo Sung; Choi, So Yeon [Ajou University School of Medicine, Suwon (Korea, Republic of)

    2013-12-15

    Evaluate the progression of coronary atherosclerotic plaque during follow-up, and its association with cardiovascular risk factors. Fifty-six atherosclerotic patients with plaque were enrolled in this retrospective study. Patient's plaque was detected on repeat 64-slice multidetector CT scans with a mean interval of 25 ± 10 months changes in calcified and non-calcified plaque volumes and cardiovascular risk factors were assessed over time. Absolute and relative changes in plaque volume were compared, and the association between rapid progression and cardiovascular risk factors was determined. Diameter of the stenosis, length, calcified and non-calcified lesion plaque volumes increased significantly on follow-up CT. Absolute and relative annual changes in plaque volumes were significantly greater in non-calcified plaque (median, 22.7 mm{sup 3}, 90.4%) than in calcified plaque (median, 0.7 mm{sup 3}, 0%). Obesity, smoking, hypertension, hypercholesterolemia, and low high-density lipoprotein were significant predictors of progression of non-calcified plaque. Progression of calcified plaque was not associated with any cardiovascular risk factors. Coronary plaque volume increased significantly on follow-up CT. The rate of progression is related to non-calcified plaque than to calcified plaque. Cardiovascular risk factors are independently associated with the rapid progression of non-calcified plaque volume, but not associated with the progression of calcified plaque.

  14. Probing Alzheimers Disease Pathology and Early Detection at the NSLS with Infrared, XRF, and DEI

    International Nuclear Information System (INIS)

    We explored diffraction enhanced imaging (DEI) in both planar and computed tomography (CT) modes for early detection of beta amyloid deposition, a hallmark feature in Alzheimer's disease (AD). Since amyloid plaques precede clinical symptoms by years, their early detection is of great interest. These findings were correlated with results from synchrotron infrared microspectroscopic imaging and X-ray fluorescence microscopy, to determine the secondary structure of the amyloid beta protein and metal concentration in the amyloid plaques, respectively.

  15. Probing Alzheimers Disease Pathology and Early Detection at the NSLS with Infrared, XRF, and DEI

    Energy Technology Data Exchange (ETDEWEB)

    Zhong,Z.; Bennett, D.; Chapman, D.; Chen, J.; Connor, D.; Dilmanian, A.; Faulconer, L.; Kao, T.; Leskovjan, A.; et al

    2008-01-01

    We explored diffraction enhanced imaging (DEI) in both planar and computed tomography (CT) modes for early detection of beta amyloid deposition, a hallmark feature in Alzheimer's disease (AD). Since amyloid plaques precede clinical symptoms by years, their early detection is of great interest. These findings were correlated with results from synchrotron infrared microspectroscopic imaging and X-ray fluorescence microscopy, to determine the secondary structure of the amyloid beta protein and metal concentration in the amyloid plaques, respectively.

  16. Protective effects of Lingguizhugan decoction on amyloid-beta peptide (25-35)-induced cell injury Anti-inflammatory effects

    Institute of Scientific and Technical Information of China (English)

    Feifei Xi; Feng Sang; Chunxiang Zhou; Yun Ling

    2012-01-01

    In the present study, a human neuroblastoma cell line (SH-SY5Y) and BV-2 microglia were treated with amyloid-β peptide (25-35), as a model of Alzheimer's disease, to evaluate the protective effects of 10-3-10-8 g/mL Lingguizhugan decoction and to examine the underlying anti-inflammatory mechanism. Lingguizhugan decoction significantly enhanced the viability of SH-SY5Y cells with amyloid-β peptide-induced injury, and lowered levels of interleukin-1β, interleukin-6, tumor necrosis factor-α and nitric oxide in the culture supernatant of activated BV-2 microglia. The effects of 10-3 g/mL Lingguizhugan decoction were more significant. These results suggest that Lingguizhugan decoction can protect SH-SY5Y cells against amyloid-β peptide (25-35)-induced injury in a dose-dependent manner by inhibiting overexpression of inflammatory factors by activated microglia.

  17. Protective effects of ferulic acid in amyloid precursor protein plus presenilin-1 transgenic mouse model of Alzheimer disease.

    Science.gov (United States)

    Yan, Ji-Jing; Jung, Jun-Sub; Kim, Taek-Keun; Hasan, Ashraful; Hong, Chang-Won; Nam, Ju-Suk; Song, Dong-Keun

    2013-01-01

    We previously reported the protective effects of long-term administration of ferulic acid against the in vivo toxicity of β-amyloid peptide administered intracerebroventricularly in mice. In the present study, we investigated the effects of ferulic acid in transgenic amyloid precursor protein (APP)swe/presenilin 1 (PS1)dE9 (APP/PS1) mouse model of Alzheimer disease (AD). Chronic (for 6 months from the age of 6 to 12 months) oral administration of ferulic acid at a dose of 5.3 mg/kg/day significantly enhanced the performance in novel-object recognition task, and reduced amyloid deposition and interleukin-1 beta (IL-1β) levels in the frontal cortex. These results suggest that ferulic acid at a certain dosage could be useful for prevention and treatment of AD.

  18. Modulation of γ-secretase by EVP-0015962 reduces amyloid deposition and behavioral deficits in Tg2576 mice

    Directory of Open Access Journals (Sweden)

    Rogers Kathryn

    2012-12-01

    Full Text Available Abstract Background A hallmark of Alzheimer’s disease is the presence of senile plaques in human brain primarily containing the amyloid peptides Aβ42 and Aβ40. Many drug discovery efforts have focused on decreasing the production of Aβ42 through γ-secretase inhibition. However, identification of γ-secretase inhibitors has also uncovered mechanism-based side effects. One approach to circumvent these side effects has been modulation of γ-secretase to shift Aβ production to favor shorter, less amyloidogenic peptides than Aβ42, without affecting the overall cleavage efficiency of the enzyme. This approach, frequently called γ-secretase modulation, appears more promising and has lead to the development of new therapeutic candidates for disease modification in Alzheimer’s disease. Results Here we describe EVP-0015962, a novel small molecule γ-secretase modulator. EVP-0015962 decreased Aβ42 in H4 cells (IC50 = 67 nM and increased the shorter Aβ38 by 1.7 fold at the IC50 for lowering of Aβ42. AβTotal, as well as other carboxyl-terminal fragments of amyloid precursor protein, were not changed. EVP-0015962 did not cause the accumulation of other γ-secretase substrates, such as the Notch and ephrin A4 receptors, whereas a γ-secretase inhibitor reduced processing of both. A single oral dose of EVP-0015962 (30 mg/kg decreased Aβ42 and did not alter AβTotal peptide levels in a dose-dependent manner in Tg2576 mouse brain at an age when overt Aβ deposition was not present. In Tg2576 mice, chronic treatment with EVP-0015962 (20 or 60 mg/kg/day in a food formulation reduced Aβ aggregates, amyloid plaques, inflammatory markers, and cognitive deficits. Conclusions EVP-0015962 is orally bioavailable, detected in brain, and a potent, selective γ-secretase modulator in vitro and in vivo. Chronic treatment with EVP-0015962 was well tolerated in mice and lowered the production of Aβ42, attenuated memory deficits, and reduced Aβ plaque

  19. Preliminary study of the detectability of coronary plaque with PET

    International Nuclear Information System (INIS)

    The evaluation of coronary plaque vulnerability could be of great diagnostic value in cardiology. Positron emission tomography (PET) is a good candidate due to its ability to quantify micromolar concentrations of targeted drugs. However, the detectability of sub-voxel targets such as coronary plaque is limited by partial volume effects and by cardiorespiratory motion. The goal of this paper is to investigate the impact of these factors in the detectability of plaque uptake. Radioactive markers were implanted on the epicardium of a pig and in vivo scans were performed. This was complemented with phantom measurements to determine the minimum detectable uptake as a function of background activity. Simulations were used to evaluate the effect of cardiorespiratory motion on the reconstructed lesions. Despite cardiorespiratory motion of up to 7 mm, the markers were detectable in the in vivo scans even after the injection of background. A lower limit of 250 Bq was found for a target to be detectable. Motion reduced the contrast of the reconstructed lesions to 23% of their static counterpart. Respiratory gating improved this to 49% of the static value. The results suggest that coronary plaque evaluation with PET is possible, provided that sufficient plaque-to-myocardium uptake contrast (50 to 100) can be achieved. This requirement increases exponentially for lesions with uptake below 250 Bq. The described experiments provide a means of estimating the minimum uptake and contrast required to ensure the detectability of plaque lesions.

  20. Imaging of atherosclerotic plaques by optical coherence tomography (OCT)

    Science.gov (United States)

    Perree, Jop; van Leeuwen, Ton G. J. M.; Pasterkamp, Gerard; Izatt, Joseph A.

    2000-05-01

    Optical Coherence Tomography (OCT) is an imaging technique that measures the intensity of light back scattered from sub- surface tissue structures with a very high resolution. This report describes the qualitative and quantitative correlation of OCT and histology measurements for plaque presence and thickness of caps overlying atherosclerotic plaques, respectively. Imaging of samples (n equals 12) was performed from the luminal side with 1300 nm 1 mW or 10 mW light sources, with coherence lengths of 21 and 16 micrometer, respectively. Samples were histologically processed and stained with H&E, EvG and picro-sirius red (PSR) and histological and OCT images were matched. For each sample, the presence of plaque was assessed and the minimal cap thickness was measured by means of histomorphometry and OCT. We found a sensitivity of 6/6 and a specificity of 5/6 for detection of plaques with OCT. Quantitative analysis showed a strong and significant correlation between OCT and histology cap thickness measurements (R2 equals 0.968). Thus, OCT is a sensitive method for detection of plaques, is quantitatively comparable to histology and holds promise as a high-resolution diagnostic tool for visualization of plaque cap thickness.

  1. Treating pediatric plaque psoriasis: challenges and solutions

    Directory of Open Access Journals (Sweden)

    Thomas J

    2016-04-01

    Full Text Available Jayakar Thomas,1 Kumar Parimalam,2 1Department of Dermatology, Sree Balaji Medical College, Bharath University, Chennai, Tamil Nadu, India; 2Department of Dermatology, Villupuram Medical College, Villupuram, Tamil Nadu, India Abstract: Psoriasis is a T-lymphocyte-mediated chronic inflammatory disorder involving the skin and joints. Nearly 3.5% of the population has been diagnosed to have psoriasis. In a dermatology department, almost one-third of psoriasis patients are in the pediatric age group. With an annual prevalence of up to 0.71%, childhood psoriasis can now be regarded as a frequently seen chronic inflammatory skin disorder having a significant impact on the quality of life. Based on the age of onset, psoriasis in children can be broadly classified as infantile psoriasis that can be mostly self-limited, psoriasis having an early onset, which needs specific treatment, and psoriasis that is associated with arthritis. Treating a child with psoriasis is a challenge, considering the physical development, body metabolism, rate of cutaneous absorption, and metabolism of drugs, which are quite different from those of the adults. The long duration of sun exposure for the rest of their life makes it more demanding while considering phototherapy in children. Long-term treatment of psoriasis, with phototherapy or drugs, needs critical evaluation in children. Hence, a thorough understanding of the disease in all its aspects will certainly help manage childhood psoriasis better. Timely diagnosis and adequate management not only arrest progression but also minimize the psychological burden caused by the disease, averting disfiguring states and evolution into a metabolic syndrome. Keywords: plaque, psoriasis, children, treatment 

  2. Lipid volume fraction in atherosclerotic plaque phantoms classified under saline conditions by multispectral angioscopy at near-infrared wavelengths around 1200 nm.

    Science.gov (United States)

    Matsui, Daichi; Ishii, Katsunori; Awazu, Kunio

    2016-05-01

    To identify high-risk atherosclerotic lesions, we require detailed information on the stability of atherosclerotic plaques. In this study, we quantitatively classified the lipid volume fractions in atherosclerotic plaque phantoms by a novel angioscope combined with near-infrared multispectral imaging. The multispectral angioscope was operated at peak absorption wavelengths of lipid in vulnerable plaques (1150, 1200, and 1300 nm) and at lower absorption wavelengths of water. The potential of the multispectral angioscope was demonstrated in atherosclerotic plaque phantoms containing 10-60 vol.% lipid and immersed in saline solution. The acquired multispectral data were processed by a spectral angle mapper algorithm, which enhanced the simulated plaque areas. Consequently, we classified the lipid volume fractions into five categories (0-5, 5-15, 15-30, 30-50, and 50-60 vol.%). Multispectral angioscopy at wavelengths around 1200 nm is a powerful tool for quantitatively evaluating the stability of atherosclerotic plaques based on the lipid volume fractions. PMID:26861978

  3. Low-density lipoprotein and noncalcified coronary plaque composition in patients with newly diagnosed coronary artery disease on computed tomographic angiography.

    Science.gov (United States)

    Cheng, Victor Y; Wolak, Arik; Gutstein, Ariel; Gransar, Heidi; Wong, Nathan D; Dey, Damini; Thomson, Louise E J; Hayes, Sean W; Friedman, John D; Slomka, Piotr J; Berman, Daniel S

    2010-03-15

    We sought to determine significant relations between atherogenic lipoproteins and the contribution of calcified plaque (CP), mixed plaque (MP), and noncalcified plaque (NCP) to the total plaque (TP) burden in patients without previous coronary artery disease. From 823 adult patients without previously established coronary artery disease (52% receiving statin therapy, 34% asymptomatic) but with visible coronary plaque on coronary computed tomographic angiography, we obtained segmental CP, MP, NCP, and TP counts from contrast-enhanced, electrocardiographic-gated computed tomography. Multivariate linear regression analysis was used to determine the associations of clinical factors and lipoprotein levels to CP, MP, and NCP counts and CP/TP, MP/TP, and NCP/TP count ratios. Age, male gender, diabetes, smoking, and statin therapy were significantly associated with the CP count (p NCP counts (all p values NCP/TP ratios, including an inverse association with CP/TP (p = 0.008) and a positive association with MP/TP (p = 0.032). Analyses using non-high-density lipoprotein cholesterol in place of LDL cholesterol yielded similar results. In conclusion, among the traditional clinical factors used to estimate cardiovascular event risk, LDL cholesterol is associated with an increased MP and NCP burden and is the sole variable that independently predicted relative predominance of CP, MP, and NCP, suggesting a potentially important role for lipoprotein levels in modulating the type of detectable coronary arterial plaque.

  4. Fold modulating function: Bacterial toxins to functional amyloids

    Directory of Open Access Journals (Sweden)

    Adnan Khawaja Syed

    2014-08-01

    Full Text Available Many bacteria produce cytolytic toxins that target host cells or other competing microbes. It is well known that environmental factors control toxin expression, however recent work suggests that some bacteria manipulate the fold of these protein toxins to control their function. The β-sheet rich amyloid fold is a highly stable ordered aggregate that many toxins form in response to specific environmental conditions. When in the amyloid state, toxins become inert, losing the cytolytic activity they display in the soluble form. Emerging evidence suggest that some amyloids function as toxin storage systems until they are again needed, while other bacteria utilize amyloids as a structural matrix component of biofilms. This amyloid matrix component facilitates resistance to biofilm disruptive challenges. The bacterial amyloids discussed in this review reveal an elegant system where changes in protein fold and solubility dictate the function of proteins in response to the environment.

  5. Inhibition of insulin amyloid fibril formation by cyclodextrins.

    Science.gov (United States)

    Kitagawa, Keisuke; Misumi, Yohei; Ueda, Mitsuharu; Hayashi, Yuya; Tasaki, Masayoshi; Obayashi, Konen; Yamashita, Taro; Jono, Hirofumi; Arima, Hidetoshi; Ando, Yukio

    2015-01-01

    Localized insulin-derived amyloid masses occasionally form at the site of repeated insulin injections in patients with insulin-dependent diabetes and cause subcutaneous insulin resistance. Various kinds of insulin including porcine insulin, human insulin, and insulin analogues reportedly formed amyloid fibrils in vitro and in vivo, but the impact of the amino acid replacement in insulin molecules on amyloidogenicity is largely unknown. In the present study, we demonstrated the difference in amyloid fibril formation kinetics of human insulin and insulin analogues, which suggests an important role of the C-terminal domain of the insulin B chain in nuclear formation of amyloid fibrils. Furthermore, we determined that cyclodextrins, which are widely used as drug carriers in the pharmaceutical field, had an inhibitory effect on the nuclear formation of insulin amyloid fibrils. These findings have significant implications for the mechanism underlying insulin amyloid fibril formation and for developing optimal additives to prevent this subcutaneous adverse effect.

  6. Atomic View of a Toxic Amyloid Small Oligomer

    Energy Technology Data Exchange (ETDEWEB)

    Laganowsky, Arthur; Liu, Cong; Sawaya, Michael R.; Whitelegge, Julian P.; Park, Jiyong; Zhao, Minglei; Pensalfini, Anna; Soriaga, Angela B.; Landau, Meytal; Teng, Poh K.; Cascio, Duilio; Glabe, Charles; Eisenberg, David (UCI); (UCLA)

    2012-04-30

    Amyloid diseases, including Alzheimer's, Parkinson's, and the prion conditions, are each associated with a particular protein in fibrillar form. These amyloid fibrils were long suspected to be the disease agents, but evidence suggests that smaller, often transient and polymorphic oligomers are the toxic entities. Here, we identify a segment of the amyloid-forming protein {alpha}{beta} crystallin, which forms an oligomeric complex exhibiting properties of other amyloid oligomers: {beta}-sheet-rich structure, cytotoxicity, and recognition by an oligomer-specific antibody. The x-ray-derived atomic structure of the oligomer reveals a cylindrical barrel, formed from six antiparallel protein strands, that we term a cylindrin. The cylindrin structure is compatible with a sequence segment from the {beta}-amyloid protein of Alzheimer's disease. Cylindrins offer models for the hitherto elusive structures of amyloid oligomers.

  7. Simulations of nucleation and elongation of amyloid fibrils

    OpenAIRE

    Zhang, Jianing; Muthukumar, M.

    2009-01-01

    We present a coarse-grained model for the growth kinetics of amyloid fibrils from solutions of peptides and address the fundamental mechanism of nucleation and elongation by using a lattice Monte Carlo procedure. We reproduce the three main characteristics of nucleation of amyloid fibrils: (1) existence of lag time, (2) occurrence of a critical concentration, and (3) seeding. We find the nucleation of amyloid fibrils to require a quasi-two-dimensional configuration, where a second layer of β ...

  8. Physical and structural basis for polymorphism in amyloid fibrils

    OpenAIRE

    Tycko, Robert

    2014-01-01

    As our understanding of the molecular structures of amyloid fibrils has matured over the past 15 years, it has become clear that, while amyloid fibrils do have well-defined molecular structures, their molecular structures are not uniquely determined by the amino acid sequences of their constituent peptides and proteins. Self-propagating molecular-level polymorphism is a common phenomenon. This article reviews current information about amyloid fibril structures, variations in molecular structu...

  9. New Insights in the Amyloid-Beta Interaction with Mitochondria

    OpenAIRE

    Carlos Spuch; Saida Ortolano; Carmen Navarro

    2012-01-01

    Biochemical and morphological alterations of mitochondria may play an important role in the pathogenesis of Alzheimer’s disease (AD). Particularly, mitochondrial dysfunction is a hallmark of amyloid-beta-induced neuronal toxicity in Alzheimer’s disease. The recent emphasis on the intracellular biology of amyloid-beta and its precursor protein (APP) has led researchers to consider the possibility that mitochondria-associated and mitochondrial amyloid-beta may directly cause neurotoxicity. Both...

  10. Generation of amyloid-β is reduced by the interaction of calreticulin with amyloid precursor protein, presenilin and nicastrin.

    Directory of Open Access Journals (Sweden)

    Nina Stemmer

    Full Text Available Dysregulation of the proteolytic processing of amyloid precursor protein by γ-secretase and the ensuing generation of amyloid-β is associated with the pathogenesis of Alzheimer's disease. Thus, the identification of amyloid precursor protein binding proteins involved in regulating processing of amyloid precursor protein by the γ-secretase complex is essential for understanding the mechanisms underlying the molecular pathology of the disease. We identified calreticulin as novel amyloid precursor protein interaction partner that binds to the γ-secretase cleavage site within amyloid precursor protein and showed that this Ca(2+- and N-glycan-independent interaction is mediated by amino acids 330-344 in the C-terminal C-domain of calreticulin. Co-immunoprecipitation confirmed that calreticulin is not only associated with amyloid precursor protein but also with the γ-secretase complex members presenilin and nicastrin. Calreticulin was detected at the cell surface by surface biotinylation of cells overexpressing amyloid precursor protein and was co-localized by immunostaining with amyloid precursor protein and presenilin at the cell surface of hippocampal neurons. The P-domain of calreticulin located between the N-terminal N-domain and the C-domain interacts with presenilin, the catalytic subunit of the γ-secretase complex. The P- and C-domains also interact with nicastrin, another functionally important subunit of this complex. Transfection of amyloid precursor protein overexpressing cells with full-length calreticulin leads to a decrease in amyloid-β42 levels in culture supernatants, while transfection with the P-domain increases amyloid-β40 levels. Similarly, application of the recombinant P- or C-domains and of a synthetic calreticulin peptide comprising amino acid 330-344 to amyloid precursor protein overexpressing cells result in elevated amyloid-β40 and amyloid-β42 levels, respectively. These findings indicate that the interaction of

  11. Aggregation, impaired degradation and immunization targeting of amyloid-beta dimers in Alzheimer’s disease: a stochastic modelling approach

    Directory of Open Access Journals (Sweden)

    Proctor Carole J

    2012-07-01

    Full Text Available Abstract Background Alzheimer’s disease (AD is the most frequently diagnosed neurodegenerative disorder affecting humans, with advanced age being the most prominent risk factor for developing AD. Despite intense research efforts aimed at elucidating the precise molecular underpinnings of AD, a definitive answer is still lacking. In recent years, consensus has grown that dimerisation of the polypeptide amyloid-beta (Aß, particularly Aß42, plays a crucial role in the neuropathology that characterise AD-affected post-mortem brains, including the large-scale accumulation of fibrils, also referred to as senile plaques. This has led to the realistic hope that targeting Aß42 immunotherapeutically could drastically reduce plaque burden in the ageing brain, thus delaying AD onset or symptom progression. Stochastic modelling is a useful tool for increasing understanding of the processes underlying complex systems-affecting disorders such as AD, providing a rapid and inexpensive strategy for testing putative new therapies. In light of the tool’s utility, we developed computer simulation models to examine Aß42 turnover and its aggregation in detail and to test the effect of immunization against Aß dimers. Results Our model demonstrates for the first time that even a slight decrease in the clearance rate of Aß42 monomers is sufficient to increase the chance of dimers forming, which could act as instigators of protofibril and fibril formation, resulting in increased plaque levels. As the process is slow and levels of Aβ are normally low, stochastic effects are important. Our model predicts that reducing the rate of dimerisation leads to a significant reduction in plaque levels and delays onset of plaque formation. The model was used to test the effect of an antibody mediated immunological response. Our results showed that plaque levels were reduced compared to conditions where antibodies are not present. Conclusion Our model supports the current

  12. Acid production in dental plaque after exposure to probiotic bacteria

    Directory of Open Access Journals (Sweden)

    Keller Mette K

    2012-10-01

    Full Text Available Abstract Background The increasing interest in probiotic lactobacilli in health maintenance has raised the question of potential risks. One possible side effect could be an increased acidogenicity in dental plaque. The aim of this study was to investigate the effect of probiotic lactobacilli on plaque lactic acid (LA production in vitro and in vivo. Methods In the first part (A, suspensions of two lactobacilli strains (L. reuteri DSM 17938, L. plantarum 299v were added to suspensions of supragingival dental plaque collected from healthy young adults (n=25. LA production after fermentation with either xylitol or fructose was analyzed. In the second part (B, subjects (n=18 were given lozenges with probiotic lactobacilli (L. reuteri DSM 17938 and ATCC PTA 5289 or placebo for two weeks in a double-blinded, randomized cross-over trial. The concentration of LA in supragingival plaque samples was determined at baseline and after 2 weeks. Salivary counts of mutans streptococci (MS and lactobacilli were estimated with chair-side methods. Results Plaque suspensions with L. reuteri DSM 17938 produced significantly less LA compared with L. plantarum 299v or controls (p Conclusion Lactic acid production in suspensions of plaque and probiotic lactobacilli was strain-dependant and the present study provides no evidence of an increase in plaque acidity by the supply of selected probiotic lactobacilli when challenged by fructose or xylitol. The study protocol was approved by The Danish National Committee on Biomedical Research Ethics (protocol no H-2-2010-112. Trial registration NCT01700712

  13. Raised soluble P-selectin moderately accelerates atherosclerotic plaque progression.

    Science.gov (United States)

    Woollard, Kevin J; Lumsden, Natalie G; Andrews, Karen L; Aprico, Andrea; Harris, Emma; Irvine, Jennifer C; Jefferis, Ann-maree; Fang, Lu; Kanellakis, Peter; Bobik, Alex; Chin-Dusting, Jaye P F

    2014-01-01

    Soluble P-selectin (sP-selectin), a biomarker of inflammatory related pathologies including cardiovascular and peripheral vascular diseases, also has pro-atherosclerotic effects including the ability to increase leukocyte recruitment and modulate thrombotic responses in vivo. The current study explores its role in progressing atherosclerotic plaque disease. Apoe-/- mice placed on a high fat diet (HFD) were given daily injections of recombinant dimeric murine P-selectin (22.5 µg/kg/day) for 8 or 16 weeks. Saline or sE-selectin injections were used as negative controls. In order to assess the role of sP-selectin on atherothrombosis an experimental plaque remodelling murine model, with sm22α-hDTR Apoe-/- mice on a HFD in conjunction with delivery of diphtheria toxin to induce targeted vascular smooth muscle apoptosis, was used. These mice were similarly given daily injections of sP-selectin for 8 or 16 weeks. While plaque mass and aortic lipid content did not change with sP-selectin treatment in Apoe-/- or SM22α-hDTR Apoe-/- mice on HFD, increased plasma MCP-1 and a higher plaque CD45 content in Apoe-/- HFD mice was observed. As well, a significant shift towards a more unstable plaque phenotype in the SM22α-hDTR Apoe-/- HFD mice, with increased macrophage accumulation and lower collagen content, leading to a lower plaque stability index, was observed. These results demonstrate that chronically raised sP-selectin favours progression of an unstable atherosclerotic plaque phenotype.

  14. Deciphering the molecular profile of plaques, memory decline and neuron-loss in two mouse models for Alzheimer’s disease by deep sequencing

    Directory of Open Access Journals (Sweden)

    Yvonne eBouter

    2014-04-01

    Full Text Available One of the central research questions on the etiology of Alzheimer’s disease (AD is the elucidation of the molecular signatures triggered by the amyloid cascade of pathological events. Next generation sequencing allows the identification of genes involved in disease processes in an unbiased manner. We have combined this technique with the analysis of two AD mouse models. (1 The 5XFAD model develops early plaque formation, intraneuronal Aβ aggregation, neuron loss and behavioral deficits. (2 The Tg4-42 model expresses N-truncated Aβ4-42 and develops neuron loss and behavioral deficits albeit without plaque formation.Our results show that learning and memory deficits in the Morris water maze and fear conditioning tasks in Tg4-42 mice at 12 months of age are similar to the deficits in 5XFAD animals. This suggested that comparative gene expression analysis between the models would allow the dissection of plaque-related and -unrelated disease relevant factors. Using deep sequencing differentially expressed genes (DEG were identified and subsequently verified by qRT-PCR. 19 DEGs were identified in presymptomatic young 5XFAD mice, and none in young Tg4-42 mice. In the aged cohort, 131 DEGs were found in 5XFAD and 56 DEGs in Tg4-42 mice. Many of the DEGs specific to the 5XFAD model belong to neuroinflammatory processes typically associated with plaques. Interestingly, 36 DEGs were identified in both mouse models indicating common disease pathways associated with behavioral deficits and neuron loss.

  15. Galactic cosmic radiation leads to cognitive impairment and increased aβ plaque accumulation in a mouse model of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Jonathan D Cherry

    Full Text Available Galactic Cosmic Radiation consisting of high-energy, high-charged (HZE particles poses a significant threat to future astronauts in deep space. Aside from cancer, concerns have been raised about late degenerative risks, including effects on the brain. In this study we examined the effects of (56Fe particle irradiation in an APP/PS1 mouse model of Alzheimer's disease (AD. We demonstrated 6 months after exposure to 10 and 100 cGy (56Fe radiation at 1 GeV/µ, that APP/PS1 mice show decreased cognitive abilities measured by contextual fear conditioning and novel object recognition tests. Furthermore, in male mice we saw acceleration of Aβ plaque pathology using Congo red and 6E10 staining, which was further confirmed by ELISA measures of Aβ isoforms. Increases were not due to higher levels of amyloid precursor protein (APP or increased cleavage as measured by levels of the β C-terminal fragment of APP. Additionally, we saw no change in microglial activation levels judging by CD68 and Iba-1 immunoreactivities in and around Aβ plaques or insulin degrading enzyme, which has been shown to degrade Aβ. However, immunohistochemical analysis of ICAM-1 showed evidence of endothelial activation after 100 cGy irradiation in male mice, suggesting possible alterations in Aβ trafficking through the blood brain barrier as a possible cause of plaque increase. Overall, our results show for the first time that HZE particle radiation can increase Aβ plaque pathology in an APP/PS1 mouse model of AD.

  16. Prions, amyloids, and RNA: Pieces of a puzzle.

    Science.gov (United States)

    Nizhnikov, Anton A; Antonets, Kirill S; Bondarev, Stanislav A; Inge-Vechtomov, Sergey G; Derkatch, Irina L

    2016-05-01

    Amyloids are protein aggregates consisting of fibrils rich in β-sheets. Growth of amyloid fibrils occurs by the addition of protein molecules to the tip of an aggregate with a concurrent change of a conformation. Thus, amyloids are self-propagating protein conformations. In certain cases these conformations are transmissible / infectious; they are known as prions. Initially, amyloids were discovered as pathological extracellular deposits occurring in different tissues and organs. To date, amyloids and prions have been associated with over 30 incurable diseases in humans and animals. However, a number of recent studies demonstrate that amyloids are also functionally involved in a variety of biological processes, from biofilm formation by bacteria, to long-term memory in animals. Interestingly, amyloid-forming proteins are highly overrepresented among cellular factors engaged in all stages of mRNA life cycle: from transcription and translation, to storage and degradation. Here we review rapidly accumulating data on functional and pathogenic amyloids associated with mRNA processing, and discuss possible significance of prion and amyloid networks in the modulation of key cellular functions. PMID:27248002

  17. Heterologous amyloid seeding: revisiting the role of acetylcholinesterase in Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Létitia Jean

    Full Text Available Neurodegenerative diseases associated with abnormal protein folding and ordered aggregation require an initial trigger which may be infectious, inherited, post-inflammatory or idiopathic. Proteolytic cleavage to generate vulnerable precursors, such as amyloid-beta peptide (Abeta production via beta and gamma secretases in Alzheimer's Disease (AD, is one such trigger, but the proteolytic removal of these fragments is also aetiologically important. The levels of Abeta in the central nervous system are regulated by several catabolic proteases, including insulysin (IDE and neprilysin (NEP. The known association of human acetylcholinesterase (hAChE with pathological aggregates in AD together with its ability to increase Abeta fibrilization prompted us to search for proteolytic triggers that could enhance this process. The hAChE C-terminal domain (T40, AChE(575-614 is an exposed amphiphilic alpha-helix involved in enzyme oligomerisation, but it also contains a conformational switch region (CSR with high propensity for conversion to non-native (hidden beta-strand, a property associated with amyloidogenicity. A synthetic peptide (AChE(586-599 encompassing the CSR region shares homology with Abeta and forms beta-sheet amyloid fibrils. We investigated the influence of IDE and NEP proteolysis on the formation and degradation of relevant hAChE beta-sheet species. By combining reverse-phase HPLC and mass spectrometry, we established that the enzyme digestion profiles on T40 versus AChE(586-599, or versus Abeta, differed. Moreover, IDE digestion of T40 triggered the conformational switch from alpha- to beta-structures, resulting in surfactant CSR species that self-assembled into amyloid fibril precursors (oligomers. Crucially, these CSR species significantly increased Abeta fibril formation both by seeding the energetically unfavorable formation of amyloid nuclei and by enhancing the rate of amyloid elongation. Hence, these results may offer an explanation

  18. Amyloid Beta-peptide (25-35) changes (Ca2+) in hippocampal neurons

    DEFF Research Database (Denmark)

    Mogensen, Helle Smidt; Beatty, Diane; Morris, Stephen;

    1998-01-01

    neuroscience, Alzheimer, calcium ion, hippocampal neurons, amyloid-beta-peptide, hydrogen ion, rat......neuroscience, Alzheimer, calcium ion, hippocampal neurons, amyloid-beta-peptide, hydrogen ion, rat...

  19. Amyloid-beta Alzheimer targets — protein processing, lipid rafts, and amyloid-beta pores

    Science.gov (United States)

    Arbor, Sage C.; LaFontaine, Mike; Cumbay, Medhane

    2016-01-01

    Amyloid beta (Aβ), the hallmark of Alzheimer’s Disease (AD), now appears to be deleterious in its low number aggregate form as opposed to the macroscopic Aβ fibers historically seen postmortem. While Alzheimer targets, such as the tau protein, amyloid precursor protein (APP) processing, and immune system activation continue to be investigated, the recent discovery that amyloid beta aggregates at lipid rafts and likely forms neurotoxic pores has led to a new paradigm regarding why past therapeutics may have failed and how to design the next round of compounds for clinical trials. An atomic resolution understanding of Aβ aggregates, which appear to exist in multiple conformations, is most desirable for future therapeutic development. The investigative difficulties, structures of these small Aβ aggregates, and current therapeutics are summarized in this review. PMID:27505013

  20. Amyloid-beta Alzheimer targets - protein processing, lipid rafts, and amyloid-beta pores.

    Science.gov (United States)

    Arbor, Sage C; LaFontaine, Mike; Cumbay, Medhane

    2016-03-01

    Amyloid beta (Aβ), the hallmark of Alzheimer's Disease (AD), now appears to be deleterious in its low number aggregate form as opposed to the macroscopic Aβ fibers historically seen postmortem. While Alzheimer targets, such as the tau protein, amyloid precursor protein (APP) processing, and immune system activation continue to be investigated, the recent discovery that amyloid beta aggregates at lipid rafts and likely forms neurotoxic pores has led to a new paradigm regarding why past therapeutics may have failed and how to design the next round of compounds for clinical trials. An atomic resolution understanding of Aβ aggregates, which appear to exist in multiple conformations, is most desirable for future therapeutic development. The investigative difficulties, structures of these small Aβ aggregates, and current therapeutics are summarized in this review. PMID:27505013

  1. Formation of Toxic Amyloid Fibrils by Amyloid β-Protein on Ganglioside Clusters

    Directory of Open Access Journals (Sweden)

    Katsumi Matsuzaki

    2011-01-01

    Full Text Available It is widely accepted that the conversion of the soluble, nontoxic amyloid β-protein (Aβ monomer to aggregated toxic Aβ rich in β-sheet structures is central to the development of Alzheimer’s disease. However, the mechanism of the abnormal aggregation of Aβ in vivo is not well understood. Accumulating evidence suggests that lipid rafts (microdomains in membranes mainly composed of sphingolipids (gangliosides and sphingomyelin and cholesterol play a pivotal role in this process. This paper summarizes the molecular mechanisms by which Aβ aggregates on membranes containing ganglioside clusters, forming amyloid fibrils. Notably, the toxicity and physicochemical properties of the fibrils are different from those of Aβ amyloids formed in solution. Furthermore, differences between Aβ-(1–40 and Aβ-(1–42 in membrane interaction and amyloidogenesis are also emphasized.

  2. In vitro antiplaque activity of octenidine dihydrochloride (WIN 41464-2) against preformed plaques of selected oral plaque-forming microorganisms.

    OpenAIRE

    Slee, A M; O'Connor, J R

    1983-01-01

    The antibacterial activity of octenidine dihydrochloride (WIN 41464-2) against intact preformed in vitro plaques of four indigenous oral plaque-forming microorganisms, Streptococcus mutans, Streptococcus sanguis, Actinomyces viscosus, and Actinomyces naeslundii, was studied. Both absolute (plaque bactericidal index) and relative (chlorhexidine coefficient) indices of antiplaque efficacy were established. Octenidine dihydrochloride compared favorably with chlorhexidine digluconate with respect...

  3. Design and Construction of Large Amyloid Fibers

    Directory of Open Access Journals (Sweden)

    Devin M. Ridgley

    2015-04-01

    Full Text Available Mixtures of “template” and “adder” proteins self-assemble into large amyloid fibers of varying morphology and modulus. Fibers range from low modulus, rectangular cross-sectioned tapes to high modulus, circular cross-sectioned cylinders. Varying the proteins in the mixture can elicit “in-between” morphologies, such as elliptical cross-sectioned fibers and twisted tapes, both of which have moduli in-between rectangular tapes and cylindrical fibers. Experiments on mixtures of proteins of known amino acid sequence show that control of the large amyloid fiber morphology is dependent on the amount of glutamine repeats or “Q-blocks” relative to hydrophobic side chained amino acids such as alanine, isoleucine, leucine, and valine in the adder protein. Adder proteins with only hydrophobic groups form low modulus rectangular cross-sections and increasing the Q-block content allows excess hydrogen bonding on amide groups that results in twist and higher modulus. The experimental results show that large amyloid fibers of specific shape and modulus can be designed and controlled at the molecular level.

  4. Effect of pathogenic mutations on the structure and dynamics of Alzheimer's A beta 42-amyloid oligomers.

    Science.gov (United States)

    Kassler, Kristin; Horn, Anselm H C; Sticht, Heinrich

    2010-05-01

    Converging lines of evidence suggest that soluble A beta-amyloid oligomers play a pivotal role in the pathogenesis of Alzheimer's disease, and present direct effectors of synaptic and cognitive dysfunction. Three pathological E22-A beta-amyloid point mutants (E22G, E22K, E22Q) and the deletion mutant E22 Delta exhibit an enhanced tendency to form prefibrillar aggregates. The present study assessed the effect of these four mutations using molecular dynamics simulations and subsequent structural and energetic analyses. Our data shows that E22 plays a unique role in wild type A beta, since it has a destabilising effect on the oligomer structure due to electrostatic repulsion between adjacent E22 side chains. Mutations in which E22 is replaced by an uncharged residue result in higher oligomer stability. This effect is also observed to a lesser extent for the E22K mutation and is consistent with its lower pathogenicity compared to other mutants. Interestingly, deletion of E22 does not destroy the amyloid fold but is compensated by local changes in the backbone geometry that allow the preservation of a structurally important salt bridge. The finding that all mutant oligomers investigated exhibit higher internal stability than the wild type offers an explanation for the experimentally observed enhanced oligomer formation and stability.

  5. Turbulence intensity measurements using particle image velocimetry in diseased carotid artery models: effect of stenosis severity, plaque eccentricity, and ulceration.

    Science.gov (United States)

    Kefayati, Sarah; Holdsworth, David W; Poepping, Tamie L

    2014-01-01

    Clinical decision-making for the treatment of patients with diseased carotid artery is mainly based on the severity of the stenosis. However, stenosis severity alone is not a sensitive indicator, and other local factors for the assessment of stroke risk are required. Flow disturbance is of particular interest due to its proven association with increased thromboembolic activities. The objective of this study was to investigate the level of turbulence intensity (TI) with regards to certain geometrical features of the plaque - namely stenosis severity, eccentricity, and ulceration. A family of eight carotid-artery bifurcation models was examined using particle image velocimetry. Results showed a marked difference in turbulence intensity among these models; increasing degree of stenosis severity resulted in increased turbulence intensity, going from 0.12 m/s for mild stenosis to 0.37 m/s for severe stenosis (with concentric geometry). Moreover, independent of stenosis severity, eccentricity led to further elevations in turbulence intensity, increasing TI by 0.05-0.10 m/s over the counterpart concentric plaque. The presence of ulceration (in a 50% eccentric plaque) produced a larger portion of moderate turbulence intensity (~0.10 m/s) compared to the non-ulcerated model, more proximal to the bifurcation apex in the post-stenotic recirculation zone. The effect of plaque eccentricity and ulceration in enhancing the downstream turbulence has potential clinical implications for a more sensitive assessment of stroke risk beyond stenosis severity alone.

  6. Amyloid-β and Astrocytes Interplay in Amyloid-β Related Disorders.

    Science.gov (United States)

    Batarseh, Yazan S; Duong, Quoc-Viet; Mousa, Youssef M; Al Rihani, Sweilem B; Elfakhri, Khaled; Kaddoumi, Amal

    2016-01-01

    Amyloid-β (Aβ) pathology is known to promote chronic inflammatory responses in the brain. It was thought previously that Aβ is only associated with Alzheimer's disease and Down syndrome. However, studies have shown its involvement in many other neurological disorders. The role of astrocytes in handling the excess levels of Aβ has been highlighted in the literature. Astrocytes have a distinctive function in both neuronal support and protection, thus its involvement in Aβ pathological process may tip the balance toward chronic inflammation and neuronal death. In this review we describe the involvement of astrocytes in Aβ related disorders including Alzheimer's disease, Down syndrome, cerebral amyloid angiopathy, and frontotemporal dementia. PMID:26959008

  7. β-Secretase inhibitor increases amyloid-β precursor protein level in rat brain cortical primary neurons induced by okadaic acid

    Institute of Scientific and Technical Information of China (English)

    YU Chun-Jiang; WANG Wei-zhi; LIU Wei

    2008-01-01

    Background Senile plaques and neurofibrillary tangles (NFTs) represent two of the major histopathological hallmarks of Alzheimer's disease (AD). The plaques are primarily composed of aggregated amyloid β (Aβ) peptides. The processing of amyloid-β precursor protein (AβPP) in okadaic acid (OA)-induced tau phosphorylation primary neurons was studied.Methods Primary cultures of rat brain cortical neurons were treated with OA and β-secretase inhibitor. Neurons' viability was measured. AβPP processing was examined by immunocytochemistry and Western blotting with specific antibodies against the AβPP-N-terminus (NT) and AβPP-C-terminus (CT).Results Ten nrnol/L OA had a time-dependent suppression effect on primary neurons' viability. The suppression effect was alleviated markedly by pretreatment with β-secretase inhibitor. After OA treatment, both AβPP and β-C-terminal fragment (βCTF) were significantly increased in neurons. AβPP level was increased further in neurons pretreated with β-secretase inhibitor.Conclusions In OA-induced tau phosphorylation cell model, inhibition of β-secretase may protect neurons from death induced by OA. Because of increased accumulation of AβPP in neurons after OA treatment, more AβPP turns to be cleaved by β-secretase, producing neurotoxic βCTF. As a potential effective therapeutic target, β-secretase is worth investigating further.

  8. Individuality, stability, and variability of the plaque microbiome

    Directory of Open Access Journals (Sweden)

    Daniel R. Utter

    2016-04-01

    Full Text Available Dental plaque is a bacterial biofilm composed of a characteristic set of organisms. Relatively little information from cultivation-independent, high-throughput analyses has been published on the temporal dynamics of the dental plaque microbiome. We used Minimum Entropy Decomposition, an information theory-based approach similar to oligotyping that provides single-nucleotide resolution, to analyze a previously published time series data set and investigate the dynamics of the plaque microbiome at various analytic and taxonomic levels. At both the genus and 97% Operational Taxonomic Unit (OTU levels of resolution, the range of variation within each individual overlapped that of other individuals in the dataset. When analyzed at the oligotype level, however, the overlap largely disappeared, showing that single-nucleotide resolution enables differentiation of individuals from one another without ambiguity. The overwhelming majority of the plaque community in all samples was made up of bacteria from a moderate number of plaque-typical genera, indicating that the overall community framework is shared among individuals. Each of these genera fluctuated in abundance around a stable mean that varied between individuals, with some genera having higher inter-individual variability than others. Thus, at the genus level, differences between individuals lay not in the identity of the major genera but in consistently differing proportions of these genera from mouth to mouth. However, at the oligotype level, we detected oligotype fingerprints, a highly individual-specific set of persistently abundant oligotypes fluctuating around a stable mean over time. For example, within the genus Corynebacterium, more than a dozen oligotypes were detectable in each individual, of which a different subset reached high abundance in any given person. This pattern suggests that each mouth contains a subtly different community of organisms. We also compared the Chinese plaque

  9. Microglial responses to amyloid β peptide opsonization and indomethacin treatment

    Directory of Open Access Journals (Sweden)

    Leonard Brian

    2005-08-01

    Full Text Available Abstract Background Recent studies have suggested that passive or active immunization with anti-amyloid β peptide (Aβ antibodies may enhance microglial clearance of Aβ deposits from the brain. However, in a human clinical trial, several patients developed secondary inflammatory responses in brain that were sufficient to halt the study. Methods We have used an in vitro culture system to model the responses of microglia, derived from rapid autopsies of Alzheimer's disease patients, to Aβ deposits. Results Opsonization of the deposits with anti-Aβ IgG 6E10 enhanced microglial chemotaxis to and phagocytosis of Aβ, as well as exacerbated microglial secretion of the pro-inflammatory cytokines TNF-α and IL-6. Indomethacin, a common nonsteroidal anti-inflammatory drug (NSAID, had no effect on microglial chemotaxis or phagocytosis, but did significantly inhibit the enhanced production of IL-6 after Aβ opsonization. Conclusion These results are consistent with well known, differential NSAID actions on immune cell functions, and suggest that concurrent NSAID administration might serve as a useful adjunct to Aβ immunization, permitting unfettered clearance of Aβ while dampening secondary, inflammation-related adverse events.

  10. The Surprising Role of Amyloid Fibrils in HIV Infection.

    Science.gov (United States)

    Castellano, Laura M; Shorter, James

    2012-01-01

    Despite its discovery over 30 years ago, human immunodeficiency virus (HIV) continues to threaten public health worldwide. Semen is the principal vehicle for the transmission of this retrovirus and several endogenous peptides in semen, including fragments of prostatic acid phosphatase (PAP248-286 and PAP85-120) and semenogelins (SEM1 and SEM2), assemble into amyloid fibrils that promote HIV infection. For example, PAP248-286 fibrils, termed SEVI (Semen derived Enhancer of Viral Infection), potentiate HIV infection by up to 105-fold. Fibrils enhance infectivity by facilitating virion attachment and fusion to target cells, whereas soluble peptides have no effect. Importantly, the stimulatory effect is greatest at low viral titers, which mimics mucosal transmission of HIV, where relatively few virions traverse the mucosal barrier. Devising a method to rapidly reverse fibril formation (rather than simply inhibit it) would provide an innovative and urgently needed preventative strategy for reducing HIV infection via the sexual route. Targeting a host-encoded protein conformer represents a departure from traditional microbicidal approaches that target the viral machinery, and could synergize with direct antiviral approaches. Here, we review the identification of these amyloidogenic peptides, their mechanism of action, and various strategies for inhibiting their HIV-enhancing effects.

  11. Protein components in saliva and plaque fluid from irradiated primates

    Energy Technology Data Exchange (ETDEWEB)

    Edgar, W.M.; Bowen, W.H.; Cole, M.F. (Caries Prevention and Research Branch, National Caries Program, NIDR, Bethesda, Maryland, USA)

    1982-01-01

    Irradiation of the major salivary glands of monkeys (Macaca mulatta) fed cariogenic diets leads to caries clinically indistinguishable from radiation caries in man. This study compares the organic compostion of individual samples of plaque fluid and saliva from irradiated and control monkeys receiving the same cariogenic diet. Plaque and saliva were collected from fasting, tranquillised animals. Four irradiated animals were sampled repeatedly as were non-irradiated controls. Total protein, albumin, immunoglobulins A, G, and M, and the third component of complement (C'3) were quantitated in plaque fluid and whole saliva. Salivary amylase and peroxidase activities were also determined. Plaque fluid and saliva samples were also subjected to polyacrylamide gel electrophoresis. The total viable anaerobic count and numbers of Streptococcus mutans were determined in samples of plaque. The results suggest that the major effect of irradiation leading to increased numbers of S. mutans and caries susceptibility is in the amount, and not the composition, of the saliva produced by the residual gland tissue. The scanty flow of saliva may reduce the effectiveness of cleansing, buffering and lubrication mechanisms as well as resulting in a marked reduction in the total amount of specific and non-specific immune factors entering the mouth.

  12. Restriction of bacteriophage plaque formation in Streptomyces spp.

    Science.gov (United States)

    Cox, K L; Baltz, R H

    1984-08-01

    Several Streptomyces species that produce restriction endonucleases were characterized for their ability to propagate 10 different broad host range bacteriophages. Each species displayed a different pattern of plaque formation. A restrictionless mutant of S. albus G allowed plaque formation by all 10 phages, whereas the wild-type strain showed plaques with only 2 phages. DNA isolated from three of the phages was analyzed for the presence of restriction sites for Streptomyces species-encoded enzymes, and a very strong correlation was established between the failure to form plaques on Streptomyces species that produced particular restriction enzymes and the presence of the corresponding restriction sites in the phage DNA. Also, the phages that lacked restriction sites in their DNA generally formed plaques on the corresponding restriction endonuclease-producing hosts at high efficiency. The DNAs from the three phages analyzed also generally contained either many or no restriction sites for the Streptomyces species-produced enzymes, suggesting a strong evolutionary trend to either eliminate all or tolerate many restriction sites. The data indicate that restriction plays a major role in host range determination for Streptomyces phages. Analysis of bacteriophage host ranges of many other uncharacterized Streptomyces hosts has identified four relatively nonrestricting hosts, at least two of which may be suitable hosts for gene cloning. The data also suggest that several restriction systems remain to be identified in the genus Streptomyces.

  13. Clinical Study of Acoustic Densitometry Technique in Detecting Atherosclerotic Plaque

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    Objective: To investigate the effect of Quyu Xiaoban Capsule (祛瘀消斑, QYXB) on the regressive treatment of atherosclerosis (AS) with acoustic densitometry (AD) technique. Methods: Eighty patients with AS were randomly divided into two groups, trial group was treated with QYXB and conventional medicine, and control group was treated with conventional medicine alone. Normal arterial wall and different types of atherosclerotic plaques were detected with AD technique before treatment and 10 months later. Resuits: The corrected averages in intimal echo intensity (AIIc%) were elevated in both groups but without significant difference, AIIc% of fatty plaques were increased in both groups and the value after treatment was significantly higher than that of pre-treatment in the trial group (68.12±5.54 vs 61.43±5.37, P<0.05).The increment rate of AIIc% in trial group was significantly higher than that in control group (10.9±5.1% vs2.5±5.5%, P<0.05). Conclusion: QYXB can stabilize the atherosclerotic plaque by increasing its acoustic density. Acoustic densitometry technique can differentiate the different histological plaques and monitor the histological changes of plaques during treatment.

  14. Protein components in saliva and plaque fluid from irradiated primates

    International Nuclear Information System (INIS)

    Irradiation of the major salivary glands of monkeys (Macaca mulatta) fed cariogenic diets leads to caries clinically indistinguishable from radiation caries in man. This study compares the organic compostion of individual samples of plaque fluid and saliva from irradiated and control monkeys receiving the same cariogenic diet. Plaque and saliva were collected from fasting, tranquillised animals. Four irradiated animals were sampled repeatedly as were non-irradiated controls. Total protein, albumin, immunoglobulins A, G, and M, and the third component of complement (C'3) were quantitated in plaque fluid and whole saliva. Salivary amylase and peroxidase activities were also determined. Plaque fluid and saliva samples were also subjected to polyacrylamide gel electrophoresis. The total viable anaerobic count and numbers of Streptococcus mutans were determined in samples of plaque. The results suggest that the major effect of irradiation leading to increased numbers of S. mutans and caries susceptibility is in the amount, and not the composition, of the saliva produced by the residual gland tissue. The scanty flow of saliva may reduce the effectiveness of cleansing, buffering and lubrication mechanisms as well as resulting in a marked reduction in the total amount of specific and non-specific immune factors entering the mouth. (author)

  15. Low Copper and High Manganese Levels in Prion Protein Plaques

    Directory of Open Access Journals (Sweden)

    Debbie McKenzie

    2013-02-01

    Full Text Available Accumulation of aggregates rich in an abnormally folded form of the prion protein characterize the neurodegeneration caused by transmissible spongiform encephalopathies (TSEs. The molecular triggers of plaque formation and neurodegeneration remain unknown, but analyses of TSE-infected brain homogenates and preparations enriched for abnormal prion protein suggest that reduced levels of copper and increased levels of manganese are associated with disease. The objectives of this study were to: (1 assess copper and manganese levels in healthy and TSE-infected Syrian hamster brain homogenates; (2 determine if the distribution of these metals can be mapped in TSE-infected brain tissue using X-ray photoelectron emission microscopy (X-PEEM with synchrotron radiation; and (3 use X-PEEM to assess the relative amounts of copper and manganese in prion plaques in situ. In agreement with studies of other TSEs and species, we found reduced brain levels of copper and increased levels of manganese associated with disease in our hamster model. We also found that the in situ levels of these metals in brainstem were sufficient to image by X-PEEM. Using immunolabeled prion plaques in directly adjacent tissue sections to identify regions to image by X-PEEM, we found a statistically significant relationship of copper-manganese dysregulation in prion plaques: copper was depleted whereas manganese was enriched. These data provide evidence for prion plaques altering local transition metal distribution in the TSE-infected central nervous system.

  16. Low copper and high manganese levels in prion protein plaques.

    Science.gov (United States)

    Johnson, Christopher J; Gilbert, P U P A; Abrecht, Mike; Baldwin, Katherine L; Russell, Robin E; Pedersen, Joel A; Aiken, Judd M; McKenzie, Debbie

    2013-02-01

    Accumulation of aggregates rich in an abnormally folded form of the prion protein characterize the neurodegeneration caused by transmissible spongiform encephalopathies (TSEs). The molecular triggers of plaque formation and neurodegeneration remain unknown, but analyses of TSE-infected brain homogenates and preparations enriched for abnormal prion protein suggest that reduced levels of copper and increased levels of manganese are associated with disease. The objectives of this study were to: (1) assess copper and manganese levels in healthy and TSE-infected Syrian hamster brain homogenates; (2) determine if the distribution of these metals can be mapped in TSE-infected brain tissue using X-ray photoelectron emission microscopy (X-PEEM) with synchrotron radiation; and (3) use X-PEEM to assess the relative amounts of copper and manganese in prion plaques in situ. In agreement with studies of other TSEs and species, we found reduced brain levels of copper and increased levels of manganese associated with disease in our hamster model. We also found that the in situ levels of these metals in brainstem were sufficient to image by X-PEEM. Using immunolabeled prion plaques in directly adjacent tissue sections to identify regions to image by X-PEEM, we found a statistically significant relationship of copper-manganese dysregulation in prion plaques: copper was depleted whereas manganese was enriched. These data provide evidence for prion plaques altering local transition metal distribution in the TSE-infected central nervous system.

  17. The effect of chewing gum on dental plaque accumulation

    Directory of Open Access Journals (Sweden)

    Karami Nogourani M

    2010-06-01

    Full Text Available "nBackground and Aims: Studies show that sucrose containing chewing gums are cariogenic. The aim of this study was to evaluate the effect of two commercial chewing gums with and without sucrose on dental plaque accumulation compared with the control group. "nMaterials and Methods: In this clinical study, plaque accumulation during three 7-day periods (with two weeks interval was recorded (Sillness & Loe Index in a group of 23 volunteer male dental students who chewed in the first two periods sugar-free or sugar-containing chewing gums (Olips and Orbit, respectively and in the last period did not chew any gum. Participants were asked to chew daily five gum sticks after meals for about twenty minutes. The data were statistically analyzed using Repeated Measure ANOVA and paired-T test. "nResults: The results showed that chewing any gum even sucrose-containing gum decreased the level of dental plaque accumulation (P<0.001. However, the decreasing effect of sugar-free gums was significantly higher (P<0.001. "nConclusion: Although sugar free gum was more effective than sugar containing gum on reducing dental plaque accumulation, chewing even sugar containing gums could decrease the level of dental plaque.

  18. Low copper and high manganese levels in prion protein plaques

    Science.gov (United States)

    Johnson, Christopher J.; Gilbert, P.U.P.A.; Abrecth, Mike; Baldwin, Katherine L.; Russell, Robin E.; Pedersen, Joel A.; McKenzie, Debbie

    2013-01-01

    Accumulation of aggregates rich in an abnormally folded form of the prion protein characterize the neurodegeneration caused by transmissible spongiform encephalopathies (TSEs). The molecular triggers of plaque formation and neurodegeneration remain unknown, but analyses of TSE-infected brain homogenates and preparations enriched for abnormal prion protein suggest that reduced levels of copper and increased levels of manganese are associated with disease. The objectives of this study were to: (1) assess copper and manganese levels in healthy and TSE-infected Syrian hamster brain homogenates; (2) determine if the distribution of these metals can be mapped in TSE-infected brain tissue using X-ray photoelectron emission microscopy (X-PEEM) with synchrotron radiation; and (3) use X-PEEM to assess the relative amounts of copper and manganese in prion plaques in situ. In agreement with studies of other TSEs and species, we found reduced brain levels of copper and increased levels of manganese associated with disease in our hamster model. We also found that the in situ levels of these metals in brainstem were sufficient to image by X-PEEM. Using immunolabeled prion plaques in directly adjacent tissue sections to identify regions to image by X-PEEM, we found a statistically significant relationship of copper-manganese dysregulation in prion plaques: copper was depleted whereas manganese was enriched. These data provide evidence for prion plaques altering local transition metal distribution in the TSE-infected central nervous system.

  19. Infliximab in the treatment of plaque type psoriasis

    Directory of Open Access Journals (Sweden)

    Rosita Saraceno

    2009-04-01

    Full Text Available Rosita Saraceno, Andrea Saggini, Lucia Pietroleonardo, Sergio ChimentiDepartment of Dermatology, University of Rome Tor Vergata, Rome, Viale Oxford 81, Rome, ItalyAbstract: Psoriasis is a chronic and immunomediated skin disease characterized by erythematous scaly plaques. Psoriasis affects approximately 1% to 3% of the Caucasian population. Tumor necrosis factor alpha (TNF-α is a proinflammatory cytokine that plays a critical role in the pathogenesis of psoriasis. Infliximab is an anti-TNF-α drug widely used for the treatment of plaque type psoriasis and psoriatic arthritis. Controlled clinical trials demonstrated that infliximab is characterized by a high degree of clinical response in moderate to severe plaque psoriasis. Moreover infliximab showed rapid efficacy in nail psoriasis which represents a therapeutic challenge for dermatologists and a relevant source of distress for patients with plaque psoriasis. This anti-TNF-α has an encouraging safety profile, especially as long as physicians are watchful in prevention and early diagnosis of infections and infuse reactions. The efficacy, tolerability and safety profiles suggest infliximab as a suitable anti-psoriatic drug in the long-term treatment of a chronic disease such as plaque-type psoriasis.Keywords: psoriasis, nail psoriasis, infliximab, long-term treatment

  20. Microglial Amyloid-β1-40 Phagocytosis Dysfunction Is Caused by High-Mobility Group Box Protein-1: Implications for the Pathological Progression of Alzheimer’s Disease

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    Kazuyuki Takata

    2012-01-01

    Full Text Available In Alzheimer disease (AD patient brains, the accumulation of amyloid-β (Aβ peptides is associated with activated microglia. Aβ is derived from the amyloid precursor protein; two major forms of Aβ, that is, Aβ1-40 (Aβ40 and Aβ1-42 (Aβ42, exist. We previously reported that rat microglia phagocytose Aβ42, and high mobility group box protein 1 (HMGB1, a chromosomal protein, inhibits phagocytosis. In the present study, we investigated the effects of exogenous HMGB1 on rat microglial Aβ40 phagocytosis. In the presence of exogenous HMGB1, Aβ40 markedly increased in microglial cytoplasm, and the reduction of extracellular Aβ40 was inhibited. During this period, HMGB1 was colocalized with Aβ40 in the cytoplasm. Furthermore, exogenous HMGB1 inhibited the degradation of Aβ40 induced by the rat microglial cytosolic fraction. Thus, extracellular HMGB1 may internalize with Aβ40 in the microglial cytoplasm and inhibit Aβ40 degradation by microglia. This may subsequently delay Aβ40 clearance. We further confirmed that in AD brains, the parts of senile plaques surrounded by activated microglia are composed of Aβ40, and extracellular HMGB1 is deposited on these plaques. Taken together, microglial Aβ phagocytosis dysfunction may be caused by HMGB1 that accumulates extracellularly on Aβ plaques, and it may be critically involved in the pathological progression of AD.

  1. Mechanisms of U87 astrocytoma cell uptake and trafficking of monomeric versus protofibril Alzheimer's disease amyloid-β proteins.

    Directory of Open Access Journals (Sweden)

    Yali Li

    Full Text Available A significant hallmark of Alzheimer's disease is the formation of senile plaques in the brain due to the unbalanced levels of amyloid-beta (Aβ. However, although how Aβ is produced from amyloid precursor proteins is well understood, little is known regarding the clearance and metabolism of various Aβ aggregates from the brain. Similarly, little is known regarding how astrocytes internalize and degrade Aβ, although astrocytes are known to play an important role in plaque maintenance and Aβ clearance. The objective of this study is to investigate the cellular mechanisms that mediate the internalization of soluble monomeric versus oligomeric Aβ by astrocytes. We used a combination of laser confocal microscopy and genetic and pharmacological experiments to dissect the internalization of sAβ42 and oAβ42 and their postendocytic transport by U87 human brain astrocytoma cell line. Both Aβ42 species were internalized by U87 cells through fluid phase macropinocytosis, which required dynamin 2. Depleting LDL receptor-related protein 1 (LRP1 decreased sAβ42 uptake more significantly than that of oAβ42. We finally show that both Aβ42 species were rapidly transported to lysosomes through an endolytic pathway and subjected to proteolysis after internalization, which had no significant toxic effects to the U87 cells under relatively low concentrations. We propose that macropinocytic sAβ42 and oAβ42 uptake and their subsequent proteolytic degradation in astroglial cells is a significant mechanism underlying Aβ clearance from the extracellular milieu. Understanding the molecular events involved in astrocytic Aβ internalization may identify potential therapeutic targets for Alzheimer's disease.

  2. In vivo labelling of hippocampal beta-amyloid in triple-transgenic mice with a fluorescent acetylcholinesterase inhibitor released from nanoparticles.

    Science.gov (United States)

    Härtig, Wolfgang; Kacza, Johannes; Paulke, Bernd-Reiner; Grosche, Jens; Bauer, Ute; Hoffmann, Anke; Elsinghorst, Paul W; Gütschow, Michael

    2010-01-01

    The drastic loss of cholinergic projection neurons in the basal forebrain is a hallmark of Alzheimer's disease (AD), and drugs most frequently applied for the treatment of dementia include inhibitors of the acetylcholine-degrading enzyme acetylcholinesterase (AChE). This protein is known to act as a ligand of beta-amyloid (Abeta) in senile plaques, a further neuropathological sign of AD. Recently, we have shown that the fluorescent, heterodimeric AChE inhibitor PE154 allows for the histochemical staining of cortical Abeta plaques in triple-transgenic (TTG) mice with age-dependent beta-amyloidosis and tau hyperphosphorylation, an established animal model for aspects of AD. In the present study, we have primarily demonstrated the targeting of Abeta-immunopositive plaques with PE154 in vivo for 4 h up to 1 week after injection into the hippocampi of 13-20-month-old TTG mice. Numerous plaques, double-stained for PE154 and Abeta-immunoreactivity, were revealed by confocal laser-scanning microscopy. Additionally, PE154 targeted hippocampal Abeta deposits in aged TTG mice after injection of carboxylated polyglycidylmethacrylate nanoparticles delivering the fluorescent marker in vivo. Furthermore, biodegradable core-shell polystyrene/polybutylcyanoacrylate nanoparticles were found to be suitable, alternative vehicles for PE154 as a useful in vivo label of Abeta. Moreover, we were able to demonstrate that PE154 targeted Abeta, but neither phospho-tau nor reactive astrocytes surrounding the plaques. In conclusion, nanoparticles appear as versatile carriers of AChE inhibitors and other promising drugs for the treatment of AD.

  3. Zooming in on the genesis of atherosclerotic plaque microcalcifications.

    Science.gov (United States)

    Ruiz, Jessica L; Weinbaum, Sheldon; Aikawa, Elena; Hutcheson, Joshua D

    2016-06-01

    Epidemiological evidence conclusively demonstrates that calcium burden is a significant predictor of cardiovascular morbidity and mortality; however, the underlying mechanisms remain largely unknown. These observations have challenged the previously held notion that calcification serves to stabilize the atherosclerotic plaque. Recent studies have shown that microcalcifications that form within the fibrous cap of the plaques lead to the accrual of plaque-destabilizing mechanical stress. Given the association between calcification morphology and cardiovascular outcomes, it is important to understand the mechanisms leading to calcific mineral deposition and growth from the earliest stages. We highlight the open questions in the field of cardiovascular calcification and include a review of the proposed mechanisms involved in extracellular vesicle-mediated mineral deposition. PMID:27040360

  4. Radiation regression patterns after cobalt plaque insertion for retinoblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Buys, R.J.; Abramson, D.H.; Ellsworth, R.M.; Haik, B.

    1983-08-01

    An analysis of 31 eyes of 30 patients who had been treated with cobalt plaques for retinoblastoma disclosed that a type I radiation regression pattern developed in 15 patients; type II, in one patient, and type III, in five patients. Nine patients had a regression pattern characterized by complete destruction of the tumor, the surrounding choroid, and all of the vessels in the area into which the plaque was inserted. This resulting white scar, corresponding to the sclerae only, was classified as a type IV radiation regression pattern. There was no evidence of tumor recurrence in patients with type IV regression patterns, with an average follow-up of 6.5 years, after receiving cobalt plaque therapy. Twenty-nine of these 30 patients had been unsuccessfully treated with at least one other modality (ie, light coagulation, cryotherapy, external beam radiation, or chemotherapy).

  5. Radiation regression patterns after cobalt plaque insertion for retinoblastoma

    International Nuclear Information System (INIS)

    An analysis of 31 eyes of 30 patients who had been treated with cobalt plaques for retinoblastoma disclosed that a type I radiation regression pattern developed in 15 patients; type II, in one patient, and type III, in five patients. Nine patients had a regression pattern characterized by complete destruction of the tumor, the surrounding choroid, and all of the vessels in the area into which the plaque was inserted. This resulting white scar, corresponding to the sclerae only, was classified as a type IV radiation regression pattern. There was no evidence of tumor recurrence in patients with type IV regression patterns, with an average follow-up of 6.5 years, after receiving cobalt plaque therapy. Twenty-nine of these 30 patients had been unsuccessfully treated with at least one other modality (ie, light coagulation, cryotherapy, external beam radiation, or chemotherapy)