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Sample records for cerebral amyloid angiopathy

  1. Pathogenesis of cerebral amyloid angiopathy.

    NARCIS (Netherlands)

    Rensink, A.A.M.; Waal, R.M.W. de; Kremer, H.P.H.; Verbeek, M.M.

    2003-01-01

    Cerebral amyloid angiopathy (CAA) is the result of the deposition of an amyloidogenic protein in cortical and leptomeningeal vessels. The most common type of CAA is caused by amyloid beta-protein (Abeta), which is particularly associated with Alzheimer's disease (AD). Excessive Abeta-CAA formation c

  2. Cerebral amyloid angiopathy

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    ... needed for weakness or clumsiness. This can include physical, occupational, or speech therapy. Sometimes, medicines that help improve memory, such as those for Alzheimer disease, are used. Seizures, also called amyloid spells, may ...

  3. Structural network alterations and neurological dysfunction in cerebral amyloid angiopathy

    NARCIS (Netherlands)

    Reijmer, Yael D.; Fotiadis, Panagiotis; Martinez-Ramirez, Sergi; Salat, David H.; Schultz, Aaron; Shoamanesh, Ashkan; Ayres, Alison M.; Vashkevich, Anastasia; Rosas, Diana; Schwab, Kristin; Leemans, Alexander; Biessels, Geert Jan; Rosand, Jonathan; Johnson, Keith A.; Viswanathan, Anand; Gurol, M. Edip; Greenberg, Steven M.

    2015-01-01

    Cerebral amyloid angiopathy is a common form of small-vessel disease and an important risk factor for cognitive impairment. The mechanisms linking small-vessel disease to cognitive impairment are not well understood. We hypothesized that in patients with cerebral amyloid angiopathy, multiple small s

  4. Outcome markers for clinical trials in cerebral amyloid angiopathy

    NARCIS (Netherlands)

    S.M. Greenberg (Steven); R.A.S. Salman (Rustam Al-Shahi); G.J. Biessels (Geert Jan); M.A. van Buchem (Mark); C. Cordonnier (Charlotte); J.-M. Lee (Jin-Moo); J. Montaner (Joan); J.A. Schneider (Julie); E.E. Smith (Eric); M.W. Vernooij (Meike); D.J. Werring (David)

    2014-01-01

    textabstractEfforts are underway for early-phase trials of candidate treatments for cerebral amyloid angiopathy, an untreatable cause of haemorrhagic stroke and vascular cognitive impairment. A major barrier to these trials is the absence of consensus on measurement of treatment effectiveness. A ran

  5. Structural network alterations and neurological dysfunction in cerebral amyloid angiopathy

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    Reijmer, Yael D.; Fotiadis, Panagiotis; Martinez-Ramirez, Sergi; Salat, David H.; Schultz, Aaron; Shoamanesh, Ashkan; Ayres, Alison M.; Vashkevich, Anastasia; Rosas, Diana; Schwab, Kristin; Leemans, Alexander; Biessels, Geert-Jan; Rosand, Jonathan; Johnson, Keith A.; Viswanathan, Anand; Gurol, M. Edip

    2015-01-01

    Cerebral amyloid angiopathy is a common form of small-vessel disease and an important risk factor for cognitive impairment. The mechanisms linking small-vessel disease to cognitive impairment are not well understood. We hypothesized that in patients with cerebral amyloid angiopathy, multiple small spatially distributed lesions affect cognition through disruption of brain connectivity. We therefore compared the structural brain network in patients with cerebral amyloid angiopathy to healthy control subjects and examined the relationship between markers of cerebral amyloid angiopathy-related brain injury, network efficiency, and potential clinical consequences. Structural brain networks were reconstructed from diffusion-weighted magnetic resonance imaging in 38 non-demented patients with probable cerebral amyloid angiopathy (69 ± 10 years) and 29 similar aged control participants. The efficiency of the brain network was characterized using graph theory and brain amyloid deposition was quantified by Pittsburgh compound B retention on positron emission tomography imaging. Global efficiency of the brain network was reduced in patients compared to controls (0.187 ± 0.018 and 0.201 ± 0.015, respectively, P < 0.001). Network disturbances were most pronounced in the occipital, parietal, and posterior temporal lobes. Among patients, lower global network efficiency was related to higher cortical amyloid load (r = −0.52; P = 0.004), and to magnetic resonance imaging markers of small-vessel disease including increased white matter hyperintensity volume (P < 0.001), lower total brain volume (P = 0.02), and number of microbleeds (trend P = 0.06). Lower global network efficiency was also related to worse performance on tests of processing speed (r = 0.58, P < 0.001), executive functioning (r = 0.54, P = 0.001), gait velocity (r = 0.41, P = 0.02), but not memory. Correlations with cognition were independent of age, sex, education level, and other magnetic resonance imaging

  6. Recurrent craniospinal subarachnoid hemorrhage in cerebral amyloid angiopathy

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    Mathew Alexander

    2013-01-01

    Full Text Available Cerebral amyloid angiopathy (CAA usually manifests as cerebral hemorrhage, especially as nontraumatic hemorrhages in normotensive elderly patients. Other manifestations are subarachnoid (SAH, subdural, intraventricular hemorrhage (IVH and superficial hemosiderosis. A 52-year-old hypertensive woman presented with recurrent neurological deficits over a period of 2 years. Her serial brain magnetic resonance imaging and computed tomography scans showed recurrent SAH hemorrhage, and also intracerebral, IVH and spinal hemorrhage, with superficial siderosis. Cerebral angiograms were normal. Right frontal lobe biopsy showed features of CAA. CAA can present with unexplained recurrent SAH hemorrhage, and may be the initial and prominent finding in the course of disease in addition to superficial cortical siderosis and intracerebal and spinal hemorrhages.

  7. Cerebrospinal Fluid Biomarkers in Dementia Patients with Cerebral Amyloid Angiopathy

    Institute of Scientific and Technical Information of China (English)

    Yan-feng Li; Fang-fang Ge; Yong Zhang; Hui You; Zhen-xin Zhang

    2015-01-01

    Objective To study the changes of biomarkers in cerebrospinal fluid (CSF) in cerebral amyloid angiopathy (CAA) dementia and Alzheimer's disease. Methods Levels of amyloid proteinβ (Aβ42, Aβ40) and phosphorylated Tau-protein (P-tau) in CSF and ratio of Aβ42/Aβ40 were tested in 5 cases with CAA dementia and 20 cases with Alzheimer's disease collected at Peking Union Medical College Hospital from December 2001 to March 2011. Results The levels of Aβ42, Aβ40, and P-tau in CSF and ratio of Aβ42/Aβ40 were (660.4±265.2) ng/L, (7111.0±1033.4) ng/L, (71.8±51.5) ng/L, and 0.077±0.033, respectively in CAA dementia and (663.6±365.6) ng/L, (5115.0±2931.1) ng/L, (47.7±38.8) ng/L, and 0.192±0.140, respectively in Alzheimer's disease patients. There were no statistically significant differences between CAA dementia and Alzheimer's disease in terms of these CSF biomarkers (allP>0.05). Conclusion Measurements of CSF biomarkers may not be helpful in differential diagnosis of CAA and Alzheimer's disease.

  8. Arterioles in cerebral amyloid angiopathy and vascular dementia

    Institute of Scientific and Technical Information of China (English)

    ZHU Guang-ming; ZHANG Wei-wei; LIU Ying; LI Juan

    2009-01-01

    Background Small cerebrovascular lesions are one of the most important factors in cerebral amyloid angiopathy (CM) and vascular dementia (VaD). We analyzed the difference of arteriolar pathology between CM patients (CMs) and vascular dementia patients without CAA (VaDs).Methods Ten deceased CMs and twelve deceased VaDs were available for this study. Five deceased patients without known cerebrovascular diseases served as controls. These patients were all autopsy cases. All transversely cut arterioles in the gray matter and white matter with an external diameter equal to or larger than 30 μm and with a maximum of 300 μm were examined. The internal and external diameters of arterioles were measured. Results The external diameter of gray matter arterioles in the CAAs was significantly greater than in controls. In gray matter arterioles, the diameter of the lumen in VaDs was markedly smaller than in the CAAs, whereas there was no significant difference between CAAs and controls. CMs and VaDs may cause remarkable thickening of the arteriolar walls in either white matter or gray matter. The sclerotic index of arterioles in VaDs was significantly greater than in CAAs and controls. Conclusions Stenosis of arterioles occurred in both CM and VaD, but the tendency was greater in VaD. Arterioles of CM were also expanded in gray matter, which may be related to lobar hemorrhage. The loss and/or degeneration of vascular smooth muscle cells was predominant in CM, while the over-proliferation of vascular smooth muscle cells was greater in VaD.

  9. Severe pathological manifestation of cerebral amyloid angiopathy correlates with poor outcome from cerebral amyloid angiopathy related intracranial hemorrhage

    Institute of Scientific and Technical Information of China (English)

    TANG Ya-juan; WANG Shuo; ZHU Ming-wei; SUN Yi-lin; ZHAO Ji-zong

    2013-01-01

    Background Cerebral amyloid angiopathy (CAA) is one of the main causes of spontaneous intracranial hemorrhage (ICH).No established link is available between pathological scores of CAA and its outcome.This study aimed to identify the correlations between pathological severity and poor postoperative outcome in the Chinese population.Methods Between May 2006 and April 2011,367 consecutive patients who underwent surgery for CAA-related ICH in 71 hospitals throughout the mainland of China were enrolled in this study.Twelve months after surgery,we evaluated these patients' outcomes according to the modified Rankin Scale (mRS) and statistically correlated risk factors (demographics,medical history,pathological results,and surgical details) that are associated with a favorable (mRS <3)and poor (mRS >3) outcome groups.Results Risk factors for poor postoperative outcome in 367 patients with CAA-related ICH included advanced age (OR 1.034,95% Cl 1.001-1.067,P=-0.042),CAA pathology severity (OR 2.074,95% CI 7.140-16.25,P <0.001),lobar hematoma (OR 0.225,95% Cl 0.104-0.486,P <0.001),presence of intraventricular hemorrhage (OR 0.478,95% CI 0.229-1.001,P=-0.050),and/or subarachnoid hemorrhage (OR 2.629,95% CI,1.051-6.577,P=-0.039).Conclusions Poor postoperative outcome of patients with CAA-related ICH was more related to the severe pathological manifestation instead of other factors.Prior ischemia may present an early stage of CAA.

  10. Multiple intracranial hemorrhages in a normotensive demented patient: A probable cerebral amyloid angiopathy.

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    Chitsaz, Ahmad; Norouzi, Rasul; Marashi, Seyed Mohammad Javad; Salimianfard, Marzieh; Fard, Salman Abbasi

    2012-01-01

    Cerebral amyloid angiopathy (CAA) is the most common cause of lobar intracerebral hemorrhage. Repeated bleeding may be presented with vascular dementia. We have reported a 68-year-old normotensive demented patient with probable CAA presented with hemiparesia, headache and vomiting. According to the experience of this case, it is recommended to consider CAA for normotensive elderly patients presented with multiple and superficial intracerebral hemorrhage.

  11. Predicting sites of new hemorrhage with amyloid imaging in cerebral amyloid angiopathy

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    Dierksen, Gregory; Betensky, Rebecca; Gidicsin, Christopher; Halpin, Amy; Becker, Alex; Carmasin, Jeremy; Ayres, Alison; Schwab, Kristin; Viswanathan, Anand; Salat, David; Rosand, Jonathan; Johnson, Keith A.; Greenberg, Steven M.

    2012-01-01

    Objective: We aimed to determine whether amyloid imaging can help predict the location and number of future hemorrhages in cerebral amyloid angiopathy (CAA). Methods: We performed a longitudinal cohort study of 11 patients with CAA without dementia who underwent serial brain MRIs after baseline amyloid imaging with Pittsburgh compound B (PiB). Mean distribution volume ratio (DVR) of PiB was determined at the sites of new micro/macrobleeds identified on follow-up MRI and compared with PiB retention at “simulated” hemorrhages, randomly placed in the same subjects using a probability distribution map of CAA-hemorrhage location. Mean PiB retention at the sites of observed new bleeds was also compared to that in shells concentrically surrounding the bleeds. Finally the association between number of incident bleeds and 3 regional amyloid measures were obtained. Results: Nine of 11 subjects had at least one new microbleed on follow-up MRI (median 4, interquartile range [IQR] 1–9) and 2 had 5 new intracerebral hemorrhages. Mean DVR was greater at the sites of incident bleeds (1.34, 95% confidence interval [CI] 1.23–1.46) than simulated lesions (1.14, 95% CI 1.07–1.22, p < 0.0001) in multivariable models. PiB retention decreased with increasing distance from sites of observed bleeds (p < 0.0001). Mean DVR in a superior frontal/parasagittal region of interest correlated independently with number of future hemorrhages after adjustment for relevant covariates (p = 0.003). Conclusions: Our results provide direct evidence that new CAA-related hemorrhages occur preferentially at sites of increased amyloid deposition and suggest that PiB-PET imaging may be a useful tool in prediction of incident hemorrhages in patients with CAA. PMID:22786597

  12. Clinical and pathological study on 10 cases of cerebral lobe hemorrhage related with cerebral amyloid angiopathy

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    Xiao-qi LI

    2015-07-01

    Full Text Available Objective To summarize the clinical data and pathological features of 10 cases of cerebral lobar hemorrhage related with cerebral amyloid angiopathy (CAA diagnosed pathologically, thereby to improve the knowledge and diagnosis of the disease. Methods The clinical data of 10 cases of cerebral lobar hemorrhage related with CAA, collected in the General Hospital of Shenyang Command from 1983 up to now, were retrospectively analyzed, and the clinical and neuropathological features of these cases were summarized. Results Of the 10 patients, 2 suffered from single lobar hemorrhage and 8 multiple lobar hemorrhage, all of them were confirmed pathologically to have ruptured into the subarachnoid space. Pathological examination revealed microaneurysm in 2 cases, "double barrel" change in 4 cases, multiple arteriolar clusters in 5 cases, obliterative onion-liked intima change in 4 cases, and fibrinoid necrosis of vessel wall in 7 cases. In addition, neurofibrillary tangles were found in 8 cases, and senile plaque was observed in 5 cases. Conclusions Cerebral lobar hemorrhage related with CAA is mainly located in the parietal, temporal and occipital lobes, readily breaking into the subarachnoid space, and it is often multiple and recurrent. The CAA associated microvasculopathy was found frequently in the autopsy sample of CAA related cerebral lobar hemorrhage, and it may contribute to the pathogenesis of cerebral hemorrhage. DOI: 10.11855/j.issn.0577-7402.2015.07.04

  13. Failure of perivascular drainage of β-amyloid in cerebral amyloid angiopathy.

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    Hawkes, Cheryl A; Jayakody, Nimeshi; Johnston, David A; Bechmann, Ingo; Carare, Roxana O

    2014-07-01

    In Alzheimer's disease, amyloid-β (Aβ) accumulates as insoluble plaques in the brain and deposits in blood vessel walls as cerebral amyloid angiopathy (CAA). The severity of CAA correlates with the degree of cognitive decline in dementia. The distribution of Aβ in the walls of capillaries and arteries in CAA suggests that Aβ is deposited in the perivascular pathways by which interstitial fluid drains from the brain. Soluble Aβ from the extracellular spaces of gray matter enters the basement membranes of capillaries and drains along the arterial basement membranes that surround smooth muscle cells toward the leptomeningeal arteries. The motive force for perivascular drainage is derived from arterial pulsations combined with the valve effect of proteins present in the arterial basement membranes. Physical and biochemical changes associated with arteriosclerosis, aging and possession of apolipoprotein E4 genotype lead to a failure of perivascular drainage of soluble proteins, including Aβ. Perivascular cells associated with arteries and the lymphocytes recruited in the perivenous spaces contribute to the clearance of Aβ. The failure of perivascular clearance of Aβ may be a major factor in the accumulation of Aβ in CAA and may have significant implications for the design of therapeutics for the treatment of Alzheimer's disease.

  14. Cerebral amyloid angiopathy presenting as a posterior leukoencephalopathy: A case report and review of the literature

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    Maramattom Boby Varkey

    2004-10-01

    Full Text Available Cerebral amyloid angiopathy (CAA is well known to present with lobar intracerebral hemorrhage, dementia or transient neurological events. White matter changes with CAA have only been recently described and can be seen with either sporadic or familial CAA. We present a 50-year-old man with rapidly progressive dementia in whom MRI brain showed symmetrical white matter changes in the parieto-occipital regions. Brain biopsy revealed changes of CAA along with features of Alzheimer′s disease. Immunohistochemistry revealed amyloid beta protein. The subcortical lesions were thought to occur from hypoperfusion of the distal white matter. The role of amyloid in the pathogenesis of CAA and the mechanism of leukoencephalopathy are discussed.

  15. Visualization of microhemorrhages with optical histology in mouse model of cerebral amyloid angiopathy (Conference Presentation)

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    Lo, Patrick; Crouzet, Christian; Vasilevko, Vitaly; Choi, Bernard

    2016-03-01

    Cerebral amyloid angiopathy (CAA) is a neurovascular disease that is strongly associated with an increase in the number and size of spontaneous microhemorrhages. Conventional methods, such as magnetic resonance imaging (MRI), can detect microhemorrhages while positron emission tomography (PET) with Pittsburgh Compound B can detect amyloid deposits. MRI and PET can separately demonstrate the presence of microhemorrhages and CAA in affected brains in vivo; however, there is still a lack of strong evidence for the direct involvement of CAA in the presence of microhemorrhage formation. In this study, we use optical histology, a method which combines histochemical staining, chemical optical clearing, and optical imaging, in a Tg2576 mouse model of Alzheimer's disease to enable simultaneous, co-registered three-dimensional visualization of cerebral microvasculature, microhemorrhages, and amyloid deposits. Our data strongly suggest that microhemorrhages are localized within the brain regions affected by amyloid deposits. All but two observed microhemorrhages (n=18) were closely localized with vessels affected by CAA whereas no microhemorrhages or amyloid deposits were observed in wild type mouse brain sections. Our data also suggest that the predominant type of CAA-related microhemorrhage is associated with leaky or ruptured hemorrhagic microvasculature within the hippocampus and cerebral cortex rather than occluded ischemic microvasculature. The proposed optical histology method will allow future studies about the relationship between CAA and microhemorrhages during disease development and in response to treatment strategies.

  16. Cerebral Amyloid Angiopathy Burden Associated with Leukoaraiosis:a PET/MRI Study

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    Gurol, M. Edip; Viswanathan, Anand; Gidicsin, Christopher; Hedden, Trey; Ramirez-Martinez, Sergi; Dumas, Andrew; Vashkevich, Anastasia; Ayres, Alison M.; Auriel, Eitan; van Etten, Ellis; Becker, Alex; Carmasin, Jeremy; Schwab, Kristin; Rosand, Jonathan; Johnson, Keith A.; Greenberg, Steven M.

    2013-01-01

    Objective We hypothesized that vascular amyloid contributes to chronic brain ischemia, therefore amyloid burden measured by Pittsburgh Compound B retention on PET (PiB-PET) would correlate with the extent of MRI white matter hyperintensities (WMHor leukoaraiosis) in patients with high vascular amyloid deposition (Cerebral Amyloid Angiopathy, CAA) but not high parenchymal amyloid deposition (Alzheimer’s Disease, AD; Mild Cognitive Impairment, MCI) or healthy elderly (HE). Methods Fourty-two non-demented CAA patients, 50 HE subjects and 43 AD/MCI patients had brain MRI and PiB-PET. Multivariate linear regression was used to assess the independent association between PiB retention and WMD volume controlling for age, gender, apolipoprotein E genotype, and vascular risk factors within each group. Results CAA patients were younger than HE and AD (68±10 vs 73.3±7 and 74±7.4, p<0.01) but had higher amounts of WMH (medians: 21ml vs 3.2ml and 10.8ml respectively, p<0.05 for both comparisons). Global PiB retention and WMH showed strong correlation (rho=0.52, p<0.001) in the CAA group but not in HE or AD. These associations did not change in the multivariate models. Lobar microbleed count, another marker of CAA severity also remained as an independent predictor of WMH volume. Interpretation Our results indicate that amyloid burden in CAA subjects (with primarily vascular amyloid) but not AD subjects (with primarily parenchymal amyloid) independently correlate with WMH volume. These findings support the idea that vascular amyloid burden directly contributes to chronic cerebral ischemia and highlights the possible utility of amyloid imaging as a marker of CAA severity. PMID:23424091

  17. Cerebral Amyloid Angiopathy-Related Inflammation: Report of a Case with Very Difficult Therapeutic Management

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    Francesca Crosta

    2015-01-01

    Full Text Available Background. Cerebral amyloid angiopathy-related inflammation (CAA-ri results from autoimmune response to beta-amyloid deposits in cerebral vessels. Its clinical course and complications have seldom been described in literature. Case Report. In a patient presenting with delirium and left hemiparesis the diagnosis of CAA-ri was supported by the finding of elevated anti-amyloid autoantibodies in the cerebrospinal fluid (CSF. Steroid therapy produced significant improvements in clinical and investigational assessments, but after two months, it caused Acute Respiratory Distress Syndrome. After steroid therapy discontinuation the patient presented a rapidly progressive dementia, Guillain-Barré syndrome, new cerebral ischemic lesions, and thrombosis of the right cephalic and subclavian veins that were treated with subcutaneous heparin. After a week the patient died because of brain hemorrhage. Conclusion. This case suggests caution in steroid therapy discontinuation and antithrombotic therapy administration in patients with CAA-ri. The CSF search of anti-amyloid autoantibodies could be helpful to support the diagnosis.

  18. Cerebral Amyloidal Angiopathy--a disease with implications for neurology and psychiatry.

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    Gahr, Maximilian; Nowak, Dennis A; Connemann, Bernhard J; Schönfeldt-Lecuona, Carlos

    2013-06-26

    Cerebral Amyloidal Angiopathy (CAA), which occurs sporadically in most cases but can also occur hereditarily, belongs to the group amyloidoses and is characterized by the deposition and accumulation of beta-amyloid (Aβ) in smaller arterial vessels of the brain. The deposition of Aβ leads to degenerative changes in the cerebral vessel system (thickening of the vessel wall, microaneurysm, constriction of vascular lumen, dissection), which favour the development of the clinical symptomatology most often associated with CAA. Besides haemorrhages, cerebral ischaemia, transient neurological symptoms, leukoencephalopathy as well as cognitive decline and even dementia may appear in connection with CAA. A definite diagnosis of CAA can only be made on the basis of a pathological assessment, even though diagnostic findings of cerebral neuroimaging and clinical symptoms allow the diagnosis of a probable CAA. At present, no causal therapy options are available. Although CAA is placed within the range of neurological illnesses, psychiatric symptoms such as cognitive impairment, personality change or behavioural problems as well as depression are plausible clinical manifestations of CAA and may even dominate the clinical picture. Apart from epidemiological, pathogenetical, clinical and diagnostical aspects, possible psychiatric implications of CAA are discussed in the review article.

  19. Association of angiitis of central nervous system, cerebral amyloid angiopathy, and Alzheimer’s disease: Report of an autopsy case

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    Cédric Annweiler

    2008-12-01

    Full Text Available Cédric Annweiler1, Marc Paccalin2, Gilles Berrut3, Caroline Hommet4, Christian Lavigne1, Jean-Paul Saint-André5, Olivier Beauchet11Department of Geriatrics and Internal Medicine, Angers University Hospital, France; 2Department of Geriatrics, Poitiers University Hospital, France; 3Department of Geriatrics, Nantes University Hospital, France; 4Department of Geriatrics, Tours University Hospital, France; 5Department of Anatomopatholgy, Angers University Hospital, FranceAbstract: The association of angiitis of central nervous system (ACNS with cerebral amyloid angiopathy (CAA suggests a physiopathological relationship between these two affections. Few cases are reported in patients with Alzheimer’s disease (AD. We describe here a clinicopathological case associating ACNS, CAA, and AD. We discuss the aetiology of ACNS and its relationship with cerebral deposition of beta A4 amyloid protein (βA4.Keywords: cerebral angiopathy, Alzheimer’s disease

  20. Effect of cerebral amyloid angiopathy on brain iron, copper, and zinc in Alzheimer's disease.

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    Schrag, Matthew; Crofton, Andrew; Zabel, Matthew; Jiffry, Arshad; Kirsch, David; Dickson, April; Mao, Xiao Wen; Vinters, Harry V; Domaille, Dylan W; Chang, Christopher J; Kirsch, Wolff

    2011-01-01

    Cerebral amyloid angiopathy (CAA) is a vascular lesion associated with Alzheimer's disease (AD) present in up to 95% of AD patients and produces MRI-detectable microbleeds in many of these patients. It is possible that CAA-related microbleeding is a source of pathological iron in the AD brain. Because the homeostasis of copper, iron, and zinc are so intimately linked, we determined whether CAA contributes to changes in the brain levels of these metals. We obtained brain tissue from AD patients with severe CAA to compare to AD patients without evidence of vascular amyloid-β. Patients with severe CAA had significantly higher non-heme iron levels. Histologically, iron was deposited in the walls of large CAA-affected vessels. Zinc levels were significantly elevated in grey matter in both the CAA and non-CAA AD tissue, but no vascular staining was noted in CAA cases. Copper levels were decreased in both CAA and non-CAA AD tissues and copper was found to be prominently deposited on the vasculature in CAA. Together, these findings demonstrate that CAA is a significant variable affecting transition metals in AD.

  1. New therapeutic approaches for Alzheimer’s disease and cerebral amyloid angiopathy

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    Satoshi eSaito

    2014-10-01

    Full Text Available Accumulating evidence has shown a strong relationship between Alzheimer’s disease (AD, cerebral amyloid angiopathy (CAA, and cerebrovascular disease. Cognitive impairment in AD patients can result from cortical microinfarcts associated with CAA, as well as the synaptic and neuronal disturbances caused by cerebral accumulations of β-amyloid (Aβ and tau proteins. The pathophysiology of AD may lead to a toxic chain of events consisting of Aβ overproduction, impaired Aβ clearance, and brain ischemia. Insufficient removal of Aβ leads to development of CAA and plays a crucial role in sporadic AD cases, implicating promotion of Aβ clearance as an important therapeutic strategy. Aβ is mainly eliminated by three mechanisms: 1 enzymatic/glial degradation, 2 transcytotic delivery, and 3 perivascular drainage (3-‘d’ mechanisms. Enzymatic degradation may be facilitated by activation of Aβ-degrading enzymes such as neprilysin, angiotensin-converting enzyme, and insulin-degrading enzyme. Transcytotic delivery can be promoted by inhibition of the receptor for advanced glycation end products (RAGE, which mediates transcytotic influx of circulating Aβ into brain. Successful use of the RAGE inhibitor TTP488 in Phase II testing has led to a Phase III clinical trial for AD patients. The perivascular drainage system seems to be driven by motive force generated by cerebral arterial pulsations, suggesting that vasoactive drugs can facilitate Aβ clearance. One of the drugs promoting this system is cilostazol, a selective inhibitor of type 3 phosphodiesterase. The clearance of fluorescent soluble Aβ tracers was significantly enhanced in cilostazol-treated CAA model mice. Given that the balance between Aβ synthesis and clearance determines brain Aβ accumulation, and that Aβ is cleared by several pathways stated above, multi-drugs combination therapy could provide a mainstream cure for sporadic AD.

  2. Cerebral amyloid angiopathy: pathogenesis and effects on the ageing and Alzheimer brain.

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    Weller, Roy O; Nicoll, James A

    2003-09-01

    Cerebral amyloid angiopathy (CAA) is a feature of ageing and Alzheimer's disease (AD); it is also associated with intracerebral hemorrhage and stroke. Here, the pathogenesis of CAA and its effects on the brain are reviewed and the possible effects of CAA on therapies for Alzheimer's disease are evaluated. Tracer experiments in animals and observations on human brains suggest that peptides such as A beta are eliminated along the peri-arterial interstitial fluid drainage pathways that are effectively the lymphatics of the brain. In CAA, A beta becomes entrapped in drainage pathways in the walls of cerebral arteries, reflecting a failure of elimination of A beta from the ageing brain. One consequence of failure in clearance of A beta is accumulation of soluble and insoluble A beta associated with cognitive decline in AD. Replacement of vascular smooth muscle cells by A beta occurs in severe CAA with weakening of artery walls and increased risk of vessel rupture and intracerebral hemorrhage. Risk factors for CAA include mutations of the amyloid precursor protein (APP) gene and possession of the epsilon 4 allele of apolipoprotein E. There is also evidence that cerebrovascular disease may be a factor in the failure of elimination of A beta along perivascular pathways in sporadic AD; this would link ageing in cerebral arteries with the pathogenesis of Alzheimer's disease. If therapeutic agents, including anti-A beta antibodies, are to be used to eliminate A beta in the treatment of Alzheimer's disease, the effects of CAA on the treatment and the effects of the treatment on the CAA need to be considered.

  3. Tissue transglutaminase colocalizes with extracellular matrix proteins in cerebral amyloid angiopathy.

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    de Jager, Mieke; van der Wildt, Berend; Schul, Emma; Bol, John G J M; van Duinen, Sjoerd G; Drukarch, Benjamin; Wilhelmus, Micha M M

    2013-04-01

    Cerebral amyloid angiopathy (CAA) is a key histopathological hallmark of Alzheimer's disease (AD) and hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D). CAA is characterized by amyloid-beta (Aβ) depositions and remodeling of the extracellular matrix (ECM) in brain vessels and plays an important role in the development and progression of both AD and HCHWA-D. Tissue transglutaminase (tTG) modulates the ECM by molecular cross-linking of ECM proteins. Here, we investigated the distribution pattern, cellular source, and activity of tTG in CAA in control, AD, and HCHWA-D cases. We observed increased tTG immunoreactivity and colocalization with Aβ in the vessel wall in early stage CAA, whereas in later CAA stages, tTG and its cross-links were present in halos enclosing the Aβ deposition. In CAA, tTG and its cross-links at the abluminal side of the vessel were demonstrated to be either of astrocytic origin in parenchymal vessels, of fibroblastic origin in leptomeningeal vessels, and of endothelial origin at the luminal side of the deposited Aβ. Furthermore, the ECM proteins fibronectin and laminin colocalized with the tTG-positive halos surrounding the deposited Aβ in CAA. However, we observed that in situ tTG activity was present throughout the vessel wall in late stage CAA. Together, our data suggest that tTG and its activity might play a differential role in the development and progression of CAA, possibly evolving from direct modulation of Aβ aggregation to cross-linking of ECM proteins resulting in ECM restructuring.

  4. Cerebral amyloid angiopathy-related inflammation: imaging findings and clinical outcome

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    Martucci, Matia [Vall d' Hebron University Hospital, Neuroradiology Unit, Radiology Department (IDI), Barcelona (Spain); Catholic University of Sacred Heart, ' ' A. Gemelli' ' University Hospital, Department of Radiological Sciences, Rome (Italy); Sarria, Silvana; Coscojuela, Pilar; Vert, Carla; Siurana, Sahyly; Auger, Cristina; Rovira, Alex [Vall d' Hebron University Hospital, Neuroradiology Unit, Radiology Department (IDI), Barcelona (Spain); Toledo, Manuel [Vall d' Hebron University Hospital, Epilepsy Unit, Neurology Department, Barcelona (Spain)

    2014-04-15

    We aim to investigate the clinical onset, computed tomography (CT) and magnetic resonance (MR) imaging findings, and follow-up of patients with cerebral amyloid angiopathy (CAA)-related inflammation, an uncommon but clinically striking presentation of CAA. We retrospectively reviewed the clinical manifestations, CT/MR imaging findings, and outcome of ten consecutive patients with CAA-related inflammation. In each patient, a brain CT study was performed at hospital admission, and brain MR imaging was carried out 2 to 4 days later. Clinical and radiologic follow-up findings were evaluated in all patients. The most common clinical onset was rapidly progressive cognitive decline, followed by focal neurological signs. Brain CT/MR showed unenhanced expansive subcortical lesions, corresponding to areas of vasogenic edema, associated with chronic lobar, cortical, or cortical-subcortical micro/macrohemorrhages. Clinical symptoms recovered in a few weeks under treatment in eight patients and spontaneously in the remaining two. MRI follow-up at 2 to 12 months after treatment showed resolution of the lesions. Three patients experienced symptomatic disease recurrence, with new lesions on CT/MR. In the absence of histological data, early recognition of the clinical symptoms and typical radiologic features of CAA-related inflammation is essential to enable timely establishment of proper treatment. (orig.)

  5. Recurrent Stereotyped Episodes in Cerebral Amyloid Angiopathy: Response to Migraine Prophylaxis in Two Patients

    Directory of Open Access Journals (Sweden)

    R.W. Paterson

    2013-05-01

    Full Text Available Background: Cerebral amyloid angiopathy (CAA typically presents with cognitive decline or symptomatic intracerebral hemorrhage, but episodes of recurrent stereotyped limb attacks have also been reported. Methods: Retrospective review of the medical records of 4 patients referred to the general neurology services and a specialist stroke center with clinically probable CAA. Results: Four subjects, all Caucasian, mean age 74 years, were followed up over a mean duration of 20 months. They all experienced recurrent prolonged stereotyped attacks of sensory symptoms, lasting 5-30 min, that resolved completely between attacks. Three subjects developed intracerebral hemorrhage, and 2 had an irreversible rapid cognitive decline. Two patients experienced symptomatic improvement with migraine prophylaxis (verapamil or topiramate. Conclusions: Recurrent stereotyped prolonged attacks with sensory and motor elements can predate the development of intracerebral hemorrhage in individuals with clinically probable CAA. When evaluating patients with such attacks, neurologists need to consider CAA as a possible mimic of transient ischemic attacks. We suggest a trial of migraine prophylaxis for symptomatic management.

  6. Anti-Aβ Autoantibodies in Amyloid Related Imaging Abnormalities (ARIA): Candidate Biomarker for Immunotherapy in Alzheimer’s Disease and Cerebral Amyloid Angiopathy

    Science.gov (United States)

    DiFrancesco, Jacopo C.; Longoni, Martina; Piazza, Fabrizio

    2015-01-01

    Amyloid-related imaging abnormalities (ARIA) represent the major severe side effect of amyloid-beta (Aβ) immunotherapy for Alzheimer’s disease (AD). Early biomarkers of ARIA represent an important challenge to ensure safe and beneficial effects of immunotherapies, given that different promising clinical trials in prodromal and subjects at risk for AD are underway. The recent demonstration that cerebrospinal fluid (CSF) anti-Aβ autoantibodies play a key role in the development of the ARIA-like events characterizing cerebral amyloid angiopathy-related inflammation generated great interest in the field of immunotherapy. Herein, we critically review the growing body of evidence supporting the monitoring of CSF anti-Aβ autoantibody as a promising candidate biomarker for ARIA in clinical trials. PMID:26441825

  7. 脑淀粉样血管病的病理生理学机制%Pathophysiologic mechanisms in cerebral amyloid angiopathy

    Institute of Scientific and Technical Information of China (English)

    史焕昌

    2011-01-01

    Cerebral amyloid angiopathy (CAA) is characterized by leptomeningeal and β-amyloid deposition in arteriole wall in cortex, and it is one of the common cerebral vascular diseases in the elderly. It is correlated with Alzheimer's disease, intracerebral hemorrhage, cerebral infarction and leukoencephalopathy. CAA is divided into hereditary and sporadic types, and the latter is most common. This article reviews the advances in research on the pathophysiological mechanisms of sporadic CAA, particularly the production of β-amyloid protein and clearance mechanism in brain tissue.%脑淀粉样血管病(cerebral amyloid angiopathy,CAA)以软脑膜和皮质中小动脉壁内的β-淀粉样蛋白沉积为特征,是老年人的常见脑血管病变之一,与阿尔茨海默病、脑出血、脑梗死和白质脑病相关.CAA分为遗传性和散发性2种形式,以后者居多.文章就散发性CAA的病理生理学机制研究进展,特别是脑组织β-淀粉样蛋白的产生和清除机制进行了综述.

  8. Early-Phase 11C-PiB PET in Amyloid Angiopathy-Related Symptomatic Cerebral Hemorrhage: Potential Diagnostic Value?

    Science.gov (United States)

    Farid, Karim; Hong, Young T; Aigbirhio, Franklin I; Fryer, Tim D; Menon, David K; Warburton, Elizabeth A; Baron, Jean-Claude

    2015-01-01

    Although late-phase (>35min post-administration) 11C-PiB-PET has good sensitivity in cerebral amyloid angiopathy (CAA), its specificity is poor due to frequently high uptake in healthy aged subjects. By detecting perfusion-like abnormalities, early-phase 11C-PiB-PET might add diagnostic value. Early-frame (1-6min) 11C-PiB-PET was obtained in 11 non-demented patients with probable CAA-related symptomatic lobar intracerebral haemorrhage (70±7yrs), 9 age-matched healthy controls (HCs) and 10 HCs PiB data did not change the sensitivity and specificity of late-phase PiB, but combined early- and late-phase positivity entails a very high suspicion of underlying Aβ-related clinical disorder, i.e., CAA or Alzheimer disease (AD). In order to clarify this ambiguity, we then show that the occipital/posterior cingulate ratio is markedly lower in CAA than in AD (N = 7). These pilot data suggest that early-phase 11C-PiB-PET may not only add to late-phase PiB-PET with respect to the unclear situation of late-phase positivity, but also help differentiate CAA from AD.

  9. 脑淀粉样变性相关炎症反应的研究进展%Recent advance in cerebral amyloid angiopathy related inflammation

    Institute of Scientific and Technical Information of China (English)

    陈赛男; 孙玉莹; 王扬扬; 许予明; 吴军

    2016-01-01

    脑淀粉样血管病变(CAA)是一种老年入常见的颅内微血管病变,主要病理特征是β淀粉样蛋白(Aβ)在大脑皮层及皮层下、软脑膜中及小血管的中外膜沉积.脑淀粉样变性相关炎症反应是最近公认的发生在一部分脑淀粉样变性患者中的可逆性的脑病.本文就脑淀粉样变性相关炎症反应的病理机制、临床表现及进程、相关辅助检查、诊断及鉴别诊断和治疗方面的最新进展进行综述.%Cerebral amyloid angiopathy (CAA) is a disorder characterized by amyloid deposition in the walls of leptomeningeal and cortical arteries,arterioles,and it is one of the common cerebral vascular diseases in the elderly.Cerebral amyloid angiopathy related inflammation (CAA-Ⅰ),is a recently recognized syndrome of reversible encephalopathy seen in a subset of patients with CAA.Here,we review the advances in research on the pathological mechanism,clinical features and course,investigations,diagnosis and differential diagnosis,and treatment of CAA-Ⅰ.

  10. 99mTc(CO)3-Labeled Benzothiazole Derivatives Preferentially Bind Cerebrovascular Amyloid: Potential Use as Imaging Agents for Cerebral Amyloid Angiopathy.

    Science.gov (United States)

    Jia, Jianhua; Cui, Mengchao; Dai, Jiapei; Liu, Boli

    2015-08-03

    Cerebral amyloid angiopathy (CAA) is a disorder affecting the elderly that is characterized by amyloid-β (Aβ) deposition in blood vessel walls of the brain. A series of 99mTc(CO)3-labeled benzothiazole derivatives as potential SPECT imaging probes for cerebrovascular Aβ deposition is reported. Rhenium surrogate displayed high affinities to Aβ aggregates with Ki values ranging from 106 to 42 nM, and they strongly stained Aβ deposits in transgenic mice (Tg) and Alzheimer's disease (AD) patients. In vitro autoradiography on brain sections of Tg and AD patients confirmed that [99mTc]24 possessed sufficient affinity for Aβ plaques, and [99mTc]24 could only label Aβ deposition in blood vessels but not Aβ plaques in the parenchyma of the brain of AD patients. Moreover, [99mTc]24 possessed favorable initial uptake (1.21% ID/g) and fast blood washout (blood2 min/blood60 min=23) in normal mice. These preliminary results suggest that [99mTc]24 may be used as an Aβ imaging probe for the detection of CAA.

  11. Genetic determinants of white matter hyperintensities and amyloid angiopathy in familial Alzheimer's disease

    NARCIS (Netherlands)

    Ryan, Natalie S.; Biessels, Geert Jan; Kim, Lois; Nicholas, Jennifer M.; Barber, Philip A.; Walsh, Phoebe; Gami, Priya; Morris, Huw R.; Bastos-Leite, António J.; Schott, Jonathan M.; Beck, Jon; Mead, Simon; Chavez-Gutierrez, Lucia; de Strooper, Bart; Rossor, Martin N.; Revesz, Tamas; Lashley, Tammaryn; Fox, Nick C.

    2015-01-01

    Familial Alzheimer's disease (FAD) treatment trials raise interest in the variable occurrence of cerebral amyloid angiopathy (CAA); an emerging important factor in amyloid-modifying therapy. Previous pathological studies reported particularly severe CAA with postcodon 200 PSEN1 mutations and amyloid

  12. Cerebral amyloid angiopathy-related inflammation presenting with steroid-responsive higher brain dysfunction: case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Maeda Yasushi

    2011-09-01

    Full Text Available Abstract A 56-year-old man noticed discomfort in his left lower limb, followed by convulsion and numbness in the same area. Magnetic resonance imaging (MRI showed white matter lesions in the right parietal lobe accompanied by leptomeningeal or leptomeningeal and cortical post-contrast enhancement along the parietal sulci. The patient also exhibited higher brain dysfunction corresponding with the lesions on MRI. Histological pathology disclosed β-amyloid in the blood vessels and perivascular inflammation, which highlights the diagnosis of cerebral amyloid angiopathy (CAA-related inflammation. Pulse steroid therapy was so effective that clinical and radiological findings immediately improved. CAA-related inflammation is a rare disease, defined by the deposition of amyloid proteins within the leptomeningeal and cortical arteries associated with vasculitis or perivasculitis. Here we report a patient with CAA-related inflammation who showed higher brain dysfunction that improved with steroid therapy. In cases with atypical radiological lesions like our case, cerebral biopsy with histological confirmation remains necessary for an accurate diagnosis.

  13. Topography of Cortical Microbleeds in Alzheimer's Disease with and without Cerebral Amyloid Angiopathy: A Post-Mortem 7.0-Tesla MRI Study.

    Science.gov (United States)

    De Reuck, J; Auger, F; Durieux, N; Deramecourt, V; Cordonnier, C; Pasquier, F; Maurage, C A; Leys, D; Bordet, R

    2015-11-01

    Cortical microbleeds (CMBs) detected on T2*-weighted gradient-echo (GRE) magnetic resonance imaging (MRI) are considered as a possible hallmark of cerebral amyloid angiopathy (CAA). The present post-mortem 7.0-tesla MRI study investigates whether topographic differences exist in Alzheimer's brains without (AD) and with CAA (AD-CAA). The distribution of CMBs in thirty-two post-mortem brains, consisting of 12 AD, 8 AD-CAA and 12 controls, was mutually compared on T2*-GRE MRI of six coronal sections of a cerebral hemisphere. The mean numbers of CMBs were determined in twenty-two different gyri. As a whole there was a trend of more CMBs on GRE MRI in the prefrontal section of the AD, the AD-CAA as well as of the control brains. Compared to controls AD brains had significantly more CMBs in the superior frontal, the inferior temporal, the rectus and the cinguli gyrus, and in the insular cortex. In AD-CAA brains CMBs were increased in all gyri with exception of the medial parietal gyrus and the hippocampus. AD-CAA brains showed a highly significant increase of CMBs in the inferior parietal gyrus (p value: 0.001) and a significant increase in the precuneus and the cuneus (p value: 0.01) compared to the AD brains. The differences in topographic distribution of CMBs between AD and AD-CAA brains should be further investigated on MRI in clinically suspected patients.

  14. Murine cerebrovascular cells as a cell culture model for cerebral amyloid angiopathy: isolation of smooth muscle and endothelial cells from mouse brain.

    Science.gov (United States)

    Gauthier, Sebastien A; Sahoo, Susmita; Jung, Sonia S; Levy, Efrat

    2012-01-01

    The use of murine cerebrovascular endothelial and smooth muscle cells has not been widely employed as a cell culture model for the investigation of cellular mechanisms involved in cerebral amyloid angiopathy (CAA). Difficulties in isolation and propagation of murine cerebrovascular cells and insufficient yields for molecular and cell culture studies have deterred investigators from using mice as a source for cerebrovascular cells in culture. Instead, cerebrovascular cells from larger mammals are preferred and several methods describing the isolation of endothelial and smooth muscle cells from human, canine, rat, and guinea pig have been published. In recent years, several transgenic mouse lines showing CAA pathology have been established; consequently murine cerebrovascular cells derived from these animals can serve as a key cellular model to study CAA. Here, we describe a procedure for isolating murine microvessels that yields healthy smooth muscle and endothelial cell populations and produce sufficient material for experimental purposes. Murine smooth muscle cells isolated using this protocol exhibit the classic "hill and valley" morphology and are immunoreactive for the smooth muscle cell marker α-actin. Endothelial cells display a "cobblestone" pattern phenotype and show the characteristic immunostaining for the von Willebrand factor and the factor VIII-related antigen. In addition, we describe methods designed to preserve these cells by storage in liquid nitrogen and reestablishing viable cell cultures. Finally, we compare our methods with protocols designed to isolate and maintain human cerebrovascular cell cultures.

  15. Cerebral microvascular amyloid beta protein deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant amyloid beta precursor protein.

    NARCIS (Netherlands)

    Miao, J.; Xu, F.; Davis, J.; Otte-Holler, I.; Verbeek, M.M.; Nostrand, W.E. van

    2005-01-01

    Cerebral vascular amyloid beta-protein (Abeta) deposition, also known as cerebral amyloid angiopathy, is a common pathological feature of Alzheimer's disease. Additionally, several familial forms of cerebral amyloid angiopathy exist including the Dutch (E22Q) and Iowa (D23N) mutations of Abeta. Incr

  16. [Acute benign cerebral angiopathy. 6 cases].

    Science.gov (United States)

    Rousseaux, P; Scherpereel, B; Bernard, M H; Guyot, J F

    1983-10-08

    The 6 cases reported here constitute, with 5 previously published cases, a special nosological entity tentatively called "acute benign cerebral angiopathy" by the authors. These 11 cases have in common certain radiological and clinical features. Arteriography shows segmental, multifocal and assymetrical stenoses involving the cerebral arteries between Willis' circle and the terminal arterioles and looking like "strings of sausages". The lesions disappear within one month and present the radiological characteristics of arteritis of medium caliber vessels. The clinical symptoms are suggestive of meningeal haemorrhage or acute cerebromeningeal oedema, with acute repetitive attacks of severe headache and agitation with obnubilation; epileptic seizures and transient neurological deficit may occur. True meningeal haemorrhage confirmed by lumbar puncture is seen in nearly one half of the cases; it seems to be due to alterations in the blood-brain barrier induced by the angiopathy. Intracerebral haematoma may develop, but the disease is usually benign and regresses spontaneously in a few days. None of the usual causes of cerebral arteritis (intra-cranial infection, collagen disease, allergic or toxic angitis) has been found. Pseudo-arteritis (notably spasm of ruptured arterial aneurysms) has been excluded. No aetiological factor common to the 11 cases reported has been elicited, although 6 of the patients had recently given birth and our 6 patients had benign virus infection before or during the clinical manifestations of the disease. In the authors' opinion, the most rewarding line of research would be the role of short acute attacks of arterial hypertension.

  17. Correlation between Radiological and Clinical Features of Cerebral Amyloid Angiopathy%脑淀粉样血管病的影像学标志物及临床相关性研究进展

    Institute of Scientific and Technical Information of China (English)

    王全; 朱以诚; 倪俊

    2015-01-01

    Cerebral amyloid angiopathy (CAA) is a common form of cerebral small vessel disease among elderly persons. It is different with hypertensive cerebral small vessel disease, which mainly cause deep brain vascular disease, that CAA mainly affects the small cortical and leptomeningeal arteries and arterioles. Multiple lobar microbleeds are the radiologic hallmark of CAA and have been considered as a potential cause of intracranial hemorrhage and cognitive impairment. With further researches on radiologic markers of cerebral small vessel disease, convexity subarachnoid hemorrhage and cortical superifcial siderosis have been regarded as relatively speciifc radiologic ifndings of CAA. Besides, white matter hyperintensities and small infarcts have been found in CAA commonly, which indicates ischemic injuries are as important as hemorrhagic lesions of CAA.%脑淀粉样血管病(cerebral amyloid angiopathy,CAA)是一种多见于老年人群中的脑小血管病,不同于高血压导致的脑小血管病易累及脑深部区域,CAA多累及皮层及软脑膜小血管。多发脑叶微出血是CAA患者常见的影像学表现,研究认为其与症状性脑叶出血及进行性认知功能下降相关。随着近年来对脑小血管病影像学表现的深入研究,发现皮层蛛网膜下腔出血与皮层表面含铁血黄素沉积是CAA相对特异的影像学表现,并且与短暂性局灶性神经系统症状发作相关。此外,脑白质高信号、小梗死灶等脑小血管病影像学标志均在CAA患者中出现,提示除外临床较关注的出血性改变,CAA患者的缺血性损伤也是导致临床症状的重要因素。

  18. Uncomplicated pregnancy and delivery after previous severe postpartum cerebral angiopathy.

    Science.gov (United States)

    Rémi, Jan; Pfefferkorn, Thomas; Fesl, Gunther; Rogenhofer, Nina; Straube, Andreas; Klein, Matthias

    2011-09-01

    Postpartum cerebral angiopathy (PCA) is a cerebral vasoconstriction syndrome developing shortly after delivery, without signs of preceding eclampsia. The risk for recurrence of PCA is unknown. Here, we report on a closely monitored, uneventful pregnancy of a woman with a previous severe episode of PCA. In summary, this case report demonstrates that PCA does not necessarily recur in following pregnancies, even after previous severe episodes.

  19. Uncomplicated Pregnancy and Delivery after Previous Severe Postpartum Cerebral Angiopathy

    Directory of Open Access Journals (Sweden)

    Jan Rémi

    2011-10-01

    Full Text Available Postpartum cerebral angiopathy (PCA is a cerebral vasoconstriction syndrome developing shortly after delivery, without signs of preceding eclampsia. The risk for recurrence of PCA is unknown. Here, we report on a closely monitored, uneventful pregnancy of a woman with a previous severe episode of PCA. In summary, this case report demonstrates that PCA does not necessarily recur in following pregnancies, even after previous severe episodes.

  20. Utilidad de las secuencias potenciadas en susceptibilidad paramagnética (SWI para diferenciar crisis somestésicas de accidentes isquémicos transitorios en un paciente con angiopatía amiloide cerebral The use of SWI-MRI to differentiate between seizures and transient ischemic attacks in a patient with cerebral amyloid angiopathy

    Directory of Open Access Journals (Sweden)

    C. Gasca-Salas

    2011-08-01

    Full Text Available Introducción. La angiopatía amiloide cerebral (AAC se caracteriza por el depósito de β-amiloide en la pared de las arterias de pequeño y mediano calibre de la corteza cerebral y leptomeninges. La sintomatología puede incluir eventos transitorios de diverso origen, pudiendo ser difícil el diagnóstico diferencial en el momento agudo. Caso clínico. Varón con antecedente de ictus isquémico, que presentó crisis somestésicas secundarias a microsangrado cerebral por AAC que simulaban ataques isquémicos transitorios. Se redujo la medicación antiagregante y posteriormente se inició tratamiento antiepiléptico desapareciendo los episodios. Las secuencias de susceptibilidad paramagnética en Resonancia Magnética cerebral fueron de gran utilidad para el diagnóstico (SWI-RM. Conclusiones. Los microsangrados de la AAC pueden manifestarse en forma de crisis, simulando déficits focales sensitivos transitorios que pueden ser atribuidos erróneamente a isquemia cerebral. Este caso sugiere que, incluso si existe historia de accidentes cerebrovasculares isquémicos, deberían considerarse microsangrados por AAC como causa posible de pseudoaccidentes isquémicos transitorios. Las secuencias SWI-RM pueden ser útiles para identificarlos. De este modo puede prevenirse el inicio o escalada del tratamiento antiagregante o anticoagulante, evitando complicaciones potencialmente devastadoras.Background. Cerebral amyloid angiopathy (CAA is characterized by the deposit of β-amyloid on the walls of small and medium-sized arteries of the cerebral cortex and leptomeninges causing cerebral bleeding. Clinical presentations may include transient neurological events for which differential diagnosis can be difficult. Case report. We report a subject with a medical history of recent stroke who presented somesthetic seizures mimicking transient ischemic attacks owing to CAA microbleeding. Antiplatelet treatment was reduced and after lamotrigine was commenced the

  1. A retrospective study of 26 cases of pathologically established cerebral amyloid angiopathy%病理证实的淀粉样脑血管病26例临床分析

    Institute of Scientific and Technical Information of China (English)

    李晓秋; 苏东风; 王耀山

    2011-01-01

    Objective To study the clinical feature of 26 cases which were diagnosed pathologically as cerebral amyloid angiopathy ( CAA ) and to improve the level of diagnosis.Methods The clinical characteristics of the 26 cases with CAA in our hospital from 1983 to 1999 were retrospectively reviewed and analyzed,including previous history,clinical manifestation,and laboratory examination.Results Of the 26 CAA patients,there were 17 men and 9 women with age ranging from 45 to 78 years.Eight patients (30.7% ) had the history of hypertension; 6 cases (23.1% ) suffered from diabetes; 2 patients(7.6% ) were taking anticoagulant or antiplatelet agents in whom serious CAA and multiple hemorrhages were histopathologically confirmed by autopsy.There were 20 cases diagnosed as cerebral hemorrhage,including 2 patients with single lobe hemorrhage,8 patients with multiple lobe hemorrhage,5 patients with putamen hemorrhage,2 patients with cerebral ganglion hemorrhage,2 patients with cerebellar hemorrhage,and 1 patient with brain stem hemorrhage.Of the 26 CAA patients,there were 2 patients with subaracchnoid hemorrhage,1 patient with hemorrhagic cerebral infarction,1 patient with basal ganglia infarction,1 patient with basilar artery occlusion,1 patient with subdural hematoma.The clinical manifestation of the 20 cases diagnosed as cerebral hemorrhage included headache,limb palsy,coma,and hyperspasmia.Conclusions CAA always begin as cerebrovascular disease symptoms with or without hypertension.The most common manifestation of CAA is lobe hemorrhage,while the CAA-related hemorrhage seldom occurs in basal ganglia,cerebellum and brainstem.CAA can also manifest cerebral infarction and subarachnoid hemorrhage.Anticoagulant (warfarin) or antiplatelet agents (aspirin) maybe a contributing factor for CAA-related hemorrhage.%目的 总结26例尸检证实的淀粉样脑血管病的临床资料特点,以提高对本病的认识和诊断水平.方法 回顾性分析我院1983--1999

  2. Severe cerebral congophilic angiopathy coincident with increased brain aluminium in a resident of Camelford, Cornwall, UK.

    Science.gov (United States)

    Exley, C; Esiri, M M

    2006-07-01

    In July 1988, 20 tonnes of aluminium sulphate was discharged by the South West Water Authority into the drinking water supplied to a large region of North Cornwall. Up to 20,000 people were exposed to concentrations of aluminium which were 500-3000 times the acceptable limit under European Union legislation (0.200 mg/l). Although this incident is currently the topic of a government inquiry, nothing is known about its longer-term repercussions on human health. The first neuropathological examination of a person who was exposed and died of an unspecified neurological condition was carried out. A rare form of sporadic early-onset beta amyloid angiopathy in cerebral cortical and leptomeningeal vessels, and in leptomeningeal vessels over the cerebellum was identified. In addition, high concentrations of aluminium were found coincident with the severely affected regions of the cortex. Although the presence of aluminium is highly unlikely to be adventitious, determining its role in the observed neuropathology is impossible. A clearer understanding of aluminium's role in this rare form of Alzheimer's related disease should be provided by future research on other people from the exposed population as well as similar neuropathologies in people within or outside this group.

  3. Amyloid angiopathy of the floor of the mouth: a case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Kokong Daniel D

    2007-10-01

    Full Text Available Abstract Amyloidosis is a rare disease characterised by the deposition of insoluble extracellular fibrillar proteins in various tissues of the body. The pattern of manifestation is organ dependent and also on whether the disease is localised or systemic, primary or secondary. Though the disease is usually fatal with a 5-year survival rate of 20%, there is still paucity of literature on this disease entity worldwide. Diagnosis has remained mostly at autopsy. A case of amyloid angiopathy involving the submandibular gland and floor of the mouth with an associated fatal bleed is reported. The purpose of this case report is to reiterate the importance of a high index of suspicion in the approach to the management of head and neck swellings.

  4. Acute Hemiparesis in a Child as a Presenting Symptom of Hemispheric Cerebral Proliferative Angiopathy

    Directory of Open Access Journals (Sweden)

    J. J. Gold

    2013-01-01

    Full Text Available A 9-year-old girl with a several-month history of unilateral intermittent headaches presented to the hospital with worsening headaches and unsteadiness. Neurologic exam was positive for a mild right hemiparesis and right homonymous hemianopsia. Noncontrast computed tomography revealed an engorged sagittal and straight sinus with prominent cortical veins concerning an arteriovenous malformation and the patient was admitted to the pediatric intensive care unit. Computed tomography angiogram demonstrated a left hemispheric vascular malformation, without evidence of dural arteriovenous fistula on conventional angiogram consistent with a diagnosis of cerebral proliferative angiopathy. There was no evidence of infarct on magnetic resonance imaging, and the patient’s symptoms were completely resolved within 24 hours. Cerebral proliferative angiopathy is a rare but important vascular malformation distinct from classic arteriovenous malformations that may present with stroke-like symptoms in childhood.

  5. Dementia with non-hereditary cystatin C angiopathy

    DEFF Research Database (Denmark)

    Benedikz, Eirikur; Blöndal, H; Jóhannesson, G

    1989-01-01

    Brain biopsies from two patients with non-hereditary cerebral hemorrhages and eighty autopsied cases with the clinical diagnosis of dementia are presented. The biopsied cases, both males aged 64 and 59, had a sudden onset of cerebral hemorrhage, mild progressive dementia and cystatin C cerebral...... amyloid angiopathy. Of the autopsied cases 59 had senile plaques and cerebral amyloid angiopathy was also found in 36 of them. Both senile plaques and the blood vessel amyloid stained positively with beta-protein antibodies, and five of them also showed a positive reaction to cystatin C antibodies....... These cystatin C positive cases were three males aged 76, 80 and 83, and one female 93 years old and the fifth case was a female aged 47 with Down's syndrome....

  6. Differential gene expression in human brain pericytes induced by amyloid-beta protein.

    NARCIS (Netherlands)

    Rensink, A.A.M.; Otte-Holler, I.; Donkelaar, H.J. ten; Waal, R.M.W. de; Kremer, H.P.H.; Verbeek, M.M.

    2004-01-01

    Cerebral amyloid angiopathy is one of the characteristics of Alzheimer's disease (AD) and this accumulation of fibrillar amyloid-beta (Alphabeta) in the vascular wall is accompanied by marked vascular damage. In vitro, Abeta1-40 carrying the 'Dutch' mutation (DAbeta1-40) induces degeneration of cult

  7. Postpartum cerebral angiopathy presenting with non-aneurysmal subarachnoid hemorrhage and interval development of neurological deficits: A case report and review of literature

    Directory of Open Access Journals (Sweden)

    Li Yang

    2013-01-01

    Full Text Available Postpartum cerebral angiopathy (PCA is a cerebrovascular disease that occurs during the postpartum period. It is characterized by reversible multifocal vasoconstriction of the cerebral arteries. We report a patient with PCA proven by cerebral angiography that revealed multifocal, segmental narrowing of the cerebral arteries and non-aneurysmal subarachnoid hemorrhage. The patient suddenly deteriorated with focal neurological deficits on the 5 th day of hospitalization. She was treated with calcium-channel blockers and monitored with daily transcranial Doppler ultrasound. Her symptoms gradually improved and she was discharged on the 11 th day of hospitalization. At 1-month follow-up, patient was completely symptom-free with no neurological deficits.

  8. Presentation of amyloidosis in carriers of the codon 692 mutation in the amyloid precursor protein gene (APP692)

    NARCIS (Netherlands)

    F. Forey; H.L.J. Tanghe (Hervé); M.F. Niermeijer (Martinus); C.M. van Duijn (Cock); J.C. van Swieten (John); F. van Harskamp (Frans); I. de Koning (Inge); M. Cruts (Marc); C. de Jonghe (Chris); S. Kumar-Singh (Samir); A. Tibben (Arend); C. van Broeckhoven (Christine); A. Hofman (Albert)

    2000-01-01

    textabstractSeveral mutations in the amyloid precursor protein (APP) gene may lead to either Alzheimer's disease or cerebral haemorrhage due to congophilic amyloid angiopathy (CAA). A single family is known in which both types of pathology are expressed because of a missense mutati

  9. Prevalence of cerebral amyloid pathology in persons without dementia

    DEFF Research Database (Denmark)

    Jansen, Willemijn J; Ossenkoppele, Rik; Knol, Dirk L;

    2015-01-01

    IMPORTANCE: Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies....... OBJECTIVE: To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). DATA SOURCES: Relevant biomarker studies identified...... for amyloid positivity. DATA EXTRACTION AND SYNTHESIS: Individual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies. MAIN OUTCOMES AND MEASURES: Prevalence of amyloid pathology on positron emission tomography...

  10. Statin Therapy and the Development of Cerebral Amyloid Angiopathy—A Rodent in Vivo Approach

    Directory of Open Access Journals (Sweden)

    Björn Reuter

    2016-01-01

    Full Text Available Background: Cerebral amyloid angiopathy (CAA is characterized by vascular deposition of amyloid β (Aβ with a higher incidence of cerebral microbleeds (cMBs and spontaneous hemorrhage. Since statins are known for their benefit in vascular disease we tested for the effect on CAA. Methods: APP23-transgenic mice received atorvastatin-supplemented food starting at the age of eight months (n = 13, 12 months (n = 7, and 16 months (n = 6, respectively. Controls (n = 16 received standard food only. At 24 months of age cMBs were determined with T2*-weighted 9.4T magnetic resonance imaging and graded by size. Results: Control mice displayed an average of 35 ± 18.5 cMBs (mean ± standard deviation, compared to 29.3 ± 9.8 in mice with eight months (p = 0.49, 24.9 ± 21.3 with 12 months (p = 0.26, and 27.8 ± 15.4 with 16 months of atorvastatin treatment (p = 0.27. In combined analysis treated mice showed lower absolute numbers (27.4 ± 15.6, p = 0.16 compared to controls and also after adjustment for cMB size (p = 0.13. Conclusion: Despite to a non-significant trend towards fewer cMBs our results failed to provide evidence for beneficial effects of long-term atorvastatin treatment in the APP23-transgenic mouse model of CAA. A higher risk for bleeding complications was not observed.

  11. Traffic jam at the blood-brain barrier promotes greater accumulation of Alzheimer's disease amyloid-β proteins in the cerebral vasculature.

    Science.gov (United States)

    Agyare, Edward K; Leonard, Sarah R; Curran, Geoffry L; Yu, Caroline C; Lowe, Val J; Paravastu, Anant K; Poduslo, Joseph F; Kandimalla, Karunya K

    2013-05-06

    Amyloid-β (Aβ) deposition in the brain vasculature results in cerebral amyloid angiopathy (CAA), which occurs in about 80% of Alzheimer's disease (AD) patients. While Aβ42 predominates parenchymal amyloid plaques in AD brain, Aβ40 is prevalent in the cerebrovascular amyloid. Dutch mutation of Aβ40 (E22Q) promotes aggressive cerebrovascular accumulation and leads to severe CAA in the mutation carriers; knowledge of how DutchAβ40 drives this process more efficiently than Aβ40 could reveal various pathophysiological events that promote CAA. In this study we have demonstrated that DutchAβ40 shows preferential accumulation in the blood-brain-barrier (BBB) endothelial cells due to its inefficient blood-to-brain transcytosis. Consequently, DutchAβ40 establishes a permeation barrier in the BBB endothelium, prevents its own clearance from the brain, and promotes the formation of amyloid deposits in the cerebral microvessels. The BBB endothelial accumulation of native Aβ40 is not robust enough to exercise such a significant impact on its brain clearance. Hence, the cerebrovascular accumulation of Aβ40 is slow and may require other copathologies to precipitate into CAA. In conclusion, the magnitude of Aβ accumulation in the BBB endothelial cells is a critical factor that promotes CAA; hence, clearing vascular endothelium of Aβ proteins may halt or even reverse CAA.

  12. Induction of complement proteins in a mouse model for cerebral microvascular Aβ deposition

    OpenAIRE

    DeFilippis Kelly; Fan Rong; Van Nostrand William E

    2007-01-01

    Abstract The deposition of amyloid β-protein (Aβ) in cerebral vasculature, known as cerebral amyloid angiopathy (CAA), is a common pathological feature of Alzheimer's disease and related disorders. In familial forms of CAA single mutations in the Aβ peptide have been linked to the increase of vascular Aβ deposits accompanied by a strong localized activation of glial cells and elevated expression of neuroinflammatory mediators including complement proteins. We have developed human amyloid-β pr...

  13. Amyloid-Beta Related Angiitis of the Central Nervous System: Case Report and Topic Review

    Directory of Open Access Journals (Sweden)

    Amre eNouh

    2014-02-01

    Full Text Available Amyloid-beta related angiitis (ABRA of the central nervous system (CNS is a rare disorder with overlapping features of primary angiits of the CNS (PACNS and cerebral amyloid angiopathy (CAA. We evaluated a 74-year-old man with intermittent left sided weakness and MRI findings of leptomeningeal enhancement, vasogenic edema and subcortical white matter disease proven to have ABRA. We discuss clinicopathological features and review the topic of ABRA.

  14. 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.

  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...... angiopathy, and the tauopathy, to possible neurofibrillary tangles. Six aged monkeys were selected based on their spatial memory performance and profile of biomarkers of AD, divided equally to affected aged subject - with Memory-affected and low amyloid level, and aged with higher performance in memory...... and amyloid, as the age-matched subjects. Using immunohistochemistry, plaques of amyloid beta1-42 were observed in two out of three brains of aged subjects with memory impairment and biomarkers indicative of AD. The cerebral amyloid angiopathy was observed in both aged monkey groups, and unlike in the human...

  16. Preparation of Amyloid Fibrils Seeded from Brain and Meninges.

    Science.gov (United States)

    Scherpelz, Kathryn P; Lu, Jun-Xia; Tycko, Robert; Meredith, Stephen C

    2016-01-01

    Seeding of amyloid fibrils into fresh solutions of the same peptide or protein in disaggregated form leads to the formation of replicate fibrils, with close structural similarity or identity to the original fibrillar seeds. Here we describe procedures for isolating fibrils composed mainly of β-amyloid (Aβ) from human brain and from leptomeninges, a source of cerebral blood vessels, for investigating Alzheimer's disease and cerebral amyloid angiopathy. We also describe methods for seeding isotopically labeled, disaggregated Aβ peptide solutions for study using solid-state NMR and other techniques. These methods should be applicable to other types of amyloid fibrils, to Aβ fibrils from mice or other species, tissues other than brain, and to some non-fibrillar aggregates. These procedures allow for the examination of authentic amyloid fibrils and other protein aggregates from biological tissues without the need for labeling the tissue.

  17. Mirror Image of the Amyloid-β Species in Cerebrospinal Fluid and Cerebral Amyloid in Alzheimer's Disease.

    Science.gov (United States)

    Catania, Marcella; Di Fede, Giuseppe; Tonoli, Elisa; Benussi, Luisa; Pasquali, Claudio; Giaccone, Giorgio; Maderna, Emanuela; Ghidoni, Roberta; Tagliavini, Fabrizio

    2015-01-01

    Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation in brain that is paralleled by Aβ(1-42) reduction in cerebrospinal fluid (CSF). We analyzed the pattern of Aβ peptides, including the N- and C-terminal truncated fragments, in brain and CSF from two familial and one sporadic AD cases. We found that (i) each patient is characterized by a distinct Aβ profile in CSF and brain deposits and (ii) the CSF Aβ pattern mirrors the Aβ profile of cerebral amyloid. These results suggest the existence of different molecular AD subtypes which can be recognized by CSF analysis, enabling patient stratification.

  18. Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease

    DEFF Research Database (Denmark)

    Weiner, H L; Lemere, C A; Maron, R;

    2000-01-01

    Progressive cerebral deposition of amyloid-beta (Abeta) peptide, an early and essential feature of Alzheimer's disease (AD), is accompanied by an inflammatory reaction marked by microgliosis, astrocytosis, and the release of proinflammatory cytokines. Mucosal administration of disease......-Abeta antibodies of the IgG1 and IgG2b classes, and mononuclear cells in the brain expressing the anti-inflammatory cytokines interleukin-4, interleukin-10, and tumor growth factor-beta. Our results demonstrate that chronic nasal administration of Abeta peptide can induce an immune response to Abeta that decreases...

  19. Association of brain amyloid-β with cerebral perfusion and structure in Alzheimer's disease and mild cognitive impairment.

    Science.gov (United States)

    Mattsson, Niklas; Tosun, Duygu; Insel, Philip S; Simonson, Alix; Jack, Clifford R; Beckett, Laurel A; Donohue, Michael; Jagust, William; Schuff, Norbert; Weiner, Michael W

    2014-05-01

    Patients with Alzheimer's disease have reduced cerebral blood flow measured by arterial spin labelling magnetic resonance imaging, but it is unclear how this is related to amyloid-β pathology. Using 182 subjects from the Alzheimer's Disease Neuroimaging Initiative we tested associations of amyloid-β with regional cerebral blood flow in healthy controls (n = 51), early (n = 66) and late (n = 41) mild cognitive impairment, and Alzheimer's disease with dementia (n = 24). Based on the theory that Alzheimer's disease starts with amyloid-β accumulation and progresses with symptoms and secondary pathologies in different trajectories, we tested if cerebral blood flow differed between amyloid-β-negative controls and -positive subjects in different diagnostic groups, and if amyloid-β had different associations with cerebral blood flow and grey matter volume. Global amyloid-β load was measured by florbetapir positron emission tomography, and regional blood flow and volume were measured in eight a priori defined regions of interest. Cerebral blood flow was reduced in patients with dementia in most brain regions. Higher amyloid-β load was related to lower cerebral blood flow in several regions, independent of diagnostic group. When comparing amyloid-β-positive subjects with -negative controls, we found reductions of cerebral blood flow in several diagnostic groups, including in precuneus, entorhinal cortex and hippocampus (dementia), inferior parietal cortex (late mild cognitive impairment and dementia), and inferior temporal cortex (early and late mild cognitive impairment and dementia). The associations of amyloid-β with cerebral blood flow and volume differed across the disease spectrum, with high amyloid-β being associated with greater cerebral blood flow reduction in controls and greater volume reduction in late mild cognitive impairment and dementia. In addition to disease stage, amyloid-β pathology affects cerebral blood flow across the span from controls to

  20. Association between Cerebral Amyloid Deposition and Clinical Factors Including Cognitive Function in Geriatric Depression: Pilot Study Using Amyloid Positron Emission Tomography

    Science.gov (United States)

    Kim, Hye-Geum; Kong, Eun-Jung; Cheon, Eun-Jin; Kim, Hae-Won; Koo, Bon-Hoon

    2016-01-01

    The purpose of this study was to explore the relationship between cerebral amyloid deposition and overall clinical factors including cognitive functions in geriatric depression by using 18F-florbetaben positron emission tomography. Thirteen subjects aged over 60 years who had a history of major depressive disorder and also had subjective memory complaint were included. Of all subjects, 3 subjects judged as amyloid positive, and the others judged as amyloid negative. Their memory, visuospatial functions and attention abilities were negatively correlated with amyloid deposition in specific brain regions, but their language and recognition abilities were not correlated with any region. The amyloid deposition of the whole brain region was significantly negatively correlated with immediate memory. PMID:27776391

  1. Cystatin C (CST3), the candidate gene for hereditary cystatin C amyloid angiopathy (HCCAA), and other members of the cystatin gene family are clustered on chromosome 20p11. 2

    Energy Technology Data Exchange (ETDEWEB)

    Schnittger, S.; Gopal Rao, V.V.N.; Hansmann, I. (Universitaet Goettingen (Germany)); Abrahamson, M. (Univ. of Lund (Sweden))

    1993-04-01

    The cystatin C gene (CST3) encodes a low-molecular-weight cysteine proteinase inhibitor belonging to family II of the cystatin superfamily and is mutated in cases of hereditary cystatin C amyloid angiopathy (HCCAA). CST3, which along with other family II cystatin genes is a member of the cystatin gene family, has been assigned to chromosome 20. To investigate the genomic organization on chromosome 20, the CST3 gene and related sequences were regionally mapped by fluorescence in situ hybridization (FISH), Southern blot, and pulsed-field gel electrophoresis (PFGE) analysis using the CDNA cystatin C probe C6a and three genomic probes, C3E1, C3E2, and C3E2-2. Probe C3E2-2, which like probe C3E2 is specific for CST3, hybridized to only one HindIII and one XbaI fragment on Southern blots and to a 300-kb BssHII PFGE fragment. FISH with probe C3E2 mapped this locus to chromosome 20p11.2, with an FL-pter value of 0.37 [+-] 0.07 on the physical map. Probe C3E1 containing the most conserved cystatin gene exon (exon 1) and its flanking sequences hybridized with more fragments, e.g., to eight XbaI and nine HindIII fragments on conventional Southern blots and to eight SmaI, two BssHII (900 and 300 kb), and two Notl fragments after PFGE. FISH with C3E1 revealed only one single site at 20p11.2 with an FL-pter value of 0.37 [+-] 0.04, identical to that obtained with C3E2. From these results it is concluded that (1) exon 1 and its flanking sequences are preferentially conserved within the cystatin gene family and that (2) CST3 and probably seven other members of the cystatin gene family are clustered within an at maximum 1.2-Mb segment on chromosome 20p11.2. 45 refs., 5 figs., 1 tab.

  2. Intravenous delivery of targeted liposomes to amyloid-β pathology in APP/PSEN1 transgenic mice.

    Directory of Open Access Journals (Sweden)

    Eric A Tanifum

    Full Text Available Extracellular amyloid-β (Aβ plaques and intracellular neurofibrillary tangles constitute the major neuropathological hallmarks of Alzheimer's disease (AD. It is now apparent that parenchymal Aβ plaque deposition precedes behavioral signs of disease by several years. The development of agents that can target these plaques may be useful as diagnostic or therapeutic tools. In this study, we synthesized an Aβ-targeted lipid conjugate, incorporated it in stealth liposomal nanoparticles and tested their ability to bind amyloid plaque deposits in an AD mouse model. The results show that the particles maintain binding profiles to synthetic Aβ aggregates comparable to the free ligand, and selectively bind Aβ plaque deposits in brain tissue sections of an AD mouse model (APP/PSEN1 transgenic mice with high efficiency. When administered intravenously, these long circulating nanoparticles appear to cross the blood-brain barrier and bind to Aβ plaque deposits, labeling parenchymal amyloid deposits and vascular amyloid characteristic of cerebral amyloid angiopathy.

  3. Amyloid-β and Astrocytes Interplay in Amyloid-β Related Disorders

    Directory of Open Access Journals (Sweden)

    Yazan S. Batarseh

    2016-03-01

    Full Text Available 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.

  4. Cerebral serotonin 4 receptors and amyloid-β in early Alzheimer's disease

    DEFF Research Database (Denmark)

    Madsen, Karine; Neumann, Wolf-Julian; Holst, Klaus Kähler

    2011-01-01

    patients and eight healthy controls additionally underwent a [11C]PIB PET scan to measure the cortical Aß burden. When AD patients were defined on clinical criteria, no difference in cerebral 5-HT4 receptor binding between AD patients and healthy controls was found (p = 0.54). However, when individuals...... were reassigned to groups according to their amyloid status, the PIB-positive individuals had 13% higher 5-HT4 receptor levels than PIB-negative individuals (p = 0.02) and the importance of classification of groups is emphasized. The 5-HT4 receptor binding was a positively correlated to Aß burden (p...

  5. Cerebral small vessel disease: targeting oxidative stressas a novel therapeutic strategy?

    Directory of Open Access Journals (Sweden)

    Alyson Anne Miller

    2016-03-01

    Full Text Available Cerebral small vessel disease (SVD is a major contributor to stroke, and a leading cause of cognitive impairment and dementia. Despite the devastating effects of cerebral SVD, the pathogenesis of cerebral SVD is still not completely understood. Moreover, there are no specific pharmacological strategies for its prevention or treatment. Cerebral SVD is characterized by marked functional and structural abnormalities of the cerebral microcirculation. The clinical manifestations of these pathological changes include lacunar infarcts, white matter hyperintensities, and cerebral microbleeds. The main purpose of this review is to discuss evidence implicating oxidative stress in the ateriopathy of both non-amyloid and amyloid (cerebral amyloid angiopathy forms of cerebral SVD and its most important risk factors (hypertension and aging, as well as its contribution to cerebral SVD-related brain injury and cognitive impairment. We also highlight current evidence of the involvement of the NADPH oxidases in the development of oxidative stress, enzymes that are a major source of reactive oxygen species in the cerebral vasculature. Lastly, we discuss potential pharmacological strategies for oxidative stress in cerebral SVD, including some of the historical and emerging NADPH oxidase inhibitors.

  6. Absence of beta-amyloid in cortical cataracts of donors with and without Alzheimer's disease.

    Science.gov (United States)

    Michael, Ralph; Rosandić, Jurja; Montenegro, Gustavo A; Lobato, Elvira; Tresserra, Francisco; Barraquer, Rafael I; Vrensen, Gijs F J M

    2013-01-01

    Eye lenses from human donors with and without Alzheimer's disease (AD) were studied to evaluate the presence of amyloid in cortical cataract. We obtained 39 lenses from 21 postmortem donors with AD and 15 lenses from age-matched controls provided by the Banco de Ojos para Tratamientos de la Ceguera (Barcelona, Spain). For 17 donors, AD was clinically diagnosed by general physicians and for 4 donors the AD diagnosis was neuropathologically confirmed. Of the 21 donors with AD, 6 had pronounced bilateral cortical lens opacities and 15 only minor or no cortical opacities. As controls, 7 donors with pronounced cortical opacities and 8 donors with almost transparent lenses were selected. All lenses were photographed in a dark field stereomicroscope. Histological sections were analyzed using a standard and a more sensitive Congo red protocol, thioflavin staining and beta-amyloid immunohistochemistry. Brain tissue from two donors, one with cerebral amyloid angiopathy and another with advanced AD-related changes and one cornea with lattice dystrophy were used as positive controls for the staining techniques. Thioflavin, standard and modified Congo red staining were positive in the control brain tissues and in the dystrophic cornea. Beta-amyloid immunohistochemistry was positive in the brain tissues but not in the cornea sample. Lenses from control and AD donors were, without exception, negative after Congo red, thioflavin, and beta-amyloid immunohistochemical staining. The results of the positive control tissues correspond well with known observations in AD, amyloid angiopathy and corneas with lattice dystrophy. The absence of staining in AD and control lenses with the techniques employed lead us to conclude that there is no beta-amyloid in lenses from donors with AD or in control cortical cataracts. The inconsistency with previous studies of Goldstein et al. (2003) and Moncaster et al. (2010), both of which demonstrated positive Congo red, thioflavin, and beta-amyloid

  7. Cholinergic Neurons - Keeping Check on Amyloid beta in the Cerebral Cortex

    Directory of Open Access Journals (Sweden)

    Saak V. Ovsepian

    2013-12-01

    Full Text Available The physiological relevance of the uptake of ligands with no apparent trophic functions via the p75 neurotrophin receptor (p75NTR remains unclear. Herein, we propose a homeostatic role for this in clearance of amyloid β (Aβ in the brain. We hypothesize that uptake of Aβ in conjunction with p75NTR followed by its degradation in lysosomes endows cholinergic basalo-cortical projections enriched in this receptor a facility for maintaining physiological levels of Aβ in target areas. Thus, in addition to the diffuse modulator influence and channeling of extra-thalamic signals, cholinergic innervations could supply the cerebral cortex with an elaborate system for Aβ drainage. Interpreting the emerging relationship of new molecular data with established role of cholinergic modulator system in regulating cortical network dynamics should provide new insights into the brain physiology and mechanisms of neuro-degenerative diseases.

  8. Diabetic angiopathy and angiogenic defects

    Directory of Open Access Journals (Sweden)

    Xu Ling

    2012-08-01

    Full Text Available Abstract Diabetes is one of the most serious health problems in the world. A major complication of diabetes is blood vessel disease, termed angiopathy, which is characterized by abnormal angiogenesis. In this review, we focus on angiogenesis abnormalities in diabetic complications and discuss its benefits and drawbacks as a therapeutic target for diabetic vascular complications. Additionally, we discuss glucose metabolism defects that are associated with abnormal angiogenesis in atypical diabetic complications such as cancer.

  9. Targeting vascular amyloid in arterioles of Alzheimer disease transgenic mice with amyloid β protein antibody-coated nanoparticles.

    Science.gov (United States)

    Poduslo, Joseph F; Hultman, Kristi L; Curran, Geoffry L; Preboske, Gregory M; Chamberlain, Ryan; Marjańska, Małgorzata; Garwood, Michael; Jack, Clifford R; Wengenack, Thomas M

    2011-08-01

    The relevance of cerebral amyloid angiopathy (CAA) to the pathogenesis of Alzheimer disease (AD) and dementia in general emphasizes the importance of developing novel targeting approaches for detecting and treating cerebrovascular amyloid (CVA) deposits. We developed a nanoparticle-based technology that uses a monoclonal antibody against fibrillar human amyloid-β42 that is surface coated onto a functionalized phospholipid monolayer. We demonstrate that this conjugated nanoparticle binds to CVA deposits in arterioles of AD transgenic mice (Tg2576) after infusion into the external carotid artery using 3 different approaches. The first 2 approaches use a blood vessel enrichment of homogenized brain and a leptomeningeal vessel preparation from thin tangential brain slices from the surface of the cerebral cortex. Targeting of CVA by the antibody-coated nanoparticle was visualized using fluorescent lissamine rhodamine-labeled phospholipids in the nanoparticles, which were compared with fluorescent staining of the endothelial cells and amyloid deposits using confocal laser scanning microscopy. The third approach used high-field strength magnetic resonance imaging of antibody-coated iron oxide nanoparticles after infusion into the external carotid artery. Dark foci of contrast enhancement in cortical arterioles were observed in T2*-weighted images of ex vivo AD mouse brains that correlated histologically with CVA deposits. The targeting ability of these nanoparticles to CVA provides opportunities for the prevention and treatment of CAA.

  10. Bapineuzumab alters aβ composition: implications for the amyloid cascade hypothesis and anti-amyloid immunotherapy.

    Directory of Open Access Journals (Sweden)

    Alex E Roher

    Full Text Available The characteristic neuropathological changes associated with Alzheimer's disease (AD and other lines of evidence support the amyloid cascade hypothesis. Viewing amyloid deposits as the prime instigator of dementia has now led to clinical trials of multiple strategies to remove or prevent their formation. We performed neuropathological and biochemical assessments of 3 subjects treated with bapineuzumab infusions. Histological analyses were conducted to quantify amyloid plaque densities, Braak stages and the extent of cerebral amyloid angiopathy (CAA. Amyloid-β (Aβ species in frontal and temporal lobe samples were quantified by ELISA. Western blots of amyloid-β precursor protein (AβPP and its C-terminal (CT fragments as well as tau species were performed. Bapineuzumab-treated (Bapi-AD subjects were compared to non-immunized age-matched subjects with AD (NI-AD and non-demented control (NDC cases. Our study revealed that Bapi-AD subjects exhibited overall amyloid plaque densities similar to those of NI-AD cases. In addition, CAA was moderate to severe in NI-AD and Bapi-AD patients. Although histologically-demonstrable leptomeningeal, cerebrovascular and neuroparenchymal-amyloid densities all appeared unaffected by treatment, Aβ peptide profiles were significantly altered in Bapi-AD subjects. There was a trend for reduction in total Aβ42 levels as well as an increase in Aβ40 which led to a corresponding significant decrease in Aβ42:Aβ40 ratio in comparison to NI-AD subjects. There were no differences in the levels of AβPP, CT99 and CT83 or tau species between Bapi-AD and NI-AD subjects. The remarkable alteration in Aβ profiles reveals a dynamic amyloid production in which removal and depositional processes were apparently perturbed by bapineuzumab therapy. Despite the alteration in biochemical composition, all 3 immunized subjects exhibited continued cognitive decline.

  11. The presence of heparan sulfate proteoglycans in the neuritic plaques and congophilic angiopathy in Alzheimer's disease.

    OpenAIRE

    Snow, A. D.; Mar, H.; Nochlin, D.; Kimata, K.; Kato, M; Suzuki, S.; Hassell, J.; Wight, T. N.

    1988-01-01

    Two immunocytochemical probes were used to specifically identify and localize heparan sulphate proteoglycans (HSPGs) in 17 cases of Alzheimer's disease (AD). A monoclonal (HK-102) and an affinity-purified polyclonal antibody, each recognizing specific domains on the protein core of a basement membrane-derived HSPG, localized HSPGs to the amyloid fibrils present in neuritic plaques (NPs) and congophilic angiopathy (CA) in the brains of Alzheimer's patients, with weak to no immunostaining in ne...

  12. Influence of apolipoprotein E and its receptors on cerebral amyloid precursor protein metabolism following traumatic brain injury

    Institute of Scientific and Technical Information of China (English)

    ZHOU Shuai; SUN Xiao-chuan

    2012-01-01

    Traumatic brain injury (TBI) is the leading cause of mortality and disability among young individuals in our society,and globally the incidence of TBI is rising sharply.Mounting evidence has indicated that apolipoprotein E (apoE:protein; APOE:gene) genotype influences the outcome after TBI.The proposed mechanism by which APOE affects the clinicopathological consequences of TBI is multifactorial and includes amyloid deposition,disruption of lipid distribution,dysfunction of mitochondrial energy production,oxidative stress and increases intracellular calcium in response to injury.This paper reviews the current state of knowledge regarding the influence of apoE and its receptors on cerebral amyloid betaprotein precursor metabolism following TBI.

  13. Matrix metalloproteinase 2 (MMP-2) degrades soluble vasculotropic amyloid-beta E22Q and L34V mutants, delaying their toxicity for human brain microvascular endothelial cells.

    Science.gov (United States)

    Hernandez-Guillamon, Mar; Mawhirt, Stephanie; Fossati, Silvia; Blais, Steven; Pares, Mireia; Penalba, Anna; Boada, Merce; Couraud, Pierre-Olivier; Neubert, Thomas A; Montaner, Joan; Ghiso, Jorge; Rostagno, Agueda

    2010-08-27

    Patients carrying mutations within the amyloid-beta (Abeta) sequence develop severe early-onset cerebral amyloid angiopathy with some of the related variants manifesting primarily with hemorrhagic phenotypes. Matrix metalloproteases (MMPs) are typically associated with blood brain barrier disruption and hemorrhagic transformations after ischemic stroke. However, their contribution to cerebral amyloid angiopathy-related hemorrhage remains unclear. Human brain endothelial cells challenged with Abeta synthetic homologues containing mutations known to be associated in vivo with hemorrhagic manifestations (AbetaE22Q and AbetaL34V) showed enhanced production and activation of MMP-2, evaluated via Multiplex MMP antibody arrays, gel zymography, and Western blot, which in turn proteolytically cleaved in situ the Abeta peptides. Immunoprecipitation followed by mass spectrometry analysis highlighted the generation of specific C-terminal proteolytic fragments, in particular the accumulation of Abeta-(1-16), a result validated in vitro with recombinant MMP-2 and quantitatively evaluated using deuterium-labeled internal standards. Silencing MMP-2 gene expression resulted in reduced Abeta degradation and enhanced apoptosis. Secretion and activation of MMP-2 as well as susceptibility of the Abeta peptides to MMP-2 degradation were dependent on the peptide conformation, with fibrillar elements of AbetaE22Q exhibiting negligible effects. Our results indicate that MMP-2 release and activation differentially degrades Abeta species, delaying their toxicity for endothelial cells. However, taking into consideration MMP ability to degrade basement membrane components, these protective effects might also undesirably compromise blood brain barrier integrity and precipitate a hemorrhagic phenotype.

  14. Brain Endothelial Cells Produce Amyloid β from Amyloid Precursor Protein 770 and Preferentially Secrete the O-Glycosylated Form*

    Science.gov (United States)

    Kitazume, Shinobu; Tachida, Yuriko; Kato, Masaki; Yamaguchi, Yoshiki; Honda, Takashi; Hashimoto, Yasuhiro; Wada, Yoshinao; Saito, Takashi; Iwata, Nobuhisa; Saido, Takaomi; Taniguchi, Naoyuki

    2010-01-01

    Deposition of amyloid β (Aβ) in the brain is closely associated with Alzheimer disease (AD). Aβ is generated from amyloid precursor protein (APP) by the actions of β- and γ-secretases. In addition to Aβ deposition in the brain parenchyma, deposition of Aβ in cerebral vessel walls, termed cerebral amyloid angiopathy, is observed in more than 80% of AD individuals. The mechanism for how Aβ accumulates in blood vessels remains largely unknown. In the present study, we show that brain endothelial cells expressed APP770, a differently spliced APP mRNA isoform from neuronal APP695, and produced Aβ40 and Aβ42. Furthermore, we found that the endothelial APP770 had sialylated core 1 type O-glycans. Interestingly, Ο-glycosylated APP770 was preferentially processed by both α- and β-cleavage and secreted into the media, suggesting that O-glycosylation and APP processing involved related pathways. By immunostaining human brain sections with an anti-APP770 antibody, we found that APP770 was expressed in vascular endothelial cells. Because we were able to detect O-glycosylated sAPP770β in human cerebrospinal fluid, this unique soluble APP770β has the potential to serve as a marker for cortical dementias such as AD and vascular dementia. PMID:20952385

  15. Inhibiting p38 mitogen-activated protein kinase attenuates cerebral ischemic injury in Swedish mutant amyloid precursor protein transgenic mice

    Institute of Scientific and Technical Information of China (English)

    Liangyu Zou; Haiyan Qin; Yitao He; Heming Huang; Yi Lu; Xiaofan Chu

    2012-01-01

    Cerebral ischemia was induced using photothrombosis 1 hour after intraperitoneal injection of the p38 mitogen-activated protein kinase (MAPK) inhibitor SB239063 into Swedish mutant amyloid precursor protein (APP/SWE) transgenic and non-transgenic mice. The number of surviving neurons in the penumbra was quantified using Nissl staining, and the activity of p38 MAPKs was measured by western blotting. The number of surviving neurons in the penumbra was significantly reduced in APP/SWE transgenic mice compared with non-transgenic controls 7 days after cerebral ischemia, but the activity of p38 MAPKs was significantly elevated compared with the non-ischemic hemisphere in the APP/SWE transgenic mice. SB239063 prevented these changes. The APP/SWE mutation exacerbated ischemic brain injury, and this could be alleviated by inhibiting p38 MAPK activity.

  16. Colocalisation of plasma derived apo B lipoproteins with cerebral proteoglycans in a transgenic-amyloid model of Alzheimer's disease.

    Science.gov (United States)

    Lam, Virginie; Takechi, Ryusuke; Pallebage-Gamarallage, Menuka Madhavi Sompala; Galloway, Susan; Mamo, John C L

    2011-04-04

    Alzheimer's disease (AD) is characterized by cerebral proteinaceous deposits comprised of amyloid beta (Aβ). Evidence suggests that enhanced blood-to-brain delivery of Aβ occurs when plasma concentration is increased, exacerbating amyloidosis. In blood, significant Aβ is associated with apolipoprotein (apo) B lipoproteins. In this study, immunofluorescent microscopy was utilised to explore if there is an association between apo B lipoproteins and proteoglycan expression within Aβ-rich plaques in transgenic-amyloid mice. Focal accumulation of apo B was found with Aβ-plaque in APP/PS1 mice. There was enrichment in the proteoglycans, agrin, perlecan, biglycan and decorin within the core of dense Aβ-plaque. Perlecan, biglycan and decorin were positively associated with apo B lipoprotein abundance within amyloid plaque consistent with a cause-for-retention effect. These findings show that proteoglycans are an integral component of Aβ deposits in APP/PS1 mice. This study suggests that some proteoglycans contribute to Aβ retention, whilst other proteoglycans have different functions in the aetiology of AD.

  17. Differences in functional brain connectivity alterations associated with cerebral amyloid deposition in amnestic mild cognitive impairment

    Directory of Open Access Journals (Sweden)

    Dahyun eYi

    2015-02-01

    Full Text Available Despite potential implications for the early detection of impending AD, very little is known about the differences of large scale brain networks between amnestic MCI (aMCI with high cerebral amyloid beta protein (Aβ deposition (i.e., aMCI+ and aMCI with no or very little Aβ deposition (i.e., aMCI-. We first aimed to extend the current literature on altering intrinsic functional connectivity (FC of the default mode network (DMN and salience network (SN from CN to AD dementia. Second, we further examined the differences of the DMN and the SN between aMCI-, aMCI+, and CN. Forty-three older adult (12 CN, 10 aMCI+, 10 aMCI-, and 11 AD dementia subjects were included. All participants received clinical and neuropsychological assessment, resting state functional MRI, structural MRI, and Pittsburgh compound-B-PET scans. FC data were preprocessed using Multivariate Exploratory Linear Optimized Decomposition into Independent Components of FSL. Group comparisons were carried out using the dual-regression approach. In addition, to verify presence of grey matter (GM volume changes with intrinsic functional network alterations, Voxel Based Morphometry was performed on the acquired T1-weighted data. As expected, AD dementia participants exhibited decreased FC in the DMN compared to CN (in precuneus and cingulate gyrus. The degree of alteration in the DMN in aMCI+ compared to CN was intermediate to that of AD. In contrast, aMCI- exhibited increased FC in the DMN compared to CN (in precuneus as well as aMCI+. In terms of the SN, aMCI- exhibited decreased FC compared to both CN and aMCI+ particularly in the inferior frontal gyrus. FC within the SN in aMCI+ and AD did not differ from CN. Compared to CN, aMCI- showed atrophy in bilateral superior temporal gyri whereas aMCI+ showed atrophy in right precuneus. The results indicate that despite of the similarity in cross-sectional cognitive features aMCI- has quite different functional brain connectivity compared to

  18. Fertility defects in mice expressing the L68Q variant of human cystatin C: a role for amyloid in male infertility.

    Science.gov (United States)

    Whelly, Sandra; Serobian, Gaiane; Borchardt, Clinton; Powell, Jonathan; Johnson, Seethal; Hakansson, Katarina; Lindstrom, Veronica; Abrahamson, Magnus; Grubb, Anders; Cornwall, Gail A

    2014-03-14

    Hereditary cystatin C amyloid angiopathy is an autosomal dominant disorder in which a variant form of cystatin C (L68Q) readily forms amyloid deposits in cerebral arteries in affected individuals resulting in early death. L68Q protein deposits in human cystatin C amyloid angiopathy patients have also been found in tissues outside of the brain including the testis, suggesting possible effects on fertility. Heterozygous transgenic mice (L68Q) that express the human L68Q variant of cystatin C under the control of the mouse cystatin C promoter were unable to generate offspring, suggesting the presence of L68Q cystatin C amyloid affected sperm function. In vitro studies showed that epididymal spermatozoa from L68Q mice were unable to fertilize oocytes and exhibited poor sperm motility. Furthermore, spermatozoa from L68Q mice exhibited reduced cell viability compared with wild type (WT) spermatozoa and often were detected in large agglutinated clumps. Examination of the epididymal fluid and spermatozoa from L68Q mice showed increased levels and distinct forms of cystatin C amyloid that were not present in WT mice. The addition of epididymal fluid from L68Q mice to WT spermatozoa resulted in a recapitulation of the L68Q phenotype in that WT spermatozoa showed reduced cell viability and motility compared with WT spermatozoa incubated in epididymal fluid from WT mice. L68Q epididymal fluid that was depleted of cystatin C amyloids, however, did not impair the motility of WT spermatozoa. Taken together these studies suggest that amyloids in the epididymal fluid can be cytotoxic to the maturing spermatozoa resulting in male infertility.

  19. The roles of amyloid βprotein in neurovascular unit injiny%β淀粉样蛋白在神经血管单元损伤中的作用

    Institute of Scientific and Technical Information of China (English)

    魏微; 张微微

    2009-01-01

    β淀粉样蛋白(mlyloid-β,Aβ)沉积是脑淀粉样血管病(cerebral amyloid angiopathy,CAA)和阿尔茨海默病(Alzheimer's disease,AD)的关键病理学基础.目前的研究强调,神经血管单元细胞之间内环境的稳定是维持脑功能正常的关键.本文综述了Aβ与神经血管单元损伤的关系,期望对CAA和AD的临床防治提供一些新的思路.%The deposition of amyloid β-protein (Aβ is the key pathological basis of cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD). The current studies emphasis that the stability of internal environment between cells of the neurovascular unit is the key to maintain normal brain function. This article reviews the relationship between the Aβand the neurovascular unit injury, and we expect to provide some new ideas for the clinical prevention and treatment of CAA and AD.

  20. Intermolecular alignment in Y145Stop human prion protein amyloid fibrils probed by solid-state NMR spectroscopy.

    Science.gov (United States)

    Helmus, Jonathan J; Surewicz, Krystyna; Apostol, Marcin I; Surewicz, Witold K; Jaroniec, Christopher P

    2011-09-07

    The Y145Stop mutant of human prion protein, huPrP23-144, has been linked to PrP cerebral amyloid angiopathy, an inherited amyloid disease, and also serves as a valuable in vitro model for investigating the molecular basis of amyloid strains. Prior studies of huPrP23-144 amyloid by magic-angle-spinning (MAS) solid-state NMR spectroscopy revealed a compact β-rich amyloid core region near the C-terminus and an unstructured N-terminal domain. Here, with the focus on understanding the higher-order architecture of huPrP23-144 fibrils, we probed the intermolecular alignment of β-strands within the amyloid core using MAS NMR techniques and fibrils formed from equimolar mixtures of (15)N-labeled protein and (13)C-huPrP23-144 prepared with [1,3-(13)C(2)] or [2-(13)C]glycerol. Numerous intermolecular correlations involving backbone atoms observed in 2D (15)N-(13)C spectra unequivocally suggest an overall parallel in-register alignment of the β-sheet core. Additional experiments that report on intermolecular (15)N-(13)CO and (15)N-(13)Cα dipolar couplings yielded an estimated strand spacing that is within ∼10% of the distances of 4.7-4.8 Å typical for parallel β-sheets.

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

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    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.

  2. β-Amyloid (1–42 Levels in Cerebrospinal Fluid and Cerebral Atrophy in Mild Cognitive Impairment and Alzheimer’s Disease

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    Elmar Kaiser

    2011-11-01

    Full Text Available Background: Recent studies consistently reported Alzheimer’s disease (AD and, to a lower extent, mild cognitive impairment (MCI to be accompanied by reduced cerebrospinal fluid (CSF levels of β-amyloid. However, how these changes are related to brain morphological alterations is so far only partly understood. Methods: CSF levels of β-amyloid (1–42 were examined with respect to cerebral atrophy in 23 subjects with MCI, 16 patients with mild-to-moderateAlzheimer’s disease (AD and 15 age-matched controls by using magnetic resonance imaging and voxel-based morphometry (VBM. Results: When contrasted with the controls, β-amyloid (1–42 levels were significantly lower (p Conclusion: Our finding confirms the results of previous studies and suggests that both the decrease in β-amyloid (1–42 and the development of hippocampal atrophy coincide in the disease process.

  3. Hemodynamic effects of combined focal cerebral ischemia and amyloid protein toxicity in a rat model: a functional CT study.

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    Jun Yang

    Full Text Available BACKGROUND/OBJECTIVE: Clinical evidence indicates that cerebral ischemia (CI and a pathological factor of Alzheimer's disease, the β-amyloid (Aβ protein, can increase the rate of cognitive impairment in the ageing population. Using the CT Perfusion (CTP functional imaging, we sought to investigate the interaction between CI and the Aβ protein on cerebral hemodynamics. METHODS: A previously established rat model of CI and Aβ was used for the CTP study. Iodinated contrast was given intravenously, while serial CT images of sixteen axial slices were acquired. Cerebral blood flow (CBF and blood volume (CBV parametric maps were co-registered to a rat brain atlas and regions of interest were drawn on the maps. Microvascular alteration was investigated with histopathology. RESULTS: CTP results revealed that ipsilateral striatum of Aβ+CI and CI groups showed significantly lower CBF and CBV than control at the acute phase. Striatal CBF and CBV increased significantly at week 1 in the CI and Aβ+CI groups, but not in the Aβ alone or control group. Histopathology showed that average density of dilated microvessels in the ipsilateral striatum in CI and Aβ+CI groups was significantly higher than control at week 1, indicating this could be associated with hyperperfusion and hypervolemia observed from CTP results. CONCLUSION: These results demonstrate that CTP can quantitatively measure the hemodynamic disturbance on CBF and CBV functional maps in a rat model of CI interacting with Aβ.

  4. Passive immunotherapy against Aβ in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage

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    Gordon Marcia N

    2004-12-01

    Full Text Available Abstract Background Anti-Aβ immunotherapy in transgenic mice reduces both diffuse and compact amyloid deposits, improves memory function and clears early-stage phospho-tau aggregates. As most Alzheimer disease cases occur well past midlife, the current study examined adoptive transfer of anti-Aβ antibodies to 19- and 23-month old APP-transgenic mice. Methods We investigated the effects of weekly anti-Aβ antibody treatment on radial-arm water-maze performance, parenchymal and vascular amyloid loads, and the presence of microhemorrhage in the brain. 19-month-old mice were treated for 1, 2 or 3 months while 23-month-old mice were treated for 5 months. Only the 23-month-old mice were subject to radial-arm water-maze testing. Results After 3 months of weekly injections, this passive immunization protocol completely reversed learning and memory deficits in these mice, a benefit that was undiminished after 5 months of treatment. Dramatic reductions of diffuse Aβ immunostaining and parenchymal Congophilic amyloid deposits were observed after five months, indicating that even well-established amyloid deposits are susceptible to immunotherapy. However, cerebral amyloid angiopathy increased substantially with immunotherapy, and some deposits were associated with microhemorrhage. Reanalysis of results collected from an earlier time-course study demonstrated that these increases in vascular deposits were dependent on the duration of immunotherapy. Conclusions The cognitive benefits of passive immunotherapy persist in spite of the presence of vascular amyloid and small hemorrhages. These data suggest that clinical trials evaluating such treatments will require precautions to minimize potential adverse events associated with microhemorrhage.

  5. Amyloid-β(25-35), an amyloid-β(1-42) surrogate, and proinflammatory cytokines stimulate VEGF-A secretion by cultured, early passage, normoxic adult human cerebral astrocytes.

    Science.gov (United States)

    Chiarini, Anna; Whitfield, James; Bonafini, Clara; Chakravarthy, Balu; Armato, Ubaldo; Dal Prà, Ilaria

    2010-01-01

    Cerebrovascular angiopathy affects late-onset Alzheimer's disease (LOAD) brains by possibly increasing vascular endothelial growth factor (VEGF). A expression, thereby stimulating endothelial cell proliferation and migration. Indeed, VEGF-A gene upregulation, with increased VEGF-A protein content of reactive astrocytes and microglia, occurs in LOAD brains, and neovascularization was observed one week after injecting amyloid-β (Aβ)(1-42) into rat hippocampus. We have now found, with cultured 'normoxic' normal adult human astrocytes (NAHAs), that fibrillar Aβ(25-35) (an active Aβ(1-42) fragment) or a cytokine mixture (the (CM)-trio (interleukin [IL]-1β+interferon [IFN]-γ+tumor necrosis factor [TNF]-α), or pair (IFN-γ+TNF-α) like those produced in LOAD brains) stimulates the nuclear translocation of stabilized hypoxia-inducible factor (HIF)-1α protein and its binding to VEGF-A hypoxia-response elements; the mRNA synthesis for three VEGF-A splice variants (121, 165, 189); and the secretion of VEGF-A165. The CM-trio was the most powerful stimulus, IFN-γ+TNF-α was less potent, and other cytokine pairs or single cytokines or Aβ(35-25) were ineffective. While Aβ(25-35) did not change HIF-1β protein levels, the CM-trio increased both HIF-1α and HIF-1β protein levels, thereby giving an earlier and stronger stimulus to VEGF-A secretion by NAHAs. Thus, increased VEGF-A secretion from astrocytes stimulated by Aβ(1-42) and by microglia-released cytokines might restore angiogenesis and Aβ(1-42) vascular clearance.

  6. Electromagnetic treatment to old Alzheimer's mice reverses β-amyloid deposition, modifies cerebral blood flow, and provides selected cognitive benefit.

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    Gary W Arendash

    Full Text Available Few studies have investigated physiologic and cognitive effects of "long-term" electromagnetic field (EMF exposure in humans or animals. Our recent studies have provided initial insight into the long-term impact of adulthood EMF exposure (GSM, pulsed/modulated, 918 MHz, 0.25-1.05 W/kg by showing 6+ months of daily EMF treatment protects against or reverses cognitive impairment in Alzheimer's transgenic (Tg mice, while even having cognitive benefit to normal mice. Mechanistically, EMF-induced cognitive benefits involve suppression of brain β-amyloid (Aβ aggregation/deposition in Tg mice and brain mitochondrial enhancement in both Tg and normal mice. The present study extends this work by showing that daily EMF treatment given to very old (21-27 month Tg mice over a 2-month period reverses their very advanced brain Aβ aggregation/deposition. These very old Tg mice and their normal littermates together showed an increase in general memory function in the Y-maze task, although not in more complex tasks. Measurement of both body and brain temperature at intervals during the 2-month EMF treatment, as well as in a separate group of Tg mice during a 12-day treatment period, revealed no appreciable increases in brain temperature (and no/slight increases in body temperature during EMF "ON" periods. Thus, the neuropathologic/cognitive benefits of EMF treatment occur without brain hyperthermia. Finally, regional cerebral blood flow in cerebral cortex was determined to be reduced in both Tg and normal mice after 2 months of EMF treatment, most probably through cerebrovascular constriction induced by freed/disaggregated Aβ (Tg mice and slight body hyperthermia during "ON" periods. These results demonstrate that long-term EMF treatment can provide general cognitive benefit to very old Alzheimer's Tg mice and normal mice, as well as reversal of advanced Aβ neuropathology in Tg mice without brain heating. Results further underscore the potential for EMF

  7. Electromagnetic treatment to old Alzheimer's mice reverses β-amyloid deposition, modifies cerebral blood flow, and provides selected cognitive benefit.

    Science.gov (United States)

    Arendash, Gary W; Mori, Takashi; Dorsey, Maggie; Gonzalez, Rich; Tajiri, Naoki; Borlongan, Cesar

    2012-01-01

    Few studies have investigated physiologic and cognitive effects of "long-term" electromagnetic field (EMF) exposure in humans or animals. Our recent studies have provided initial insight into the long-term impact of adulthood EMF exposure (GSM, pulsed/modulated, 918 MHz, 0.25-1.05 W/kg) by showing 6+ months of daily EMF treatment protects against or reverses cognitive impairment in Alzheimer's transgenic (Tg) mice, while even having cognitive benefit to normal mice. Mechanistically, EMF-induced cognitive benefits involve suppression of brain β-amyloid (Aβ) aggregation/deposition in Tg mice and brain mitochondrial enhancement in both Tg and normal mice. The present study extends this work by showing that daily EMF treatment given to very old (21-27 month) Tg mice over a 2-month period reverses their very advanced brain Aβ aggregation/deposition. These very old Tg mice and their normal littermates together showed an increase in general memory function in the Y-maze task, although not in more complex tasks. Measurement of both body and brain temperature at intervals during the 2-month EMF treatment, as well as in a separate group of Tg mice during a 12-day treatment period, revealed no appreciable increases in brain temperature (and no/slight increases in body temperature) during EMF "ON" periods. Thus, the neuropathologic/cognitive benefits of EMF treatment occur without brain hyperthermia. Finally, regional cerebral blood flow in cerebral cortex was determined to be reduced in both Tg and normal mice after 2 months of EMF treatment, most probably through cerebrovascular constriction induced by freed/disaggregated Aβ (Tg mice) and slight body hyperthermia during "ON" periods. These results demonstrate that long-term EMF treatment can provide general cognitive benefit to very old Alzheimer's Tg mice and normal mice, as well as reversal of advanced Aβ neuropathology in Tg mice without brain heating. Results further underscore the potential for EMF treatment

  8. Familial Danish dementia: a novel form of cerebral amyloidosis associated with deposition of both amyloid-Dan and amyloid-beta

    DEFF Research Database (Denmark)

    Holton, J.L; Lashley, T.; Ghiso, J.;

    2002-01-01

    response using conventional techniques, immunohistochemistry, confocal microscopy, and immunoelectron microscopy. We showed that ADan is widely distributed in the central nervous system (CNS) in the leptomeninges, blood vessels, and parenchyma. A predominance of parenchymal pre-amyloid (non...

  9. What is normal in normal aging? Effects of aging, amyloid and Alzheimer's disease on the cerebral cortex and the hippocampus.

    Science.gov (United States)

    Fjell, Anders M; McEvoy, Linda; Holland, Dominic; Dale, Anders M; Walhovd, Kristine B

    2014-06-01

    What can be expected in normal aging, and where does normal aging stop and pathological neurodegeneration begin? With the slow progression of age-related dementias such as Alzheimer's disease (AD), it is difficult to distinguish age-related changes from effects of undetected disease. We review recent research on changes of the cerebral cortex and the hippocampus in aging and the borders between normal aging and AD. We argue that prominent cortical reductions are evident in fronto-temporal regions in elderly even with low probability of AD, including regions overlapping the default mode network. Importantly, these regions show high levels of amyloid deposition in AD, and are both structurally and functionally vulnerable early in the disease. This normalcy-pathology homology is critical to understand, since aging itself is the major risk factor for sporadic AD. Thus, rather than necessarily reflecting early signs of disease, these changes may be part of normal aging, and may inform on why the aging brain is so much more susceptible to AD than is the younger brain. We suggest that regions characterized by a high degree of life-long plasticity are vulnerable to detrimental effects of normal aging, and that this age-vulnerability renders them more susceptible to additional, pathological AD-related changes. We conclude that it will be difficult to understand AD without understanding why it preferably affects older brains, and that we need a model that accounts for age-related changes in AD-vulnerable regions independently of AD-pathology.

  10. Early-onset and robust amyloid pathology in a new homozygous mouse model of Alzheimer's disease.

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    Antje Willuweit

    Full Text Available BACKGROUND: Transgenic mice expressing mutated amyloid precursor protein (APP and presenilin (PS-1 or -2 have been successfully used to model cerebral beta-amyloidosis, one of the characteristic hallmarks of Alzheimer's disease (AD pathology. However, the use of many transgenic lines is limited by premature death, low breeding efficiencies and late onset and high inter-animal variability of the pathology, creating a need for improved animal models. Here we describe the detailed characterization of a new homozygous double-transgenic mouse line that addresses most of these issues. METHODOLOGY/PRINCIPAL FINDINGS: The transgenic mouse line (ARTE10 was generated by co-integration of two transgenes carrying the K670N/M671L mutated amyloid precursor protein (APP(swe and the M146V mutated presenilin 1 (PS1 both under control of a neuron-specific promoter. Mice, hemi- as well as homozygous for both transgenes, are viable and fertile with good breeding capabilities and a low rate of premature death. They develop robust AD-like cerebral beta-amyloid plaque pathology with glial inflammation, signs of neuritic dystrophy and cerebral amyloid angiopathy. Using our novel image analysis algorithm for semi-automatic quantification of plaque burden, we demonstrate an early onset and progressive plaque deposition starting at 3 months of age in homozygous mice with low inter-animal variability and 100%-penetrance of the phenotype. The plaques are readily detected in vivo by PiB, the standard human PET tracer for AD. In addition, ARTE10 mice display early loss of synaptic markers and age-related cognitive deficits. By applying a gamma-secretase inhibitor we show a dose dependent reduction of soluble amyloid beta levels in the brain. CONCLUSIONS: ARTE10 mice develop a cerebral beta-amyloidosis closely resembling the beta-amyloid-related aspects of human AD neuropathology. Unifying several advantages of previous transgenic models, this line particularly qualifies for

  11. PiB fails to map amyloid deposits in cerebral cortex of aged dogs with canine cognitive dysfunction

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    Rikke eFast

    2013-12-01

    Full Text Available Dogs with Canine Cognitive Dysfunction (CCD accumulate amyloid beta (Aβ in the brain. As the cognitive decline and neuropathology of these old dogs share features with Alzheimer’s disease (AD, the relation between Aβ and cognitive decline in animal models of cognitive decline is of interest to the understanding of AD. However, the sensitivity of the biomarker Pittsburgh Compound B (PiB to the presence of Aβ in humans and in other mammalian species is in doubt. To test the sensitivity and assess the distribution of Aβ in dog brain, we mapped the brains of dogs with signs of CCD (n=16 and a control group (n=4 of healthy dogs with radioactively labeled PiB ([11C]PiB. Structural MRI brain scans were obtained from each dog. Tracer washout analysis yielded parametric maps of PIB retention in brain. In the CCD group, dogs had significant retention of [11C]PiB in the cerebellum, compared to the cerebral cortex. Retention in the cerebellum is at variance with evidence from brains of humans with AD. To confirm the lack of sensitivity, we stained two dog brains with the immunohistochemical marker 6E10, which is sensitive to the presence of both Aβ and Aβ precursor protein (AβPP. The 6E10 stain revealed intracellular material positive for Aβ or AβPP, or both, in Purkinje cells. The brains of the two groups of dogs did not have significantly different patterns of [11C]PiB binding, suggesting that the material detected with 6E10 is AβPP rather than Aβ. As the comparison with the histological images revealed no correlation between the [11C]PiB and Aβ and AβPP deposits in post-mortem brain, the marked intracellular staining implies intracellular involvement of amyloid processing in the dog brain. We conclude that PET maps of [11C]PiB retention in brain of dogs with CCD fundamentally differ from the images obtained in most humans with AD.

  12. PiB Fails to Map Amyloid Deposits in Cerebral Cortex of Aged Dogs with Canine Cognitive Dysfunction.

    Science.gov (United States)

    Fast, Rikke; Rodell, Anders; Gjedde, Albert; Mouridsen, Kim; Alstrup, Aage K; Bjarkam, Carsten R; West, Mark J; Berendt, Mette; Møller, Arne

    2013-01-01

    Dogs with Canine Cognitive Dysfunction (CCD) accumulate amyloid beta (Aβ) in the brain. As the cognitive decline and neuropathology of these old dogs share features with Alzheimer's disease (AD), the relation between Aβ and cognitive decline in animal models of cognitive decline is of interest to the understanding of AD. However, the sensitivity of the biomarker Pittsburgh Compound B (PiB) to the presence of Aβ in humans and in other mammalian species is in doubt. To test the sensitivity and assess the distribution of Aβ in dog brain, we mapped the brains of dogs with signs of CCD (n = 16) and a control group (n = 4) of healthy dogs with radioactively labeled PiB ([(11)C]PiB). Structural magnetic resonance imaging brain scans were obtained from each dog. Tracer washout analysis yielded parametric maps of PiB retention in brain. In the CCD group, dogs had significant retention of [(11)C]PiB in the cerebellum, compared to the cerebral cortex. Retention in the cerebellum is at variance with evidence from brains of humans with AD. To confirm the lack of sensitivity, we stained two dog brains with the immunohistochemical marker 6E10, which is sensitive to the presence of both Aβ and Aβ precursor protein (AβPP). The 6E10 stain revealed intracellular material positive for Aβ or AβPP, or both, in Purkinje cells. The brains of the two groups of dogs did not have significantly different patterns of [(11)C]PiB binding, suggesting that the material detected with 6E10 is AβPP rather than Aβ. As the comparison with the histological images revealed no correlation between the [(11)C]PiB and Aβ and AβPP deposits in post-mortem brain, the marked intracellular staining implies intracellular involvement of amyloid processing in the dog brain. We conclude that PET maps of [(11)C]PiB retention in brain of dogs with CCD fundamentally differ from the images obtained in most humans with AD.

  13. Voxel-wise relationships between distribution volume ratio and cerebral blood flow: implications for analysis of β-amyloid images

    Science.gov (United States)

    Sojkova, Jitka; Goh, Joshua; Bilgel, Murat; Landman, Bennett; Yang, Xue; Zhou, Yun; An, Yang; Beason-Held, Lori L.; Kraut, Michael A.; Wong, Dean F.; Resnick, Susan M.

    2017-01-01

    Quantification of β-amyloid (Aβ) in vivo is often accomplished using the distribution volume ratio (DVR), based on a simplified reference tissue model. We investigated the local relationships between DVR and cerebral blood flow (CBF), as well as relative blood flow (R1), in nondemented older adults. Methods Fifty-five nondemented participants (mean age 78.5 years) in the Baltimore Longitudinal Study of Aging underwent 15O-H2O PET CBF and dynamic 11C-PiB-PET. 15O-H2O PET images were normalized and smoothed using SPM. A simplified reference tissue model with linear regression and spatial constraints was used to generate parametric DVR images. The DVR images were regressed on CBF images on a voxel-by-voxel basis using robust Biological Parametric Mapping, adjusting for age and sex (FDR p=0.05, k=50). DVR images were also regressed on R1 images, a measure of the transport rate constant from vascular space to tissue. All analyses were performed in the entire sample, and in high and low tertiles of mean cortical DVR. Results Voxel-based analyses showed that increased DVR is associated with increased CBF in frontal, parietal, temporal, and occipital cortices. However, this association appears to spare regions that typically show early β-amyloid (Aβ) deposition. A more robust relationship between DVR and CBF was observed in the lowest tertile of DVR, i.e., negligible cortical Aβ load, compared to the highest tertile of cortical DVR and Aβ load. Spatial distributions of the DVR-CBF and DVR-R1 correlations showed similar patterns. No reliable negative voxel-wise relationships between DVR and CBF or R1 were observed. Conclusion Robust associations between DVR and CBF at negligible Aβ levels, together with similar spatial distributions of DVR-CBF and DVR-R1 correlations, suggest that regional distribution of DVR reflects blood flow and tracer influx rather than pattern of Aβ deposition in those with minimal Aβ load. DVR-CBF associations in individuals with higher DVR

  14. Centrally Delivered BACE1 Inhibitor Activates Microglia, and Reverses Amyloid Pathology and Cognitive Deficit in Aged Tg2576 Mice.

    Science.gov (United States)

    Thakker, Deepak R; Sankaranarayanan, Sethu; Weatherspoon, Marcy R; Harrison, Jonathan; Pierdomenico, Maria; Heisel, Jennifer M; Thompson, Lorin A; Haskell, Roy; Grace, James E; Taylor, Sarah J; Albright, Charles F; Shafer, Lisa L

    2015-04-29

    Multiple small-molecule inhibitors of the β-secretase enzyme (BACE1) are under preclinical or clinical investigation for Alzheimer's disease (AD). Prior work has illustrated robust lowering of central amyloid β (Aβ) after acute administration of BACE1 inhibitors. However, very few studies have assessed the overall impact of chronically administered BACE1 inhibitors on brain amyloid burden, neuropathology, and behavioral function in aged preclinical models. We investigated the effects of a potent nonbrain-penetrant BACE1 inhibitor, delivered directly to the brain using intracerebroventricular infusion in an aged transgenic mouse model. Intracerebroventricular infusion of the BACE1 inhibitor (0.3-23.5 μg/d) for 8 weeks, initiated in 17-month-old Tg2576 mice, produced dose-dependent increases in brain inhibitor concentrations (0.2-13 μm). BACE1 inhibition significantly reversed the behavioral deficit in contextual fear conditioning, and reduced brain Aβ levels, plaque burden, and associated pathology (e.g., dystrophic neurites), with maximal effects attained with ∼1 μg/d dose. Strikingly, the BACE1 inhibitor also reversed amyloid pathology below baseline levels (amyloid burden at the start of treatment), without adversely affecting cerebral amyloid angiopathy, microhemorrhages, myelination, or neuromuscular function. Inhibitor-mediated decline in brain amyloid pathology was associated with an increase in microglial ramification. This is the first demonstration of chronically administered BACE1 inhibitor to activate microglia, reverse brain amyloid pathology, and elicit functional improvement in an aged transgenic mouse model. Thus, engagement of novel glial-mediated clearance mechanisms may drive disease-modifying therapeutic benefit with BACE1 inhibition in AD.

  15. Cerebral Blood Flow and A beta-Amyloid Estimates by WARAM Analysis of [C-11]PiB Uptake Distinguish among and between Neurodegenerative Disorders and Aging

    DEFF Research Database (Denmark)

    Rodell, Anders B.; O'Keefe, Graeme; Rowe, Christopher C.

    2017-01-01

    metabolism and reduction of blood flow by neurovascular coupling in neurodegenerative disorders, including Alzheimer’s disease. Methods: Previously reported images of [11C]PiB retention in brain of 29 subjects with cognitive impairment or dementia [16 Alzheimer’s Disease (AD), eight subjects with dementia...... among patients with dementia, including AD, and healthy volunteers, with ROC that are superior to conventional methods of analysis. The distinction between estimates of flow and amyloid load from the same dynamic emission tomograms provides valuable pathogenetic information.......Background: We report results of the novel Washout Allometric Reference Method (WARM) that uses estimates of cerebral blood flow and amyloid load from the same [11C]Pittsburgh Compound B ([11C]PiB) retention maps in brain to distinguish between patients with different forms dementia, including...

  16. Limited Proteolysis Reveals That Amyloids from the 3D Domain-Swapping Cystatin B Have a Non-Native β-Sheet Topology.

    Science.gov (United States)

    Davis, Peter J; Holmes, David; Waltho, Jonathan P; Staniforth, Rosemary A

    2015-07-31

    3D domain-swapping proteins form multimers by unfolding and then sharing of secondary structure elements, often with native-like interactions. Runaway domain swapping is proposed as a mechanism for folded proteins to form amyloid fibres, with examples including serpins and cystatins. Cystatin C amyloids cause a hereditary form of cerebral amyloid angiopathy whilst cystatin B aggregates are found in cases of Unverricht-Lundborg Syndrome, a progressive form of myoclonic epilepsy. Under conditions that favour fibrillisation, cystatins populate stable 3D domain-swapped dimers both in vitro and in vivo that represent intermediates on route to the formation of fibrils. Previous work on cystatin B amyloid fibrils revealed that the α-helical region of the protein becomes disordered and identified the conservation of a continuous 20-residue elongated β-strand (residues 39-58), the latter being a salient feature of the dimeric 3D domain-swapped structure. Here we apply limited proteolysis to cystatin B amyloid fibrils and show that not only the α-helical N-terminal of the protein (residues 1-35) but also the C-terminal of the protein (residues 80-98) can be removed without disturbing the underlying fibril structure. This observation is incompatible with previous models of cystatin amyloid fibrils where the β-sheet is assumed to retain its native antiparallel arrangement. We conclude that our data favour a more generic, at least partially parallel, arrangement for cystatin β-sheet structure in mature amyloids and propose a model that remains consistent with available data for amyloids from either cystatin B or cystatin C.

  17. APP mutations in the Aβ coding region are associated with abundant cerebral deposition of Aβ38.

    Science.gov (United States)

    Moro, Maria Luisa; Giaccone, Giorgio; Lombardi, Raffaella; Indaco, Antonio; Uggetti, Andrea; Morbin, Michela; Saccucci, Stefania; Di Fede, Giuseppe; Catania, Marcella; Walsh, Dominic M; Demarchi, Andrea; Rozemuller, Annemieke; Bogdanovic, Nenad; Bugiani, Orso; Ghetti, Bernardino; Tagliavini, Fabrizio

    2012-12-01

    Aβ is the main component of amyloid deposits in Alzheimer disease (AD) and its aggregation into oligomers, protofibrils and fibrils is considered a seminal event in the pathogenesis of AD. Aβ with C-terminus at residue 42 is the most abundant species in parenchymal deposits, whereas Aβ with C-terminus at residue 40 predominates in the amyloid of the walls of large vessels. Aβ peptides with other C-termini have not yet been thoroughly investigated. We analysed Aβ38 in the brains of patients with Aβ deposition linked to sporadic and familial AD, hereditary cerebral haemorrhage with amyloidosis, or Down syndrome. Immunohistochemistry, confocal microscopy, immunoelectron microscopy, immunoprecipitation and the electrophoresis separation of low molecular weight aggregates revealed that Aβ38 accumulates consistently in the brains of patients carrying APP mutations in the Aβ coding region, but was not detected in the patients with APP mutations outside the Aβ domain, in the patients with presenilin mutations or in subjects with Down syndrome. In the patients with sporadic AD, Aβ38 was absent in the senile plaques, but it was detected only in the vessel walls of a small subset of patients with severe cerebral amyloid angiopathy. Our results suggest that APP mutations in the Aβ coding region favour Aβ38 accumulation in the brain and that the molecular mechanisms of Aβ deposition in these patients may be different from those active in patients with familial AD associated with other genetic defects and sporadic AD.

  18. Regional cerebral blood flow estimated by early PiB uptake is reduced in mild cognitive impairment and associated with age in an amyloid-dependent manner.

    Science.gov (United States)

    Gietl, Anton F; Warnock, Geoffrey; Riese, Florian; Kälin, Andrea M; Saake, Antje; Gruber, Esmeralda; Leh, Sandra E; Unschuld, Paul G; Kuhn, Felix P; Burger, Cyrill; Mu, Linjing; Seifert, Burkhardt; Nitsch, Roger M; Schibli, Roger; Ametamey, Simon M; Buck, Alfred; Hock, Christoph

    2015-04-01

    Early uptake of [(11)C]-Pittsburgh Compound B (ePiB, 0-6 minutes) estimates cerebral blood flow. We studied ePiB in 13 PiB-negative and 10 PiB-positive subjects with mild cognitive impairment (MCI, n = 23) and 11 PiB-positive and 74 PiB-negative cognitively healthy elderly control subjects (HCS, n = 85) in 6 bilateral volumes of interest: posterior cingulate cortex (PCC), hippocampus (hipp), temporoparietal region, superior parietal gyrus, parahippocampal gyrus (parahipp), and inferior frontal gyrus (IFG) for the associations with cognitive status, age, amyloid deposition, and apolipoprotein E ε4-allele. We observed no difference in ePiB between PiB-positive and -negative subjects and carriers and noncarriers. EPiB decreased with age in PiB-positive subjects in bilateral superior parietal gyrus, bilateral temporoparietal region, right IFG, right PCC, and left parahippocampal gyrus but not in PiB-negative subjects. MCI had lower ePiB than HCS (left PCC, left IFG, and left and right hipp). Lowest ePiB values were found in MCI of 70 years and older, who also displayed high cortical PiB binding. This suggests that lowered regional cerebral blood flow indicated by ePiB is associated with age in the presence but not in the absence of amyloid pathology.

  19. Apigenin Isolated from the Medicinal Plant Elsholtzia rugulosa Prevents β-Amyloid 25–35-Induces Toxicity in Rat Cerebral Microvascular Endothelial Cells

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    Qingshan Liu

    2011-05-01

    Full Text Available Endothelial cells of cerebral capillaries forming the blood-brain barrier play an important role in the pathogenesis and therapy of Alzheimer’s disease. Amyloid-β peptides are key pathological elements in the development of this disease. Apigenin (4’,5,7-tetrahydroxyflavone is a plant flavonoid and pharmacologically active agent that can be isolated from several plant species. In the present study, effects of apigenin obtained from the medicinal plant Elsholtzia rugulosa (Labiatae on primary cultured rat cerebral microvascular endothelial cells (CMECs mediated by amyloid-β peptide 25–35 (Aβ25–35 were examined. Aβ25–35 showed toxic effects on CMECs, involving reduction of cell viability, release of lactate dehydrogenase (LDH, increase of nuclear condensation, over-production of intracellular reactive oxygen species (ROS, decrease of superoxide dismutase (SOD activity, and breakage of the barrier integrity and function. Based on this model, we demonstrated that apigenin from the medicinal plant Elsholtzia rugulosa protected cultured rat CMECs by increasing cell viability, reducing LDH release, relieving nuclear condensation, alleviating intracellular ROS generation, increasing SOD activity, and strengthening the barrier integrity through the preservation of transendothelial electrical resistance, permeability property and characteristic enzymatic activity after being exposed to Aβ25–35. In conclusion, apigenin isolated from Elsholtzia rugulosa has the ability to protect rat CMECs against Aβ25–35-induced toxicity.

  20. Natural Phenolic Compounds as Therapeutic and Preventive Agents for Cerebral Amyloidosis.

    Science.gov (United States)

    Yamada, Masahito; Ono, Kenjiro; Hamaguchi, Tsuyoshi; Noguchi-Shinohara, Moeko

    2015-01-01

    Epidemiological studies have suggested that diets rich in phenolic compounds may have preventive effects on the development of dementia or Alzheimer's disease (AD). We investigated the effects of natural phenolic compounds, such as myricetin (Myr), rosmarinic acid (RA), ferulic acid (FA), curcumin (Cur) and nordihydroguaiaretic acid (NDGA) on the aggregation of amyloid β-protein (Aβ), using in vitro and in vivo models of cerebral Aβ amyloidosis. The in vitro studies revealed that these phenolic compounds efficiently inhibit oligomerization as well as fibril formation of Aβ through differential binding, whilst reducing Aβ oligomer-induced synaptic and neuronal toxicity. Furthermore, a transgenic mouse model fed orally with such phenolic compounds showed significant reduction of soluble Aβ oligomers as well as of insoluble Aβ deposition in the brain. These data, together with an updated review of the literature, indicate that natural phenolic compounds have anti-amyloidogenic effects on Aβ in addition to well-known anti-oxidative and anti-inflammatory effects, hence suggesting their potential as therapeutic and/or preventive agents for cerebral Aβ amyloidosis, including AD and cerebral amyloid angiopathy (CAA). Well-designed clinical trials or preventive interventions with natural phenolic compounds are necessary to establish their efficacy as disease-modifying agents.

  1. Micro-MRI study of cerebral aging: ex vivo detection of hippocampal subfield reorganization, microhemorrhages and amyloid plaques in mouse lemur primates.

    Directory of Open Access Journals (Sweden)

    Anne Bertrand

    Full Text Available Mouse lemurs are non-human primate models of cerebral aging and neurodegeneration. Much smaller than other primates, they recapitulate numerous features of human brain aging, including progressive cerebral atrophy and correlation between regional atrophy and cognitive impairments. Characterization of brain atrophy in mouse lemurs has been done by MRI measures of regional CSF volume and by MRI measures of regional atrophy. Here, we further characterize mouse lemur brain aging using ex vivo MR microscopy (31 µm in-plane resolution. First, we performed a non-biased, direct volumetric quantification of dentate gyrus and extended Ammon's horn. We show that both dentate gyrus and Ammon's horn undergo an age-related reorganization leading to a growth of the dentate gyrus and an atrophy of the Ammon's horn, even in the absence of global hippocampal atrophy. Second, on these first MR microscopic images of the mouse lemur brain, we depicted cortical and hippocampal hypointense spots. We demonstrated that their incidence increases with aging and that they correspond either to amyloid deposits or to cerebral microhemorrhages.

  2. Shear-Induced Amyloid Formation in the Brain: I. Potential Vascular and Parenchymal Processes.

    Science.gov (United States)

    Trumbore, Conrad N

    2016-09-06

    Shear distortion of amyloid-beta (Aβ) solutions accelerates amyloid cascade reactions that may yield different toxic oligomers than those formed in quiescent solutions. Recent experiments indicate that cerebrospinal fluid (CSF) and interstitial fluid (ISF) containing Aβ flow through narrow brain perivascular pathways and brain parenchyma. This paper suggests that such flow causes shear distortion of Aβ molecules involving conformation changes that may be one of the initiating events in the etiology of Alzheimer's disease. Aβ shearing can occur in or around brain arteries and arterioles and is suggested as the origin of cerebral amyloid angiopathy deposits in cerebrovascular walls. Comparatively low flow rates of ISF within the narrow extracellular spaces (ECS) of the brain parenchyma are suggested as a possible initiating factor in both the formation of neurotoxic Aβ42 oligomers and amyloid fibrils. Aβ42 in slow-flowing ISF can gain significant shear energy at or near the walls of tortuous brain ECS flow paths, promoting the formation of a shear-distorted, excited state hydrophobic Aβ42* conformation. This Aβ42* molecule could possibly be involved in one of two paths, one involving rapid adsorption to a brain membrane surface, ultimately forming neurotoxic oligomers on membranes, and the other ultimately forming plaque within the ECS flow pathways. Rising Aβ concentrations combined with shear at or near critical brain membranes are proposed as contributing factors to Alzheimer's disease neurotoxicity. These hypotheses may be applicable in other neurodegenerative diseases, including tauopathies and alpha-synucleinopathies, in which shear-distorted proteins also may form in the brain ECS.

  3. 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.

  4. Brain burdens of aluminum, iron, and copper and their relationships with amyloid-β pathology in 60 human brains.

    Science.gov (United States)

    Exley, Christopher; House, Emily; Polwart, Anthony; Esiri, Margaret M

    2012-01-01

    The deposition in the brain of amyloid-β as beta sheet conformers associated with senile plaques and vasculature is frequently observed in Alzheimer’s disease. While metals, primarily aluminum, iron, zinc, and copper, have been implicated in amyloid-β deposition in vivo, there are few data specifically relating brain metal burden with extent of amyloid pathologies in human brains. Herein brain tissue content of aluminum, iron, and copper are compared with burdens of amyloid-β, as senile plaques and as congophilic amyloid angiopathy, in 60 aged human brains. Significant observations were strong negative correlations between brain copper burden and the degree of severity of both senile plaque and congophilic amyloid angiopathy pathologies with the relationship with the former reaching statistical significance. While we did not have access to the dementia status of the majority of the 60 brain donors, this knowledge for just 4 donors allowed us to speculate that diagnosis of dementia might be predicted by a combination of amyloid pathology and a ratio of the brain burden of copper to the brain burden of aluminum. Taking into account only those donor brains with either senile plaque scores ≥4 and/or congophilic amyloid angiopathy scores ≥12, a Cu:Al ratio of <20 would predict that at least 39 of the 60 donors would have been diagnosed as suffering from dementia. Future research should test the hypothesis that, in individuals with moderate to severe amyloid pathology, low brain copper is a predisposition to developing dementia.

  5. Induction of complement proteins in a mouse model for cerebral microvascular A beta deposition.

    Science.gov (United States)

    Fan, Rong; DeFilippis, Kelly; Van Nostrand, William E

    2007-09-18

    The deposition of amyloid beta-protein (A beta) in cerebral vasculature, known as cerebral amyloid angiopathy (CAA), is a common pathological feature of Alzheimer's disease and related disorders. In familial forms of CAA single mutations in the A beta peptide have been linked to the increase of vascular A beta deposits accompanied by a strong localized activation of glial cells and elevated expression of neuroinflammatory mediators including complement proteins. We have developed human amyloid-beta precursor protein transgenic mice harboring two CAA A beta mutations (Dutch E693Q and Iowa D694N) that mimic the prevalent cerebral microvascular A beta deposition observed in those patients, and the Swedish mutations (K670N/M671L) to increase A beta production. In these Tg-SwDI mice, we have reported predominant fibrillar A beta along microvessels in the thalamic region and diffuse plaques in cortical region. Concurrently, activated microglia and reactive astrocytes have been detected primarily in association with fibrillar cerebral microvascular A beta in this model. Here we show that three native complement components in classical and alternative complement pathways, C1q, C3, and C4, are elevated in Tg-SwDI mice in regions rich in fibrillar microvascular A beta. Immunohistochemical staining of all three proteins was increased in thalamus, hippocampus, and subiculum, but not frontal cortex. Western blot analysis showed significant increases of all three proteins in the thalamic region (with hippocampus) as well as the cortical region, except C3 that was below detection level in cortex. Also, in the thalamic region (with hippocampus), C1q and C3 mRNAs were significantly up-regulated. These complement proteins appeared to be expressed largely by activated microglial cells associated with the fibrillar microvascular A beta deposits. Our findings demonstrate that Tg-SwDI mice exhibit elevated complement protein expression in response to fibrillar vascular A beta deposition

  6. Induction of complement proteins in a mouse model for cerebral microvascular Aβ deposition

    Directory of Open Access Journals (Sweden)

    DeFilippis Kelly

    2007-09-01

    Full Text Available Abstract The deposition of amyloid β-protein (Aβ in cerebral vasculature, known as cerebral amyloid angiopathy (CAA, is a common pathological feature of Alzheimer's disease and related disorders. In familial forms of CAA single mutations in the Aβ peptide have been linked to the increase of vascular Aβ deposits accompanied by a strong localized activation of glial cells and elevated expression of neuroinflammatory mediators including complement proteins. We have developed human amyloid-β precursor protein transgenic mice harboring two CAA Aβ mutations (Dutch E693Q and Iowa D694N that mimic the prevalent cerebral microvascular Aβ deposition observed in those patients, and the Swedish mutations (K670N/M671L to increase Aβ production. In these Tg-SwDI mice, we have reported predominant fibrillar Aβ along microvessels in the thalamic region and diffuse plaques in cortical region. Concurrently, activated microglia and reactive astrocytes have been detected primarily in association with fibrillar cerebral microvascular Aβ in this model. Here we show that three native complement components in classical and alternative complement pathways, C1q, C3, and C4, are elevated in Tg-SwDI mice in regions rich in fibrillar microvascular Aβ. Immunohistochemical staining of all three proteins was increased in thalamus, hippocampus, and subiculum, but not frontal cortex. Western blot analysis showed significant increases of all three proteins in the thalamic region (with hippocampus as well as the cortical region, except C3 that was below detection level in cortex. Also, in the thalamic region (with hippocampus, C1q and C3 mRNAs were significantly up-regulated. These complement proteins appeared to be expressed largely by activated microglial cells associated with the fibrillar microvascular Aβ deposits. Our findings demonstrate that Tg-SwDI mice exhibit elevated complement protein expression in response to fibrillar vascular Aβ deposition that is

  7. Ischaemic stroke in children secondary to post varicella angiopathy.

    LENUS (Irish Health Repository)

    Hayes, B

    2007-01-01

    Varicella in childhood is a self-limiting disease, which usually follows a benign course. However, complications, although rare, may have serious consequences. Ischaemic stroke secondary to post varicella angiopathy is a well-described complication and is estimated to account for up to a third of all strokes in infants. We present three previously healthy children who presented to our centre with ischaemic cerebrovascular infarction due to varicella angiopathy. All three children first presented within six weeks after onset of varicella infection and had MRI changes characteristic of ischaemic stroke secondary to post varicella angiopathy. While one child made an excellent recovery being left with only a minor deficit, the remaining two children were left with considerable morbidity severely affecting quality of life. The varicella vaccine has been proven to be well tolerated, safe and effective. We conclude that varicella vaccination should be considered for inclusion in the vaccination schedule to prevent serious complications which while rare may have devastating consequences.

  8. Quercetin protects human brain microvascular endothelial cells from fibrillar β-amyloid1–40-induced toxicity

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    Yongjie Li

    2015-01-01

    Full Text Available Amyloid beta-peptides (Aβ are known to undergo active transport across the blood-brain barrier, and cerebral amyloid angiopathy has been shown to be a prominent feature in the majority of Alzheimer׳s disease. Quercetin is a natural flavonoid molecule and has been demonstrated to have potent neuroprotective effects, but its protective effect on endothelial cells under Aβ-damaged condition is unclear. In the present study, the protective effects of quercetin on brain microvascular endothelial cells injured by fibrillar Aβ1–40 (fAβ1–40 were observed. The results show that fAβ1–40-induced cytotoxicity in human brain microvascular endothelial cells (hBMECs can be relieved by quercetin treatment. Quercetin increases cell viability, reduces the release of lactate dehydrogenase, and relieves nuclear condensation. Quercetin also alleviates intracellular reactive oxygen species generation and increases superoxide dismutase activity. Moreover, it strengthens the barrier integrity through the preservation of the transendothelial electrical resistance value, the relief of aggravated permeability, and the increase of characteristic enzyme levels after being exposed to fAβ1–40. In conclusion, quercetin protects hBMECs from fAβ1–40-induced toxicity.

  9. Beta-Amyloid Downregulates MDR1-P-Glycoprotein (Abcb1 Expression at the Blood-Brain Barrier in Mice

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    Anja Brenn

    2011-01-01

    Full Text Available Neurovascular dysfunction is an important component of Alzheimer's disease, leading to reduced clearance across the blood-brain barrier and accumulation of neurotoxic β-amyloid (Aβ peptides in the brain. It has been shown that the ABC transport protein P-glycoprotein (P-gp, ABCB1 is involved in the export of Aβ from the brain into the blood. To determine whether Aβ influences the expression of key Aβ transporters, we studied the effects of 1-day subcutaneous Aβ1-40 and Aβ1-42 administration via Alzet mini-osmotic pumps on P-gp, BCRP, LRP1, and RAGE expression in the brain of 90-day-old male FVB mice. Our results demonstrate significantly reduced P-gp, LRP1, and RAGE mRNA expression in mice treated with Aβ1-42 compared to controls, while BCRP expression was not affected. The expression of the four proteins was unchanged in mice treated with Aβ1-40 or reverse-sequence peptides. These findings indicate that, in addition to the age-related decrease of P-gp expression, Aβ1-42 itself downregulates the expression of P-gp and other Aβ-transporters, which could exacerbate the intracerebral accumulation of Aβ and thereby accelerate neurodegeneration in Alzheimer's disease and cerebral β-amyloid angiopathy.

  10. 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.

  11. 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.

  12. Aβ42 Is Essential for Parenchymal and Vascular Amyloid Deposition in Mice

    Science.gov (United States)

    McGowan, Eileen; Onstead, Luisa; Eriksen, Jason; Yu, Cindy; Skipper, Lisa; Murphy, M. Paul; Beard, Jenny; Das, Pritam; Jansen, Karen; DeLucia, Michael; Lin, Wen-Lang; Dolios, Georgia; Wang, Rong; Eckman, Christopher B.; Dickson, Dennis W.; Hutton, Mike; Hardy, John; Golde, Todd

    2005-01-01

    Summary Considerable circumstantial evidence suggests that Aβ42 is the initiating molecule in Alzheimer's disease (AD) pathogenesis. However, the absolute requirement for Aβ42 for amyloid deposition has never been demonstrated in vivo. We have addressed this by developing transgenic models that express Aβ1-40 or Aβ1-42 in the absence of human amyloid β protein precursor (APP) overexpression. Mice expressing high levels of Aβ1-40 do not develop overt amyloid pathology. In contrast, mice expressing lower levels of Aβ1-42 accumulate insoluble Aβ1-42 and develop compact amyloid plaques, congophilic amyloid angiopathy (CAA), and diffuse Aβ deposits. When mice expressing Aβ1-42 are crossed with mutant APP (Tg2576) mice, there is also a massive increase in amyloid deposition. These data establish that Aβ1-42 is essential for amyloid deposition in the parenchyma and also in vessels. PMID:16039562

  13. A Simulation Model of Periarterial Clearance of Amyloid-beta from the Brain

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    Alexandra Katharina Diem

    2016-02-01

    Full Text Available The accumulation of soluble and insoluble amyloid-beta (A-beta in the brain indicates failure of elimination of A-beta from the brain with age and Alzheimer's disease. There is a variety of mechanisms for elimination of A-beta from the brain. They include the action of microglia and enzymes together with receptor-mediated absorption of A-beta into the blood and periarterial lymphatic drainage of A-beta. Although the brain possesses no conventional lymphatics, experimental studies have shown that fluid and solutes, such as A-beta, are eliminated from the brain along 100 nm wide basement membranes in the walls of cerebral capillaries and arteries. This lymphatic drainage pathway is reflected in the deposition of A-beta in the walls of human arteries with age and Alzheimer's disease as cerebral amyloid angiopathy (CAA. Initially, A-beta diffuses through the extracellular spaces of grey matter in the brain and then enters basement membranes in capillaries and arteries to flow out of the brain. Although diffusion through the extracellular spaces of the brain has been well characterised, the exact mechanism whereby perivascular elimination of A-beta occurs has not been resolved. Here we use a computational model to describe the process of periarterial drainage in the context of diffusion in the brain, demonstrating that periarterial drainage along basement membranes is very rapid compared with diffusion. Our results are a validation of experimental data and are significant in the context of failure of periarterial drainage as a mechanism underlying the pathogenesis of AD as well as complications associated with its immunotherapy.

  14. What is normal in normal aging? Effects of aging, amyloid and Alzheimer's disease on the cerebral cortex and the hippocampus

    OpenAIRE

    Fjell, Anders M.; McEvoy, Linda; Holland, Dominic; Dale, Anders M; Walhovd, Kristine B.

    2014-01-01

    What can be expected in normal aging, and where does normal aging stop and pathological neurodegeneration begin? With the slow progression of age-related dementias such as Alzheimer's disease (AD), it is difficult to distinguish age-related changes from effects of undetected disease. We review recent research on changes of the cerebral cortex and the hippocampus in aging and the borders between normal aging and AD. We argue that prominent cortical reductions are evident in fronto-temporal reg...

  15. 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.

  16. Complex interplay between brain function and structure during cerebral amyloidosis in APP transgenic mouse strains revealed by multi-parametric MRI comparison.

    Science.gov (United States)

    Grandjean, Joanes; Derungs, Rebecca; Kulic, Luka; Welt, Tobias; Henkelman, Mark; Nitsch, Roger M; Rudin, Markus

    2016-07-01

    Alzheimer's disease is a fatal neurodegenerative disorder affecting the aging population. Neuroimaging methods, in particular magnetic resonance imaging (MRI), have helped reveal alterations in the brain structure, metabolism, and function of patients and in groups at risk of developing AD, yet the nature of these alterations is poorly understood. Neuroimaging in mice is attractive for investigating mechanisms underlying functional and structural changes associated with AD pathology. Several preclinical murine models of AD have been generated based on transgenic insertion of human mutated APP genes. Depending on the specific mutations, mouse strains express different aspects of amyloid pathology, e.g. intracellular amyloid-β (Aβ) aggregates, parenchymal plaques, or cerebral amyloid angiopathy. We have applied multi-parametric MRI in three transgenic mouse lines to compare changes in brain function with resting-state fMRI and structure with diffusion tensor imaging and high resolution anatomical imaging. E22ΔAβ developing intracellular Aβ aggregates did not present functional or structural alterations compared to their wild-type littermates. PSAPP mice displaying parenchymal amyloid plaques displayed mild functional changes within the supplementary and barrel field cortices, and increased isocortical volume relative to controls. Extensive reduction in functional connectivity in the sensory-motor cortices and within the default mode network, as well as local volume increase in the midbrain relative to wild-type have been observed in ArcAβ mice bearing intracellular Aβ aggregates as well as parenchymal and vascular amyloid deposits. Patterns of functional and structural changes appear to be strain-specific and not directly related to amyloid deposition.

  17. Disruption of arterial perivascular drainage of amyloid-β from the brains of mice expressing the human APOE ε4 allele.

    Directory of Open Access Journals (Sweden)

    Cheryl A Hawkes

    Full Text Available Failure of elimination of amyloid-β (Aβ from the brain and vasculature appears to be a key factor in the etiology of sporadic Alzheimer's disease (AD and cerebral amyloid angiopathy (CAA. In addition to age, possession of an apolipoprotein E (APOE ε4 allele is a strong risk factor for the development of sporadic AD. The present study tested the hypothesis that possession of the APOE ε4 allele is associated with disruption of perivascular drainage of Aβ from the brain and with changes in cerebrovascular basement membrane protein levels. Targeted replacement (TR mice expressing the human APOE3 (TRE3 or APOE4 (TRE4 genes and wildtype mice received intracerebral injections of human Aβ(40. Aβ(40 aggregated in peri-arterial drainage pathways in TRE4 mice, but not in TRE3 or wildtype mice. The number of Aβ deposits was significantly higher in the hippocampi of TRE4 mice than in the TRE3 mice, at both 3- and 16-months of age, suggesting that clearance of Aβ was disrupted in the brains of TRE4 mice. Immunocytochemical and Western blot analysis of vascular basement membrane proteins demonstrated significantly raised levels of collagen IV in 3-month-old TRE4 mice compared with TRE3 and wild type mice. In 16-month-old mice, collagen IV and laminin levels were unchanged between wild type and TRE3 mice, but were lower in TRE4 mice. The results of this study suggest that APOE4 may increase the risk for AD through disruption and impedance of perivascular drainage of soluble Aβ from the brain. This effect may be mediated, in part, by changes in age-related expression of basement membrane proteins in the cerebral vasculature.

  18. Genetics Home Reference: hereditary angiopathy with nephropathy, aneurysms, and muscle cramps syndrome

    Science.gov (United States)

    ... can be inherited? More about Inheriting Genetic Conditions Diagnosis & Management Genetic Testing (1 link) Genetic Testing Registry: Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps Other Diagnosis and Management ...

  19. Cerebral microangiopathies; Zerebrale Mikroangiopathien

    Energy Technology Data Exchange (ETDEWEB)

    Linn, Jennifer [Klinikum der Universitaet Muenchen (Germany). Abt. fuer Neuroradiologie

    2011-03-15

    Cerebral microangiopathies are a very heterogenous group of diseases characterized by pathological changes of the small cerebral vessels. They account for 20 - 30 % of all ischemic strokes. Degenerative microangiopathy and sporadic cerebral amyloid angiography represent the typical acquired cerebral microangiopathies, which are found in over 90 % of cases. Besides, a wide variety of rare, hereditary microangiopathy exists, as e.g. CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), Fabrys disease and MELAS syndrome (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes). (orig.)

  20. Cerebral malaria Malaria cerebral

    Directory of Open Access Journals (Sweden)

    Silvia Blair Trujillo

    2003-03-01

    Full Text Available Is the most common complication of P. falciparum malaria; nearly 90% of people who have suffered CM can recover without neurological problems. Currently there are four hypotheses that explain pathogenesis of CM: cytoadherence and sequestering of parasitized red blood cells to cerebral capillaries; rosette formation and parasitized red blood cells agglutination; production of cytokines and activation of second messengers and opening of the blood-brain barrier. However the main question remains to be answered; how the host-parasite interaction in the vascular space interferes transiently with cerebral function? Recently, the beta amyloid precursor peptide has been employed as marker of neural injury in CM. It is expected that the beta amyloid precursor peptide will help to understand the pathogenesis of CM in complicated patients of endemic areas of Colombia. La malaria Cerebral (MC es la complicación más frecuente de la malaria por P. falciparum; aproximadamente el 90% de las personas que la han padecido se recuperan completamente sin secuelas neurológicas. Aún no se conoce con claridad su patogénesis pero se han postulado cuatro hipótesis o mecanismos posibles: 1 citoadherencia y secuestro de glóbulos rojos parasitados en la microvasculatura cerebral; 2 formación de rosetas y aglutinación de glóbulos rojos parasitados; 3 producción de citoquinas y activación de segundos mensajeros y, 4 apertura de la barrera hematoencefálica. Sin embargo, queda un interrogante sin resolver aún: ¿qué proceso se lleva a cabo para que el parásito, desde el espacio microvascular, pueda interferir transitoriamente con la función cerebral? Recientemente se ha utilizado el precursor de la proteína b-Amiloide como un marcador de daño neuronal en MC; este precursor será de gran ayuda en futuras investigaciones realizadas en nuestro medio que aporten información para comprender la patogénesis de la MC.

  1. 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.

  2. Alterations in Cerebral Cortical Glucose and Glutamine Metabolism Precedes Amyloid Plaques in the APPswe/PSEN1dE9 Mouse Model of Alzheimer's Disease

    DEFF Research Database (Denmark)

    Andersen, Jens V; Christensen, Sofie K; Aldana, Blanca I;

    2016-01-01

    Alterations in brain energy metabolism have been suggested to be of fundamental importance for the development of Alzheimer's disease (AD). However, specific changes in brain energetics in the early stages of AD are poorly known. The aim of this study was to investigate cerebral energy metabolism...

  3. [Interconnection of the angiopathy and neuropathy development mechanism at patients with type II pancreatic diabetes].

    Science.gov (United States)

    Saltykov, B B; Zinov'eva, O E

    2012-01-01

    In the article we summarized literature data, covered genesis of angiopathy and neuropathy at patients with type II diabetes. In the genesis of disease different metabolic, immune, hypoxic, genetic and others factors, caused affection of arteries, microcirculation and the peripheral nervous system, play an important role. Increasing changes of the great and minute vessels are interconnected with diabetic neuropathy

  4. Sexual dysfunction in nonseminoma testicular cancer patients is related to chemotherapy-induced angiopathy

    NARCIS (Netherlands)

    vanBasten, JPA; Hoekstra, HJ; vanDriel, MF; Droste, JHJ; JankerPool, G; vandeWiel, HBM; Sleijfer, DT; Schraffordt Koops, H.

    1997-01-01

    Purpose: To establish the prevalence of sexual dysfunctions after different treatment modalities for non-seminomatous testicular germ cell tumor (NSTGCT) and to investigate whether treatment-induced angiopathy and neuropathy is related to sexual dysfunction. Patient and Methods: A questionnaire asse

  5. Redox Status of β2GPI in Different Stages of Diabetic Angiopathy

    Directory of Open Access Journals (Sweden)

    Jun Ma

    2016-01-01

    Full Text Available We explored the redox status of beta 2 glycoprotein I (β2GPI in different stages of diabetic angiopathy. Type 2 diabetes mellitus (T2DM had a significantly lower proportion of reduced β2GPI as compared to healthy controls (p0.05. The mild-A-stenosis group and mild-diabetic retinopathy (DR groups had higher proportion of reduced β2GPI than their severely affected counterparts. The mild-slow nerve conduction velocity (NCVS group had higher proportion of reduced β2GPI than normal nerve conduction velocity (NCVN group and severe-NCVS groups. The proportion of reduced β2GPI was in positive correlation with 24 h urine microalbumin and total urine protein, and the proportion of reduced β2GPI was in negative correlation with serum and skin advanced glycation end products (AGEs. Taken together, our data implicate that the proportion of reduced β2GPI increased in the early stage of angiopathy and decreased with the aggravation of angiopathy.

  6. B-Amyloid Precursor Protein Staining of the Brain in Sudden Infant and Early Childhood Death

    DEFF Research Database (Denmark)

    Jensen, Lisbeth Lund; Banner, Jytte; Ulhøi, Benedicte Parm

    2013-01-01

    To develop and validate a scoring method for assessing β-amyloid precursor protein (APP) staining in cerebral white matter and to investigate the occurrence, amount and deposition pattern based on the cause of death in infants and young children.......To develop and validate a scoring method for assessing β-amyloid precursor protein (APP) staining in cerebral white matter and to investigate the occurrence, amount and deposition pattern based on the cause of death in infants and young children....

  7. Proteólisis cerebral del péptido amiloide-ß: Relevancia de la enzima degradadora de insulina en la enfermedad de Alzheimer Cerebral proteolysis of amyloid-ß peptide: Relevance of insulin-degrading enzyme in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    María Celeste Leal

    2009-10-01

    Full Text Available El aumento global de la expectativa de vida convierte a la enfermedad de Alzheimer (EA en un problema creciente. Una de las características distintivas de EA es la acumulación excesiva del péptido amiloide ß (Aß en el cerebro. En los últimos años se ha fortalecido el concepto de que la degradación de Aß por proteasas in situ es un mecanismo importante que previene su acumulación cerebral. Datos bioquímicos y genéticos mostraron que la enzima degradadora de insulina (IDE participa en la homeostasis de Aß e insulina. La expresión y la actividad de IDE están significativamente disminuidas en cerebros con EA comparados con controles de igual edad. Además, IDE se deposita con Aß en placas seniles y vasos, indicando un grosero cambio conformacional producto de distintos mecanismos post-traduccionales. Estas alteraciones en la distribución y actividad de IDE resultan en una insuficiente degradación de Aß e insulina y promueven la formación de oligómeros de Aß y la resistencia a la hormona, procesos que convergen hacia la neurodegeneración. El estudio de los mecanismos de eliminación de Aß cerebral no sólo ayudará a comprender la patogenia de EA sino que permitirá una mejor interpretación de los ensayos clínicos en curso y el desarrollo de nuevas estrategias terapéuticas.The global increase in life expectancy turns Alzheimer's disease (AD into a growing problem. One of the distinctive features of AD is the excessive accumulation of amyloid-ß (Aß peptide in the brain. In recent years, a concept that has gained strength is that degradation of Aß by proteases in situ is an important mechanism that prevents cerebral peptide accumulation. Biochemical and genetic data have shown that insulin-degrading enzyme (IDE participates in Aß and insulin homeostasis. IDE expression and activity are significantly decreased in AD brains compared to age-matched controls. Also, IDE is deposited with Aß in senile plaques and blood vessels

  8. Inhibition of amyloid-beta-induced cell death in human brain pericytes in vitro.

    NARCIS (Netherlands)

    Rensink, A.A.M.; Verbeek, M.M.; Otte-Holler, I.; Donkelaar, H.J. ten; Waal, R.M.W. de; Kremer, H.P.H.

    2002-01-01

    Amyloid-beta protein (A beta) deposition in the cerebral vascular walls is one of the key features of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). A beta(1-40) carrying the 'Dutch' mutation (HCHWA-D A beta(1-40)) induces pronounced degeneration of cul

  9. Insulin inhibits amyloid beta-induced cell death in cultured human brain pericytes.

    NARCIS (Netherlands)

    Rensink, A.A.M.; Otte-Holler, I.; Boer, R.; Bosch, R.R.; Donkelaar, H.J. ten; Waal, R.M.W. de; Verbeek, M.M.; Kremer, H.P.H.

    2004-01-01

    Amyloid-beta (Abeta) deposition in the cerebral arterial and capillary walls is one of the characteristics of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis-Dutch type. In vitro, Abeta1-40, carrying the "Dutch" mutation (DAbeta1-40), induced reproducible degeneration of cult

  10. Modeling amyloids in bacteria

    Directory of Open Access Journals (Sweden)

    Villar-Piqué Anna

    2012-12-01

    Full Text Available Abstract An increasing number of proteins are being shown to assemble into amyloid structures, self-seeding fibrillar aggregates that may lead to pathological states or play essential biological functions in organisms. Bacterial cell factories have raised as privileged model systems to understand the mechanisms behind amyloid assembly and the cellular fitness cost associated to the formation of these aggregates. In the near future, these bacterial systems will allow implementing high-throughput screening approaches to identify effective modulators of amyloid aggregation.

  11. 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...... of diabetes type II, while revealing the structure(s) of islet amyloid fibrils is necessary for potential design of therapeutic agents....

  12. {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.

  13. Highly potent soluble amyloid-β seeds in human Alzheimer brain but not cerebrospinal fluid

    Science.gov (United States)

    Kaeser, Stephan A.; Maia, Luis F.; Portelius, Erik; Pinotsi, Dorothea; Kaminski, Clemens F.; Winkler, David T.; Maetzler, Walter; Keyvani, Kathy; Spitzer, Philipp; Wiltfang, Jens; Kaminski Schierle, Gabriele S.; Zetterberg, Henrik; Staufenbiel, Matthias; Jucker, Mathias

    2017-01-01

    The soluble fraction of brain samples from patients with Alzheimer’s disease contains highly biologically active amyloid-β seeds. In this study, we sought to assess the potency of soluble amyloid-β seeds derived from the brain and cerebrospinal fluid. Soluble Alzheimer’s disease brain extracts were serially diluted and then injected into the hippocampus of young, APP transgenic mice. Eight months later, seeded amyloid-β deposition was evident even when the hippocampus received subattomole amounts of brain-derived amyloid-β. In contrast, cerebrospinal fluid from patients with Alzheimer’s disease, which contained more than 10-fold higher levels of amyloid-β peptide than the most concentrated soluble brain extracts, did not induce detectable seeding activity in vivo. Similarly, cerebrospinal fluid from aged APP-transgenic donor mice failed to induce cerebral amyloid-β deposition. In comparison to the soluble brain fraction, cerebrospinal fluid largely lacked N-terminally truncated amyloid-β species and exhibited smaller amyloid-β-positive particles, features that may contribute to the lack of in vivo seeding by cerebrospinal fluid. Interestingly, the same cerebrospinal fluid showed at least some seeding activity in an in vitro assay. The present results indicate that the biological seeding activity of soluble amyloid-β species is orders of magnitude greater in brain extracts than in the cerebrospinal fluid. PMID:25212850

  14. Temporal trajectory and progression score estimation from voxelwise longitudinal imaging measures: Application to amyloid imaging

    Science.gov (United States)

    Bilgel, Murat; Jedynak, Bruno; Wong, Dean F.; Resnick, Susan M.; Prince, Jerry L.

    2015-01-01

    Cortical β-amyloid deposition begins in Alzheimer’s disease (AD) years before the onset of any clinical symptoms. It is therefore important to determine the temporal trajectories of amyloid deposition in these earliest stages in order to better understand their associations with progression to AD. A method for estimating the temporal trajectories of voxelwise amyloid as measured using longitudinal positron emission tomography (PET) imaging is presented. The method involves the estimation of a score for each subject visit based on the PET data that reflects their amyloid progression. This amyloid progression score allows subjects with similar progressions to be aligned and analyzed together. The estimation of the progression scores and the amyloid trajectory parameters are performed using an expectation-maximization algorithm. The correlations among the voxel measures of amyloid are modeled to reflect the spatial nature of PET images. Simulation results show that model parameters are captured well at a variety of noise and spatial correlation levels. The method is applied to longitudinal amyloid imaging data considering each cerebral hemisphere separately. The results are consistent across the hemispheres and agree with a global index of brain amyloid known as mean cortical DVR. Unlike mean cortical DVR, which depends on a priori defined regions, the progression score extracted by the method is data-driven and does not make assumptions about regional longitudinal changes. Compared to regressing on age at each voxel, the longitudinal trajectory slopes estimated using the proposed method show better localized longitudinal changes. PMID:26221692

  15. Amyloid positron emission tomography and cognitive reserve

    Institute of Scientific and Technical Information of China (English)

    Matteo Bauckneht; Agnese Picco; Flavio Nobili; Silvia Morbelli

    2015-01-01

    Alzheimer’s disease(AD) is characterized by a nonlinear progressive course and several aspects influence the relationship between cerebral amount of AD pathology and the clinical expression of the disease. Brain cognitive reserve(CR) refers to the hypothesized capacity of an adult brain to cope with brain damage in order to minimize symptomatology. CR phenomenon contributed to explain the disjunction between the degree of neurodegeneration and the clinical phenotype of AD. The possibility to track brain amyloidosis(Aβ) in vivo has huge relevance for AD diagnosis and new therapeutic approaches. The clinical repercussions of positron emission tomography(PET)-assessed Aβ load are certainly mediated by CR thus potentially hampering the prognostic meaning of amyloid PET in selected groups of patients. Similarly, amyloid PET and cerebrospinal fluid amyloidosis biomarkers have recently provided new evidence for CR. The present review discusses the concept of CR in the framework of available neuroimaging studies and specifically deals with the reciprocal influences between amyloid PET and CR in AD patients and with the potential consequent interventional strategies for AD.

  16. Characterization of amyloid in equine recurrent uveitis as AA amyloid.

    Science.gov (United States)

    Ostevik, L; de Souza, G A; Wien, T N; Gunnes, G; Sørby, R

    2014-01-01

    Two horses with chronic uveitis and histological lesions consistent with equine recurrent uveitis (ERU) were examined. Microscopical findings in the ciliary body included deposits of amyloid lining the non-pigmented epithelium, intracytoplasmic, rod-shaped, eosinophilic inclusions and intraepithelial infiltration of T lymphocytes. Ultrastructural examination of the ciliary body of one horse confirmed the presence of abundant extracellular deposits of non-branching fibrils (9-11 nm in diameter) consistent with amyloid. Immunohistochemistry revealed strong positive labelling for AA amyloid and mass spectrometry showed the amyloid to consist primarily of serum amyloid A1 in both cases. The findings suggest that localized, intraocular AA amyloidosis may occur in horses with ERU.

  17. Cellular processing of the amyloidogenic cystatin C variant of hereditary cerebral hemorrhage with amyloidosis, Icelandic type

    DEFF Research Database (Denmark)

    Benedikz, Eirikur; Merz, G S; Schwenk, V

    1999-01-01

    of an amyloidogenic mutation on the intracellular processing of its protein product. The protein, a mutant of the cysteine protease inhibitor cystatin C, is the amyloid precursor protein in Hereditary Cerebral Hemorrhage with Amyloidosis--Icelandic type (HCHWA-I). The amyloid fibers are composed of mutant cystatin C...

  18. Nanomaterials for reducing amyloid cytotoxicity.

    Science.gov (United States)

    Zhang, Min; Mao, Xiaobo; Yu, Yue; Wang, Chen-Xuan; Yang, Yan-Lian; Wang, Chen

    2013-07-26

    This review is intended to reflect the recent progress on therapeutic applications of nanomaterials in amyloid diseases. The progress on anti-amyloid functions of various nanomaterials including inorganic nanoparticles, polymeric nanoparticles, carbon nanomaterials and biomolecular aggregates, is reviewed and discussed. The main functionalization strategies for general nanoparticle modifications are reviewed for potential applications of targeted therapeutics. The interaction mechanisms between amyloid peptides and nanomaterials are discussed from the perspectives of dominant interactions and kinetics. The encapsulation of anti-amyloid drugs, targeted drug delivery, controlled drug release and drug delivery crossing blood brain barrier by application of nanomaterials would also improve the therapeutics of amyloid diseases.

  19. ABCA7 Mediates Phagocytic Clearance of Amyloid-β in the Brain.

    Science.gov (United States)

    Fu, YuHong; Hsiao, Jen-Hsiang T; Paxinos, George; Halliday, Glenda M; Kim, Woojin Scott

    2016-09-06

    Alzheimer's disease (AD) is a neurodegenerative disorder characterized by dementia and abnormal deposits of aggregated amyloid-β in the brain. Recent genome-wide association studies have revealed that ABCA7 is strongly associated with AD. In vitro evidence suggests that the role of ABCA7 is related to phagocytic activity. Deletion of ABCA7 in a mouse model of AD exacerbates cerebral amyloid-β plaque load. However, the biological role of ABCA7 in AD brain pathogenesis is unknown. We show that ABCA7 is highly expressed in microglia and when monocytes are differentiated into macrophages. We hypothesized that ABCA7 plays a protective role in the brain that is related to phagocytic clearance of amyloid-β. We isolated microglia and macrophages from Abca7-/- and wild type mice and tested them for their capacity to phagocytose amyloid-β oligomers. We found that the phagocytic clearance of amyloid-β was substantially reduced in both microglia and macrophages from Abca7-/- mice compared to wild type mice. Consistent with these results, in vivo phagocytic clearance of amyloid-β oligomers in the hippocampus was reduced in Abca7-/- mice. Furthermore, ABCA7 transcription was upregulated in AD brains and in amyloidogenic mouse brains specifically in the hippocampus as a response to the amyloid-β pathogenic state. Together these results indicate that ABCA7 mediates phagocytic clearance of amyloid-β in the brain, and reveal a mechanism by which loss of function of ABCA7 increases the susceptibility to AD.

  20. Ataque cerebral

    OpenAIRE

    Takeuchi Tan, Yuri; Fundación Valle de Lili

    1998-01-01

    ¿Qué es un ataque cerebral?/¿Qué tipos de ataque cerebral existen?/¿Cuáles son los síntomas de un ataque cerebral?/Factores de riesgo para un ataque cerebral/Tratamiento médico del ataque cerebral/¿por qué es importante acudir temprano cuando se presentan las señales de alarma?/ Manejo preventivo del ataque cerebral isquémico/Tratamiento quirúrgico del ataque cerebral/Enfermedad vascular cerebral hemorrágica/¿Cómo está constituido el grupo de ataque cerebral de la fundación Clínica Valle d...

  1. Cerebral Palsy

    Science.gov (United States)

    Cerebral palsy is a group of disorders that affect a person's ability to move and to maintain balance ... do not get worse over time. People with cerebral palsy may have difficulty walking. They may also have ...

  2. Protective effects of berberine against amyloid beta-induced toxicity in cultured rat cortical neurons

    Institute of Scientific and Technical Information of China (English)

    Jing Wang; Yanjun Zhang; Shuai Du; Mixia Zhang

    2011-01-01

    Berberine, a major constituent of Coptidis rhizoma, exhibits neural protective effects. The present study analyzed the potential protective effect of berberine against amyloid G-induced cytotoxicity in rat cerebral cortical neurons. Alzheimer's disease cell models were treated with 0.5 and 2 μmol/Lberberine for 36 hours to inhibit amyloid G-induced toxicity. Methyl thiazolyl tetrazolium assay and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining results showed that berberine significantly increased cell viability and reduced cell apoptosis in primary cultured rat cortical neurons. In addition, western blot analysis revealed a protective effect of berberine against amyloid β-induced toxicity in cultured cortical neurons, which coincided with significantly decreased abnormal up-regulation of activated caspase-3. These results showed that berberine exhibited a protective effect against amyloid 13-induced cytotoxicity in cultured rat cortical neurons.

  3. MR-angiography in vasculitis and benign angiopathy of the central nervous system; MR-Angiographie in der Diagnostik von Vaskulitiden und benignen Angiopathien des Zentralnervensystems

    Energy Technology Data Exchange (ETDEWEB)

    Schlueter, A.; Hirsch, W.; Jassoy, A.; Behrmann, C.; Spielmann, R.P. [Klinik fuer Diagnostische Radiologie, Martin-Luther-Univ. Halle-Wittenberg (Germany); Kornhuber, M. [Klinik fuer Neurologie, Martin-Luther-Univ. Halle-Wittenberg (Germany); Keysser, G. [Klinik fuer Innere Medizin I, Martin-Luther-Univ. Halle-Wittenberg (Germany)

    2001-06-01

    To evaluate TOF 3D magnetic resonance angiography (MRA) of the intracranial arteries in patients with vasculitis or vasculitis-like benign angiopathy of the central nervous system (CNS). Method: The results of MRA in 20 patients with clinically and radiographically proven vasculitis (17/20) or vasculitis-like benign angiopathy (3/20) of the CNS were retrospectively analysed. Patients with hyperintense lesions of more than 3 mm on T{sub 2}-weighted MRI images were included in this trial. An inflammatory, embolic, neurodegenerative or metastatic origin of these lesions was excluded by extensive clinical studies. For the MR-examination a TOF 3D FISP sequence was used on a 1.5 T imager. Results: MRA showed characteristic changes for vasculitis or angiopathy in 15 of 20 patients (75%). Conclusions: In patients suspected of having a vasculitis or vasculitis-like angiopathy, MRA is recommended as a non-invasive modality. If the results of MRI and extensive clinical studies are carefully correlated, MRA may substitute conventional angiography in cases with typical vascular changes. (orig.) [German] Ziel der Studie war es, den Wert der TOF 3D Magnetresonanzangiographie (MRA) bei Patienten mit Vaskulitis oder vaskulitisaehnlichen, benignen Angiopathien des Zentralnervensystems (ZNS) zu erfassen. Methoden: Die MRA-Aufnahmen von 20 Patienten mit klinisch und bildgebend nachgewiesener Vaskulitis (17/20) oder vaskulitisaehnlicher, benigner Angiopathie (3/20) des ZNS wurden retrospektiv ausgewertet. Eingeschlossen wurden Patienten mit Laesionen des Hirnparenchymsgroessen 3 mm in den T{sub 2}-gewichteten Sequenzen der MRT, wobei diese Veraenderungen aufgrund umfangreicher klinischer Untersuchungen nicht auf das Vorliegen neurodegenerativer, anderweitig entzuendlicher, metastatischer oder embolischer Ursachen zurueckzufuehren waren. Fuer die MRA wurde eine TOF 3D FISP-Sequenz auf einem 1,5T MR-Geraet verwendet. Ergebnisse: MR-angiographisch wurden bei 15/20 Patienten (75

  4. 3-N-butylphthalide improves neuronal morphology after chronic cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Wanhong Zhao; Chao Luo; Jue Wang; Jian Gong; Bin Li; Yingxia Gong; Jun Wang; Hanqin Wang

    2014-01-01

    3-N-butylphthalide is an effective drug for acute ischemic stroke. However, its effects on chronic cerebral ischemia-induced neuronal injury remain poorly understood. Therefore, this study li-gated bilateral carotid arteries in 15-month-old rats to simulate chronic cerebral ischemia in aged humans. Aged rats were then intragastrically administered 3-n-butylphthalide. 3-N-butylphtha-lide administration improved the neuronal morphology in the cerebral cortex and hippocampus of rats with chronic cerebral ischemia, increased choline acetyltransferase activity, and decreased malondialdehyde and amyloid beta levels, and greatly improved cognitive function. These findings suggest that 3-n-butylphthalide alleviates oxidative stress caused by chronic cerebral ischemia, improves cholinergic function, and inhibits amyloid beta accumulation, thereby im-proving cerebral neuronal injury and cognitive deifcits.

  5. 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.

  6. 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.

  7. Neuroprotection via matrix-trophic coupling between cerebral endothelial cells and neurons

    OpenAIRE

    Guo, Shuzhen; Kim, Woo Jean; Lok, Josephine; Lee, Sun-Ryung; Besancon, Elaine; Luo, Bing-Hao; Stins, Monique F.; Wang, Xiaoying; Dedhar, Shoukat; Lo, Eng H.

    2008-01-01

    The neurovascular unit is an emerging concept that emphasizes homeostatic interactions between endothelium and cerebral parenchyma. Here, we show that cerebral endothelium are not just inert tubes for delivering blood, but they also secrete trophic factors that can be directly neuroprotective. Conditioned media from cerebral endothelial cells broadly protects neurons against oxygen-glucose deprivation, oxidative damage, endoplasmic reticulum stress, hypoxia, and amyloid neurotoxicity. This ph...

  8. Independent information from cerebrospinal fluid amyloid-β and florbetapir imaging in Alzheimer's disease.

    Science.gov (United States)

    Mattsson, Niklas; Insel, Philip S; Donohue, Michael; Landau, Susan; Jagust, William J; Shaw, Leslie M; Trojanowski, John Q; Zetterberg, Henrik; Blennow, Kaj; Weiner, Michael W

    2015-03-01

    Reduced cerebrospinal fluid amyloid-β42 and increased retention of florbetapir positron emission tomography are biomarkers reflecting cortical amyloid load in Alzheimer's disease. However, these measurements do not always agree and may represent partly different aspects of the underlying Alzheimer's disease pathology. The goal of this study was therefore to test if cerebrospinal fluid and positron emission tomography amyloid-β biomarkers are independently related to other Alzheimer's disease markers, and to examine individuals who are discordantly classified by these two biomarker modalities. Cerebrospinal fluid and positron emission tomography amyloid-β were measured at baseline in 769 persons [161 healthy controls, 68 subjective memory complaints, 419 mild cognitive impairment and 121 Alzheimer's disease dementia, mean age 72 years (standard deviation 7 years), 47% females] and used to predict diagnosis, APOE ε4 carriage status, cerebral blood flow, cerebrospinal fluid total-tau and phosphorylated-tau levels (cross-sectionally); and hippocampal volume, fluorodeoxyglucose positron emission tomography results and Alzheimer's Disease Assessment Scale-cognitive subscale scores (longitudinally). Cerebrospinal fluid and positron emission tomography amyloid-β were highly correlated, but adjusting one of these predictors for the other revealed that they both provided partially independent information when predicting diagnosis, APOE ε4, hippocampal volume, metabolism, cognition, total-tau and phosphorylated-tau (the 95% confidence intervals of the adjusted effects did not include zero). Cerebrospinal fluid amyloid-β was more strongly related to APOE ε4 whereas positron emission tomography amyloid-β was more strongly related to tau levels (P Alzheimer's disease. Reduced cerebrospinal fluid amyloid-β may be more strongly related to early stage Alzheimer's disease, whereas increased positron emission tomography amyloid-β may be more strongly related to disease

  9. Role of gut microbiota and nutrients in amyloid formation and pathogenesis of Alzheimer disease.

    Science.gov (United States)

    Pistollato, Francesca; Sumalla Cano, Sandra; Elio, Iñaki; Masias Vergara, Manuel; Giampieri, Francesca; Battino, Maurizio

    2016-10-01

    It has been hypothesized that alterations in the composition of the gut microbiota might be associated with the onset of certain human pathologies, such as Alzheimer disease, a neurodegenerative syndrome associated with cerebral accumulation of amyloid-β fibrils. It has been shown that bacteria populating the gut microbiota can release significant amounts of amyloids and lipopolysaccharides, which might play a role in the modulation of signaling pathways and the production of proinflammatory cytokines related to the pathogenesis of Alzheimer disease. Additionally, nutrients have been shown to affect the composition of the gut microbiota as well as the formation and aggregation of cerebral amyloid-β. This suggests that modulating the gut microbiome and amyloidogenesis through specific nutritional interventions might prove to be an effective strategy to prevent or reduce the risk of Alzheimer disease. This review examines the possible role of the gut in the dissemination of amyloids, the role of the gut microbiota in the regulation of the gut-brain axis, the potential amyloidogenic properties of gut bacteria, and the possible impact of nutrients on modulation of microbiota composition and amyloid formation in relation to the pathogenesis of Alzheimer disease.

  10. Familial amyloid polyneuropathy.

    Science.gov (United States)

    Planté-Bordeneuve, Violaine; Said, Gerard

    2011-12-01

    Familial amyloid polyneuropathies (FAPs) are a group of life-threatening multisystem disorders transmitted as an autosomal dominant trait. Nerve lesions are induced by deposits of amyloid fibrils, most commonly due to mutated transthyretin (TTR). Less often the precursor of amyloidosis is mutant apolipoprotein A-1 or gelsolin. The first identified cause of FAP-the TTR Val30Met mutation-is still the most common of more than 100 amyloidogenic point mutations identified worldwide. The penetrance and age at onset of FAP among people carrying the same mutation vary between countries. The symptomatology and clinical course of FAP can be highly variable. TTR FAP typically causes a nerve length-dependent polyneuropathy that starts in the feet with loss of temperature and pain sensations, along with life-threatening autonomic dysfunction leading to cachexia and death within 10 years on average. TTR is synthesised mainly in the liver, and liver transplantation seems to have a favourable effect on the course of neuropathy, but not on cardiac or eye lesions. Oral administration of tafamidis meglumine, which prevents misfolding and deposition of mutated TTR, is under evaluation in patients with TTR FAP. In future, patients with FAP might benefit from gene therapy; however, genetic counselling is recommended for the prevention of all types of FAP.

  11. 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.

  12. Diversity, biogenesis and function of microbial amyloids

    OpenAIRE

    2011-01-01

    Amyloid is a distinct β-sheet-rich fold that many proteins can acquire. Frequently associated with neurodegenerative diseases in humans, including Alzheimer’s, Parkinson’s and Huntington’s, amyloids are traditionally considered the product of protein misfolding. However, the amyloid fold is now recognized as a ubiquitous part of normal cellular biology. ‘Functional’ amyloids have been identified in nearly all facets of cellular life, with microbial functional amyloids leading the way. Unlike ...

  13. Pittsburgh compound B imaging and cerebrospinal fluid amyloid-β in a multicentre European memory clinic study

    DEFF Research Database (Denmark)

    Leuzy, Antoine; Chiotis, Konstantinos; Hasselbalch, Steen G;

    2016-01-01

    The aim of this study was to assess the agreement between data on cerebral amyloidosis, derived using Pittsburgh compound B positron emission tomography and (i) multi-laboratory INNOTEST enzyme linked immunosorbent assay derived cerebrospinal fluid concentrations of amyloid-β42; (ii) centrally me...

  14. Prion protein amyloidosis with divergent phenotype associated with two novel nonsense mutations in PRNP

    NARCIS (Netherlands)

    C. Jansen (Casper); P. Parchi (Piero); S. Capellari (Sabina); A.J. Vermeij (Ad); P. Corrado (Patrizia); F. Baas (Frank); R. Strammiello (Rosario); W.A. van Gool (Willem); J.C. van Swieten; A.J.M. Rozemuller (Annemieke)

    2010-01-01

    textabstractStop codon mutations in the gene encoding the prion protein (PRNP) are very rare and have thus far only been described in two patients with prion protein cerebral amyloid angiopathy (PrP-CAA). In this report, we describe the clinical, histopathological and pathological prion protein (PrP

  15. Drug: D06202 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 0303 139.1735 D06202.gif Treatment of mild-to-moderate Alzheimer's disease, treatment of cerebral amyloid an...giopathy Same as: C03349 map07056 Agents for Alzheimer-type dementia CAS: 3687-18-1 PubChem: 47207860 PDB-CC

  16. 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

  17. Disease: H01185 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available H01185 Cerebral amyloid angiopathy (CAA); Hereditary cerebral hemorrhage with amylo...h aging, several familial forms of CAA reported to date. Hereditary cystatin C am...M, Magoni M, Padovani A, Tagliavini F Hereditary cerebral hemorrhage with amyloidosis associated with the E6...93K mutation of APP. Arch Neurol 67:987-95 (2010) PMID:16612982 Palsdottir A, Snorradottir AO, Thorsteinsson L Hereditary

  18. Vasoespasmo cerebral

    Directory of Open Access Journals (Sweden)

    Antonio A. F. de Salles

    1987-09-01

    Full Text Available Vasoespasmo cerebral ocorre em patologias como enxaqueca, hemorragia subaracnóidea, trauma de crânio, após isquemia e/ou hipoxia. A fisiopatologia do vasoespasmo cerebral nestas patologias não está completamente desvendada. Neste artigo são analisados os fatores neuroquímicos e morfológicos responsáveis pelo controle circulatório cerebral. As alterações circulatórias que seguem a hemorragia subaracnóidea são utilizadas como exemplo. Conclui-se que fatores bioquímicos, fisiológicos e morfológicos são responsáveis pelas manifestações vasculares que ocorrem após a hemorragia subaracnóidea. Alternativas de tratamento do vasoespasmo cerebral são discutidas.

  19. Cerebral Paragonimiasis.

    Science.gov (United States)

    Miyazaki, I

    1975-01-01

    The first case of cerebral paragonimiasis was reported by Otani in Japan in 1887. This was nine years after Kerbert's discovery of the fluke in the lungs of Bengal tigers and seven years after a human pulmonary infection by the fluke was demonstrated by Baelz and Manson. The first case was a 26-year-old man who had been suffering from cough and hemosputum for one year. The patient developed convulsive seizures with subsequent coma and died. The postmortem examination showed cystic lesions in the right frontal and occipital lobes. An adult fluke was found in the occipital lesion and another was seen in a gross specimen of normal brain tissue around the affected occipital lobe. Two years after Otani's discovery, at autopsy a 29-year-old man with a history of Jacksonian seizure was reported as having cerebral paragonimiasis. Some time later, however, it was confirmed that the case was actually cerebral schistosomiasis japonica. Subsequently, cases of cerebral paragonimiasis were reported. However, the majority of these cases were not confirmed histologically. It was pointed out that some of these early cases were probably not Paragonimus infection. After World War II, reviews as well as case reports were published. Recently, investigations have been reported from Korea, with a clinicla study on 62 cases of cerebral paragonimiasis seen at the Neurology Department of the National Medical Center, Seoul, between 1958 and 1964. In 1971 Higashi described a statistical study on 105 cases of cerebral paragonimiasis that had been treated surgically in Japan.

  20. 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.

  1. alpha7 Nicotinic acetylcholine receptor knockout selectively enhances ethanol-, but not beta-amyloid-induced neurotoxicity.

    Science.gov (United States)

    de Fiebre, Nancyellen C; de Fiebre, Christopher M

    2005-01-03

    The alpha7 subtype of nicotinic acetylcholine receptor (nAChR) has been implicated as a potential site of action for two neurotoxins, ethanol and the Alzheimer's disease related peptide, beta-amyloid. Here, we utilized primary neuronal cultures of cerebral cortex from alpha7 nAChR null mutant mice to examine the role of this receptor in modulating the neurotoxic properties of subchronic, "binge" ethanol and beta-amyloid. Knockout of the alpha7 nAChR gene selectively enhanced ethanol-induced neurotoxicity in a gene dosage-related fashion. Susceptibility of cultures to beta-amyloid induced toxicity, however, was unaffected by alpha7 nAChR gene null mutation. Further, beta-amyloid did not inhibit the binding of the highly alpha7-selective radioligand, [(125)I]alpha-bungarotoxin. On the other hand, in studies in Xenopus oocytes ethanol efficaciously inhibited alpha7 nAChR function. These data suggest that alpha7 nAChRs modulate the neurotoxic effects of binge ethanol, but not the neurotoxicity produced by beta-amyloid. It is hypothesized that inhibition of alpha7 nAChRs by ethanol provides partial protection against the neurotoxic properties of subchronic ethanol.

  2. Vasoespasmo cerebral

    OpenAIRE

    1987-01-01

    Vasoespasmo cerebral ocorre em patologias como enxaqueca, hemorragia subaracnóidea, trauma de crânio, após isquemia e/ou hipoxia. A fisiopatologia do vasoespasmo cerebral nestas patologias não está completamente desvendada. Neste artigo são analisados os fatores neuroquímicos e morfológicos responsáveis pelo controle circulatório cerebral. As alterações circulatórias que seguem a hemorragia subaracnóidea são utilizadas como exemplo. Conclui-se que fatores bioquímicos, fisiológicos e morfológi...

  3. Cerebral microcirculation during experimental normovolaemic anaemia

    Directory of Open Access Journals (Sweden)

    Judith eBellapart

    2016-02-01

    Full Text Available Anaemia is accepted amongst critically ill patients as an alternative to elective blood transfusion. This practice has been extrapolated to head injury patients with only one study comparing the effects of mild anaemia on neurological outcome. There are no studies quantifying microcirculation during anaemia. Experimental studies suggest that anaemia leads to cerebral hypoxia and increased rates of infarction, but the lack of clinical equipoise when testing the cerebral effects of transfusion amongst critically injured patients, supports the need of experimental studies. The aim of this study was to quantify cerebral microcirculation and the potential presence of axonal damage in an experimental model exposed to normovolaemic anaemia, with the intention of describing possible limitations within management practices in critically ill patients. Under non-recovered anaesthesia, six Merino sheep were instrumented using an intracardiac transeptal catheter to inject coded microspheres into the left atrium to ensure systemic and non-chaotic distribution. Cytometric analyses quantified cerebral microcirculation at specific regions of the brain. Amyloid precursor protein staining was used as an indicator of axonal damage. Animals were exposed to normovolaemic anaemia by blood extractions from the indwelling arterial catheter with simultaneous fluid replacement through a venous central catheter. Simultaneous data recording from cerebral tissue oxygenation, intracranial pressure and cardiac output was monitored. A regression model was used to examine the effects of anaemia on microcirculation with a mixed model to control for repeated measures. Homogeneous and normal cerebral microcirculation with no evidence of axonal damage was present in all cerebral regions, with no temporal variability, concluding that acute normovolaemic anaemia does not result in short term effects on cerebral microcirculation in the ovine brain.

  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. Functional amyloid formation within mammalian tissue.

    Directory of Open Access Journals (Sweden)

    Douglas M Fowler

    2006-01-01

    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.

  6. Amyloid deposition in 2 feline thymomas.

    Science.gov (United States)

    Burrough, E R; Myers, R K; Hostetter, S J; Fox, L E; Bayer, B J; Felz, C L; Waller, K R; Whitley, E M

    2012-07-01

    Two cases of feline thymoma with amyloid deposition were encountered between 1982 and 2010. Neoplastic cells were separated by abundant, pale eosinophilic, homogeneous material that was congophilic and birefringent. Ultrastructurally, the neoplastic cells were connected by desmosomes, and the extracellular deposits were composed of nonbranching, hollow-cored fibrils, 8-10 nm in diameter. In the case with sufficient archived tissue for additional sections, the amyloid remained congophilic following potassium permanganate incubation, and the neoplastic cells were immunoreactive for pancytokeratin. The histologic, histochemical, ultrastructural, and immunohistochemical features of both neoplasms are consistent with epithelial-predominant thymoma with the unusual feature of intratumoral amyloid deposition. The affinity of the amyloid for Congo red following potassium permanganate incubation is consistent with non-AA amyloid. The ultrastructural findings were consistent with amyloid production by the neoplastic epithelial cells.

  7. Amyloid Goiter Secondary to Ulcerative Colitis

    Directory of Open Access Journals (Sweden)

    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.

  8. Protective effects of tea polyphenols on cerebral nerve cell apoptosis induced by D-galactose and beta-amyloid peptide 25-35%茶多酚对D-半乳糖与Aβ25~35诱导脑神经细胞凋亡的保护效应

    Institute of Scientific and Technical Information of China (English)

    曲娴; 李冰; 杨文豪; 吕俊华

    2007-01-01

    子水平变化.④小鼠脑神经细胞凋亡情况.结果:纳入大鼠90只均进入结果分析.①药物处理12周后,茶多酚中、高剂量组和维生素E组的小鼠游出迷宫时间短于模型组,进入迷宫盲端的错误次数较模型组减少,差异均有统计学意义(P<0.05~0.01).②茶多酚中、高剂量组超氧化物歧化酶活性较模型组有所增高,茶多酚高剂量组丙二醛含量较模型组有所降低,差异有统计学意义(P<0.05~0.01).③茶多酚中、高剂量组和维生素E组红细胞内和脑神经元细胞浆钙离子浓度均低于模型组,差异有统计学意义(P<0.05~0.01).④茶多酚各剂量组神经细胞凋亡率均低于模型组,差异有显著性意义(P<0.05).结论:茶多酚具有抑制D-半乳糖与Aβ25~35诱致脑神经细胞凋亡作用,并明显改善摸型小鼠学习记忆能力,其作用可能与提高全身性抗氧化能力,改善氧化应激损伤引起的细胞内钙超载有关.%BACKGROUND: Some researches demonstrate that tea polyphenols (TP) has protective effects on neurotoxicity of hippocampal nerve cells induced byβ-amyloid peptide (Aβ), 6-hydroxydopamine (6-OHDA) and oxidative substances. In addition, clinical preliminary examination indicates that TP plays a certain preventive and therapeutic effects on the reduction of recognition function in high-risk population with Alzheimer disease (AD); however, its target and mechanism are still hot topics.OBJECTIVE: To observe the interfering effects of TP on cerebral nerve cell apoptosis induced by D-galactose and Aβ25~35 in mice.DESIGN: Randomized controlled animal study.SETTING: Department of Pharmacology, Pharmacological College of Jinan University.MATERIALS: The experiment was carried out in the Experimental Center of Jinan University from September 2004 to January 2005. A total of 90 healthy Kumning mice, aged 2 months, each gender in half, weighing 26-28 g, were provided by Guangdong Provincial Medical

  9. 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.

  10. Surgical considerations about amyloid goiter.

    Science.gov (United States)

    García Villanueva, Augusto; García Villanueva, María Jesús; García Villanueva, Mercedes; Rojo Blanco, Roberto; Collado Guirao, María Vicenta; Cabañas Montero, Jacobo; Beni Pérez, Rafael; Moreno Montes, Irene

    2013-05-01

    Amyloidosis is an uncommon syndrome consisting of a number of disorders having in common an extracellular deposit of fibrillary proteins. This results in functional and structural changes in the affected organs, depending on deposit location and severity. Amyloid infiltration of the thyroid gland may occur in 50% and up to 80% of patients with primary and secondary amyloidosis respectively. Amyloid goiter (AG) is a true rarity, usually found associated to secondary amyloidosis. AG may require surgical excision, usually because of compressive symptoms. We report the case of a patient with a big AG occurring in the course of a secondary amyloidosis associated to polyarticular onset juvenile idiopathic arthritis who underwent total thyroidectomy. Current literature is reviewed, an attempt is made to provide action guidelines, and some surgical considerations on this rare condition are given.

  11. Hereditary cerebral hemorrhage with amyloidosis in patients of Dutch origin is related to Alzheimer disease

    Energy Technology Data Exchange (ETDEWEB)

    van Duinen, S.G.; Castano, E.M.; Prelli, F.; Bots, G.T.A.B.; Luyendijk, W.; Frangione, B.

    1987-08-01

    Hereditary cerebral hemorrhage with amyloidosis in Dutch patients is an autosomal dominant form of vascular amyloidosis restricted to the leptomeninges and cerebral cortex. Clinically the disease is characterized by cerebral hemorrhages leading to an early death. Immunohistochemical studies of five patients revealed that the vascular amyloid deposits reacted intensely with an antiserum raised against a synthetic peptide homologous to the Alzheimer disease-related ..beta..-protein. Silver stain-positive, senile plaque-like structures were also labeled by the antiserum, yet these lesions lacked the dense amyloid cores present in typical plaques of Alzheimer disease. No neurofibrillary tangles were present. Amyloid fibrils were purified from the leptomeningeal vessels of one patient who clinically had no signs of dementia. The protein had a molecular weight of approx. 4000 and its partial amino acid sequence to position 21 showed homology to the ..beta..-protein of Alzheimer disease and Down syndrome. These results suggest that hereditary cerebral hemorrhage with amyloidosis of Dutch origin is pathogenetically related to Alzheimer disease and support the concept that the initial amyloid deposition in this disorder occurs in the vessel walls before damaging the brain parenchyma. Thus, deposition of ..beta..-protein in brain tissue seems to be related to a spectrum of diseases involving vascular syndromes, progressive dementia, or both.

  12. Atypical presentation of atypical amyloid.

    Science.gov (United States)

    Holanda, Danniele G; Acharya, Veena K; Dogan, Ahmet; Racusen, Lorraine C; Atta, Mohamed G

    2011-01-01

    Amyloidosis is a group of diseases categorized by precipitation of a group of protein aggregates (amyloid) in tissues, including the kidney, and proteinuria is usually the commonest, though not exclusive, hallmark of clinical presentation. AL and AA are the most commonly recognized forms of amyloidosis involving the kidney, but other forms have been described. We present a case of renal amyloidosis due to a novel amyloidogenic protein, leucocyte cell-derived chemotaxin 2, without proteinuria at presentation or on subsequent follow-up.

  13. In vivo amyloid imaging with PET in frontotemporal dementia

    Energy Technology Data Exchange (ETDEWEB)

    Engler, Henry [Uruguay University Hospital of Clinics and Faculty of Science, Department of Nuclear Medicine, Montevideo (Uruguay); Uppsala University Hospital, Department of Nuclear Medicine, Uppsala (Sweden); Uppsala University, Department of Medical Sciences, Uppsala (Sweden); GE Healthcare, Uppsala Imanet, Uppsala (Sweden); Santillo, Alexander F.; Lindau, Maria; Lannfelt, Lars; Kilander, Lena [Uppsala University, Department of Public Health and Caring Sciences/Geriatrics, Uppsala (Sweden); Wang, Shu Xia [Guangdong Provincial People' s Hospital, Weilun PET Centre, Guangzhou (China); Savitcheva, Irina [Uppsala University Hospital, Department of Nuclear Medicine, Uppsala (Sweden); Nordberg, Agneta [Karolinska Institute, Division of Molecular Neuropharmacology, Stockholm (Sweden); Karolinska University Hospital Huddinge, Department of Geriatric Medicine, Stockholm (Sweden); Laangstroem, Bengt [GE Healthcare, Uppsala Imanet, Uppsala (Sweden); Uppsala University, Departments of Biochemistry and Organic Chemistry, Uppsala (Sweden)

    2008-01-15

    N-methyl[11C]2-(4'methylaminophenyl)-6-hydroxy-benzothiazole (PIB) is a positron emission tomography (PET) tracer with amyloid binding properties which allows in vivo measurement of cerebral amyloid load in Alzheimer's disease (AD). Frontotemporal dementia (FTD) is a syndrome that can be clinically difficult to distinguish from AD, but in FTD amyloid deposition is not a characteristic pathological finding. The aim of this study is to investigate PIB retention in FTD. Ten patients with the diagnosis of FTD participated. The diagnosis was based on clinical and neuropsychological examination, computed tomography or magnetic resonance imaging scan, and PET with 18Fluoro-2-deoxy-d-glucose (FDG). The PIB retention, measured in regions of interest, was normalised to a reference region (cerebellum). The results were compared with PIB retention data previously obtained from 17 AD patients with positive PIB retention and eight healthy controls (HC) with negative PIB retention. Statistical analysis was performed with a students t-test with significance level set to 0.00625 after Bonferroni correction. Eight FTD patients showed significantly lower PIB retention compared to AD in frontal (p < 0.0001), parietal (p < 0.0001), temporal (p = 0.0001), and occipital (p = 0.0003) cortices as well as in putamina (p < 0.0001). The PIB uptake in these FTD patients did not differ significantly from the HC in any region. However, two of the 10 FTD patients showed PIB retention similar to AD patients. The majority of FTD patients displayed no PIB retention. Thus, PIB could potentially aid in differentiating between FTD and AD. (orig.)

  14. Neuronal dysfunction and disconnection of cortical hubs in non-demented subjects with elevated amyloid burden

    Science.gov (United States)

    Drzezga, Alexander; Van Dijk, Koene R. A.; Sreenivasan, Aishwarya; Talukdar, Tanveer; Sullivan, Caroline; Schultz, Aaron P.; Sepulcre, Jorge; Putcha, Deepti; Greve, Doug; Johnson, Keith A.; Sperling, Reisa A.

    2011-01-01

    Disruption of functional connectivity between brain regions may represent an early functional consequence of β-amyloid pathology prior to clinical Alzheimer's disease. We aimed to investigate if non-demented older individuals with increased amyloid burden demonstrate disruptions of functional whole-brain connectivity in cortical hubs (brain regions typically highly connected to multiple other brain areas) and if these disruptions are associated with neuronal dysfunction as measured with fluorodeoxyglucose-positron emission tomography. In healthy subjects without cognitive symptoms and patients with mild cognitive impairment, we used positron emission tomography to assess amyloid burden and cerebral glucose metabolism, structural magnetic resonance imaging to quantify atrophy and novel resting state functional magnetic resonance imaging processing methods to calculate whole-brain connectivity. Significant disruptions of whole-brain connectivity were found in amyloid-positive patients with mild cognitive impairment in typical cortical hubs (posterior cingulate cortex/precuneus), strongly overlapping with regional hypometabolism. Subtle connectivity disruptions and hypometabolism were already present in amyloid-positive asymptomatic subjects. Voxel-based morphometry measures indicate that these findings were not solely a consequence of regional atrophy. Whole-brain connectivity values and metabolism showed a positive correlation with each other and a negative correlation with amyloid burden. These results indicate that disruption of functional connectivity and hypometabolism may represent early functional consequences of emerging molecular Alzheimer's disease pathology, evolving prior to clinical onset of dementia. The spatial overlap between hypometabolism and disruption of connectivity in cortical hubs points to a particular susceptibility of these regions to early Alzheimer's-type neurodegeneration and may reflect a link between synaptic dysfunction and functional

  15. Janus faces of amyloid proteins in neuroinflammation.

    Science.gov (United States)

    Steinman, Lawrence; Rothbard, Jonathan B; Kurnellas, Michael P

    2014-07-01

    Amyloid forming molecules are generally considered harmful. In Alzheimer's Disease two amyloid molecules Aβ A4 and tau vie for consideration as the main pathogenic culprit. But molecules obey the laws of chemistry and defy the way we categorize them as humans with our well-known proclivities to bias in our reasoning. We have been exploring the brains of multiple sclerosis patients to identify molecules that are associated with protection from inflammation and degeneration. In 2001 we noted that aB crystallin (cryab) was the most abundant transcript found in MS lesions, but not in healthy brains. Cryab can reverse paralysis and attenuate inflammation in several models of inflammation including experimental autoimmune encephalomyelitis (EAE), and various models of ischemia. Cryab is an amyloid forming molecule. We have identified a core structure common to many amyloids including amyloid protein Aβ A4, tau, amylin, prion protein, serum amyloid protein P, and cryab. The core hexapeptide structure is highly immune suppressive and can reverse paralysis in EAE when administered systemically. Administration of this amyloid forming hexapeptide quickly lowers inflammatory cytokines in plasma like IL-6 and IL-2. The hexapeptide bind a set of proinflammatory mediators in plasma, including acute phase reactants and complement components. The beneficial properties of amyloid forming hexapeptides provide a potential new therapeutic direction. These experiments indicate that amyloid forming molecules have Janus faces, providing unexpected benefit for neuroinflammatory conditions.

  16. Serum amyloid a in clinical practice

    Directory of Open Access Journals (Sweden)

    Jovanović Dijana B.

    2004-01-01

    Full Text Available Serum amyloid A (SAA is an acute phase first class protein discovered a quarter of the century ago. Its concentration depends on clinical findings of the patient, illness activity and the therapy applied. SAA increases moderately to markedly (100-1000 mg/l in bacterial and fungal infections, invasive malignant diseases, tissue injuries in the acute myocardial infarction and autoimmune diseases such as rheumatoid arthritis and vasculitis. Mild elevation (10-100 mg/l is often seen in viral infections, systemic lupus erythematosus and localized inflammation or tissue injuries in cystitis and cerebral infarction. SAA as sensitive, non-invasive parameter is used in organ transplantation where early and correct diagnosis is needed as well as where prompt therapy is required. Besides acute kidney allograft rejection, SAA is used in the diagnosis of rejection after liver transplantation, simultaneous pancreas and kidney transplantation and also in bone marrow transplantation (acute „graft vs. host disease". Simultaneous determination of C-reactive protein (CRP and SAA may point to acute kidney allograft rejection. Standard immunosuppressive therapy with cyclosporine A and prednisolone significantly suppresses the acute phase CRP reaction both in operation itself and acute rejection, but not in infection. On the other hand, SAA rejection in operation, acute allograft rejection and infection is present in spite of cyclosporine A and steroids therapy. Different reaction of SAA and CRP in transplant patients to cyclosporine A therapy helps in differentiation between the infection and rejection. Although CRP and SAA are sensitive and acute phase reactants, their serum concentrations cannot be valued as prognostic and diagnostic criteria without creatinine serum concentration and clinical findings. In addition, they offer important information for clinical diagnosis as well as the kind of therapy.

  17. Tackling amyloidogenesis in Alzheimer’s disease with A2V variants of Amyloid

    Science.gov (United States)

    Di Fede, Giuseppe; Catania, Marcella; Maderna, Emanuela; Morbin, Michela; Moda, Fabio; Colombo, Laura; Rossi, Alessandro; Cagnotto, Alfredo; Virgilio, Tommaso; Palamara, Luisa; Ruggerone, Margherita; Giaccone, Giorgio; Campagnani, Ilaria; Costanza, Massimo; Pedotti, Rosetta; Salvalaglio, Matteo; Salmona, Mario; Tagliavini, Fabrizio

    2016-01-01

    We developed a novel therapeutic strategy for Alzheimer’s disease (AD) exploiting the properties of a natural variant of Amyloid-β (Aβ) carrying the A2V substitution, which protects heterozygous carriers from AD by its ability to interact with wild-type Aβ, hindering conformational changes and assembly thereof. As prototypic compound we designed a six-mer mutated peptide (Aβ1-6A2V), linked to the HIV-related TAT protein, which is widely used for brain delivery and cell membrane penetration of drugs. The resulting molecule [Aβ1-6A2VTAT(D)] revealed strong anti-amyloidogenic effects in vitro and protected human neuroblastoma cells from Aβ toxicity. Preclinical studies in AD mouse models showed that short-term treatment with Aβ1-6A2VTAT(D) inhibits Aβ aggregation and cerebral amyloid deposition, but a long treatment schedule unexpectedly increases amyloid burden, although preventing cognitive deterioration. Our data support the view that the AβA2V-based strategy can be successfully used for the development of treatments for AD, as suggested by the natural protection against the disease in human A2V heterozygous carriers. The undesirable outcome of the prolonged treatment with Aβ1-6A2VTAT(D) was likely due to the TAT intrinsic attitude to increase Aβ production, avidly bind amyloid and boost its seeding activity, warning against the use of the TAT carrier in the design of AD therapeutics. PMID:26864599

  18. Tackling amyloidogenesis in Alzheimer's disease with A2V variants of Amyloid-β.

    Science.gov (United States)

    Di Fede, Giuseppe; Catania, Marcella; Maderna, Emanuela; Morbin, Michela; Moda, Fabio; Colombo, Laura; Rossi, Alessandro; Cagnotto, Alfredo; Virgilio, Tommaso; Palamara, Luisa; Ruggerone, Margherita; Giaccone, Giorgio; Campagnani, Ilaria; Costanza, Massimo; Pedotti, Rosetta; Salvalaglio, Matteo; Salmona, Mario; Tagliavini, Fabrizio

    2016-02-11

    We developed a novel therapeutic strategy for Alzheimer's disease (AD) exploiting the properties of a natural variant of Amyloid-β (Aβ) carrying the A2V substitution, which protects heterozygous carriers from AD by its ability to interact with wild-type Aβ, hindering conformational changes and assembly thereof. As prototypic compound we designed a six-mer mutated peptide (Aβ1-6A2V), linked to the HIV-related TAT protein, which is widely used for brain delivery and cell membrane penetration of drugs. The resulting molecule [Aβ1-6A2VTAT(D)] revealed strong anti-amyloidogenic effects in vitro and protected human neuroblastoma cells from Aβ toxicity. Preclinical studies in AD mouse models showed that short-term treatment with Aβ1-6A2VTAT(D) inhibits Aβ aggregation and cerebral amyloid deposition, but a long treatment schedule unexpectedly increases amyloid burden, although preventing cognitive deterioration. Our data support the view that the AβA2V-based strategy can be successfully used for the development of treatments for AD, as suggested by the natural protection against the disease in human A2V heterozygous carriers. The undesirable outcome of the prolonged treatment with Aβ1-6A2VTAT(D) was likely due to the TAT intrinsic attitude to increase Aβ production, avidly bind amyloid and boost its seeding activity, warning against the use of the TAT carrier in the design of AD therapeutics.

  19. In vivo evaluation of amyloid deposition and brain glucose metabolism of 5XFAD mice using positron emission tomography.

    Science.gov (United States)

    Rojas, Santiago; Herance, José Raúl; Gispert, Juan Domingo; Abad, Sergio; Torrent, Elia; Jiménez, Xavier; Pareto, Deborah; Perpiña, Unai; Sarroca, Sara; Rodríguez, Elisenda; Ortega-Aznar, Arantxa; Sanfeliu, Coral

    2013-07-01

    Positron emission tomography (PET) has been used extensively to evaluate the neuropathology of Alzheimer's disease (AD) in vivo. Radiotracers directed toward the amyloid deposition such as [(18)F]-FDDNP (2-(1-{6-[(2-[F]Fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile) and [(11)C]-PIB (Pittsburg compound B) have shown exceptional value in animal models and AD patients. Previously, the glucose analogue [(18)F]-FDG (2-[(18)F]fluorodeoxyglucose) allowed researchers and clinicians to evaluate the brain glucose consumption and proved its utility for the early diagnosis and the monitoring of the progression of AD. Animal models of AD are based on the transgenic expression of different human mutant genes linked to familial AD. The novel transgenic 5XFAD mouse containing 5 mutated genes in its genome has been proposed as an AD model with rapid and massive cerebral amyloid deposition. PET studies performed with animal-dedicated scanners indicate that PET with amyloid-targeted radiotracers can detect the pathological amyloid deposition in transgenic mice and rats. However, in other studies no differences were found between transgenic mice and their wild type littermates. We sought to investigate in 5XFAD mice if the radiotracers [(11)C]-PIB, and [(18)F]-Florbetapir could quantify the amyloid deposition in vivo and if [(18)F]-FDG could do so with regard to glucose consumption. We found that 5XFAD animals presented higher cerebral binding of [(18)F]-Florbetapir, [(11)C]-PIB, and [(18)F]-FDG. These results support the use of amyloid PET radiotracers for the evaluation of AD animal models. Probably, the increased uptake observed with [(18)F]-FDG is a consequence of glial activation that occurs in 5XFAD mice.

  20. 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

  1. 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.

  2. Amyloid beta-protein and lipid rafts: focused on biogenesis and catabolism.

    Science.gov (United States)

    Araki, Wataru; Tamaoka, Akira

    2015-01-01

    Cerebral accumulation of amyloid β-protein (Aβ) is thought to play a key role in the molecular pathology of Alzheimer's disease (AD). Three secretases (β-, γ-, and α-secretase) are proteases that control the production of Aβ from amyloid precursor protein. Increasing evidence suggests that cholesterol-rich membrane microdomains termed 'lipid rafts' are involved in the biogenesis and accumulation of Aβ as well as Aβ-mediated neurotoxicity. γ-Secretase is enriched in lipid rafts, which are considered an important site for Aβ generation. Additionally, Aβ-degrading peptidases located in lipid rafts, such as neprilysin, appear to play a role in Aβ catabolism. This mini-review focuses on the roles of lipid rafts in the biogenesis and catabolism of Aβ, covering recent research on the relationship between lipid rafts and the three secretases or Aβ-degrading peptidases. Furthermore, the significance of lipid rafts in Aβ aggregation and neurotoxicity is briefly summarized.

  3. Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota

    Science.gov (United States)

    Harach, T.; Marungruang, N.; Duthilleul, N.; Cheatham, V.; Mc Coy, K. D.; Frisoni, G.; Neher, J. J.; Fåk, F.; Jucker, M.; Lasser, T.; Bolmont, T.

    2017-01-01

    Alzheimer’s disease is the most common form of dementia in the western world, however there is no cure available for this devastating neurodegenerative disorder. Despite clinical and experimental evidence implicating the intestinal microbiota in a number of brain disorders, its impact on Alzheimer’s disease is not known. To this end we sequenced bacterial 16S rRNA from fecal samples of Aβ precursor protein (APP) transgenic mouse model and found a remarkable shift in the gut microbiota as compared to non-transgenic wild-type mice. Subsequently we generated germ-free APP transgenic mice and found a drastic reduction of cerebralamyloid pathology when compared to control mice with intestinal microbiota. Importantly, colonization of germ-free APP transgenic mice with microbiota from conventionally-raised APP transgenic mice increased cerebral Aβ pathology, while colonization with microbiota from wild-type mice was less effective in increasing cerebral Aβ levels. Our results indicate a microbial involvement in the development of Abeta amyloid pathology, and suggest that microbiota may contribute to the development of neurodegenerative diseases. PMID:28176819

  4. Microglial activation in the hippocampus of hypercholesterolemic rabbits occurs independent of increased amyloid production

    Directory of Open Access Journals (Sweden)

    Streit Wolfgang J

    2007-08-01

    Full Text Available Abstract Background Rabbits maintained on high-cholesterol diets are known to show increased immunoreactivity for amyloid beta protein in cortex and hippocampus, an effect that is amplified by presence of copper in the drinking water. Hypercholesterolemic rabbits also develop sporadic neuroinflammatory changes. The purpose of this study was to survey microglial activation in rabbits fed cholesterol in the presence or absence of copper or other metal ions, such as zinc and aluminum. Methods Vibratome sections of the rabbit hippocampus and overlying cerebral cortex were examined for microglial activation using histochemistry with isolectin B4 from Griffonia simplicifolia. Animals were scored as showing either focal or diffuse microglial activation with or without presence of rod cells. Results Approximately one quarter of all rabbits fed high-cholesterol diets showed evidence of microglial activation, which was always present in the hippocampus and not in the cortex. Microglial activation was not correlated spatially with increased amyloid immunoreactivity or with neurodegenerative changes and was most pronounced in hypercholesterolemic animals whose drinking water had been supplemented with either copper or zinc. Controls maintained on normal chow were largely devoid of neuroinflammatory changes, but revealed minimal microglial activation in one case. Conclusion Because the increase in intraneuronal amyloid immunoreactivity that results from administration of cholesterol occurs in both cerebral cortex and hippocampus, we deduce that the microglial activation reported here, which is limited to the hippocampus, occurs independent of amyloid accumulation. Furthermore, since neuroinflammation occurred in the absence of detectable neurodegenerative changes, and was also not accompanied by increased astrogliosis, we conclude that microglial activation occurs because of metabolic or biochemical derangements that are influenced by dietary factors.

  5. Natural polyphenols binding to amyloid: a broad class of compounds to treat different human amyloid diseases.

    Science.gov (United States)

    Ngoungoure, Viviane L Ndam; Schluesener, Jan; Moundipa, Paul F; Schluesener, Hermann

    2015-01-01

    Polyphenols are a large group of phytonutrients found in herbal beverages and foods. They have manifold biological activities, including antioxidative, antimicrobial, and anti-inflammatory properties. Interestingly, some polyphenols bind to amyloid and substantially ameliorate amyloid diseases. Misfolding, aggregation, and accumulation of amyloid fibrils in tissues or organs leads to a group of disorders, called amyloidoses. Prominent diseases are Alzheimer's, Parkinson's, and Huntington's disease, but there are other, less well-known diseases wherein accumulation of misfolded protein is a prominent feature. Amyloidoses are a major burden to public health. In particular, Alzheimer's disease shows a strong increase in patient numbers. Accelerated development of effective therapies for amyloidoses is a necessity. A viable strategy can be the prevention or reduction of protein misfolding, thus reducing amyloid build-up by restoring the cellular aggretome. Amyloid-binding polyphenols affect amyloid formation on various levels, e.g. by inhibiting fibril formation or steering oligomer formation into unstructured, nontoxic pathways. Consequently, preclinical studies demonstrate reduction of amyloid-formation by polyphenols. Amyloid-binding polyphenols might be suitable lead structures for development of imaging agents for early detection of disease and monitoring amyloid deposition. Intake of dietary polyphenols might be relevant to the prevention of amyloidoses. Nutraceutical strategies might be a way to reduce amyloid diseases.

  6. A novel CCM2 variant in a family with non-progressive cognitive complaints and cerebral microbleeds.

    OpenAIRE

    Cohn-Hokke, P. E.; Holstege, H.; Weiss, M.M.; Van Der Flier, W. M.; Barkhof, F.; Sistermans, E.A.; Pijnenburg, Y.A.; van Swieten, J. C.; Meijers-Heijboer, H; Scheltens, P

    2016-01-01

    Lobar cerebral microbleeds are most often sporadic and associated with Alzheimer's disease. The aim of our study was to identify the underlying genetic defect in a family with cognitive complaints and multiple lobar microbleeds and a positive family history for early onset Alzheimer's disease. We performed exome sequencing followed by Sanger sequencing for validation purposes on genomic DNA of three siblings with cognitive complaints, reduced amyloid-beta-42 in CSF and multiple cerebral lobar...

  7. 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.

  8. Amyloid Beta as a Modulator of Synaptic Plasticity

    OpenAIRE

    Parihar, Mordhwaj S.; Gregory J. Brewer

    2010-01-01

    Alzheimer’s disease is associated with synapse loss, memory dysfunction and pathological accumulation of amyloid beta in plaques. However, an exclusively pathological role for amyloid beta is being challenged by new evidence for an essential function of amyloid beta at the synapse. Amyloid beta protein exists in different assembly states in the central nervous system and plays distinct roles ranging from synapse and memory formation to memory loss and neuronal cell death. Amyloid beta is pres...

  9. 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

  10. 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.

  11. Effects of Shouwu-Yizhi capsule on learning and memory and the expressions of presenilin 1,β-amyloid precursor protein mRNAs in the hippocampus following cerebral ischemia reperfusion in rats%首乌益智胶囊对脑缺血再灌注大鼠学习记忆和海马β淀粉样前体蛋白、早老素1 mRNA表达的影响

    Institute of Scientific and Technical Information of China (English)

    陈超; 李长生; 杨晓妮; 程广清

    2014-01-01

    目的:探讨首乌益智胶囊对脑缺血再灌注大鼠学习记忆和早老素1(PS1)、β淀粉样前体蛋白(APP)mRNA表达的影响。方法80只大鼠按体质量随机分为假手术组、模型组、首乌益智胶囊组、脑复康组,每组20只。采用大脑中动脉闭塞法制作脑缺血再灌模型。造模后7 d,首乌益智胶囊组和脑复康组分别给予首乌益智胶囊溶液(52 mg/ml)、脑复康溶液(28 mg/ml)灌胃,均为1 ml/(100 g•d),共28 d,模型组和假手术组等体积生理盐水灌胃。采用Morris水迷宫评价学习和记忆;采用实时荧光定量PCR检测大鼠海马PS1和APP mRNA表达。结果水迷宫实验显示,模型组大鼠逃避潜伏期较假手术组[(12.98±0.70)s比(9.43±0.78)s]显著延长,穿越平台次数较假手术组[(5.08±0.39)次比(7.62±0.43)次]显著减少,首乌益智胶囊组逃避潜伏期较模型组[(9.77±0.58)s比(12.98±0.70)s]显著缩短(P均<0.01),穿越平台次数较模型组[(7.40±0.44)次比(5.08±0.39)次]显著增加(P均<0.01)。首乌益智胶囊组海马PS1和APP mRNA 表达[(0.99±0.01)比(1.08±0.03)]均较模型组[(1.06±0.03)比(1.12±0.04)]显著降低(P<0.05或0.01)。结论首乌益智胶囊可抑制脑缺血再灌大鼠海马PS1和APP mRNA表达,改善学习和记忆。%Objective To investigate the effects of Shouwu-Yizhi capsule on learning and memory, and the expressions of presenilin 1(PS1),β-amyloid precursor protein (APP) mRNAs in the hippocampus following cerebral ischemia reperfusion in rats. Methods Sprague–Dawley rats were randomly divided into a Shouwu-Yizhi group, a piracetam group, a model group, and a sham operation group with 20 rats in each group. Focal cerebral ischemia reperfusion model was induced by middle cerebral artery occlusion for 2 hours. Seven days after ischemia reperfusion, the rats in the Shouwu-Yizhi and piracetam groups were administered intragastrically Shouwu-Yizhi solution (52 mg/ml) and

  12. Cerebrolysin reduces amyloid-β deposits, apoptosis and autophagy in the thalamus and improves functional recovery after cortical infarction.

    Science.gov (United States)

    Xing, Shihui; Zhang, Jian; Dang, Chao; Liu, Gang; Zhang, Yusheng; Li, Jingjing; Fan, Yuhua; Pei, Zhong; Zeng, Jinsheng

    2014-02-15

    Focal cerebral infarction causes amyloid-β (Aβ) deposits and secondary thalamic neuronal degeneration. The present study aimed to determine the protective effects of Cerebrolysin on Aβ deposits and secondary neuronal damage in thalamus after cerebral infarction. At 24h after distal middle cerebral artery occlusion (MCAO), Cerebrolysin (5 ml/kg) or saline as control was once daily administered for consecutive 13 days by intraperitoneal injection. Sensory function and secondary thalamic damage were assessed with adhesive-removal test, Nissl staining and immunofluorescence at 14 days after MCAO. Aβ deposits, activity of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), apoptosis and autophagy were determined by TUNEL staining, immunofluorescence and immunoblot. The results showed that Cerebrolysin significantly improved sensory deficit compared to controls (pCerebrolysin, which was accompanied by decreases in neuronal loss and astroglial activation compared to controls (all p Cerebrolysin markedly inhibited cleaved caspase-3, conversion of LC3-II, downregulation of Bcl-2 and upregulation of Bax in the ipsilateral thalamus compared to controls (all pCerebrolysin reduces Aβ deposits, apoptosis and autophagy in the ipsilateral thalamus, which may be associated with amelioration of secondary thalamic damage and functional recovery after cerebral infarction.

  13. 二十二碳六烯酸降低β淀粉样蛋白25-35致大鼠皮质神经元损伤%Ducosahexaenoic acid reduces the cerebral cortical neurons injury induced by amyloid beta protein 25-35 in rats

    Institute of Scientific and Technical Information of China (English)

    刘丽莉; 王永; 胡为民; 李世芳; 张记君

    2011-01-01

    目的 观察二十二碳六烯酸(DHA)对β淀粉样蛋白25-35(Aβ25-35)致原代培养大鼠皮质神经元损伤的保护作用.方法 原代培养Wistar大鼠皮质神经元,先后给予不同剂量的DHA(20、50和100μmol/L)及Aβ25-35(25 μmol/L),用CCK-8比色法观察神经元存活率,用激光扫描共聚焦显微镜观察细胞内游离钙离子浓度.结果 1)与对照组相比,Aβ25-35使细胞存活率明显下降(31%±6%,P<0 05);使细胞内游离钙离子浓度明显升高( 249%±12%,P<0 05);2)孵育DHA可降低Aβ25-35引起的神经元存活率明显下降及细胞内游离钙离子浓度升高.结论 Aβ致细胞内钙超载是Aβ产生神经毒作用的一个方面,而DHA可部分拮抗Aβ25-35的神经毒作用.%Objective To observe the protection of Ducosahexaenoic acid ( DHA) on primary culture cortical neurons exposed to amyloid beta protein 25-35. Methods Newborn Wistar rat cortical neurons were primarily cultured, then treated with DHA of different dose(20,50,100 μmol/L) and aggregated Aβ25-35(25μmol/L). CCK-8 ( Cell Counting Kit-8 ) staining was used to detect the survival rate of cortical neurons, and LSCM (laser-scanning confocal imaging system) was used to detect the changes of intracellular free calcium concentration in neurons labeled with the fluorescent dye Fluo-3/AM. Results 1) Compared with control group, the survival rate of cortical neurons was decreased in Aβ group (31% ±6% ,P <0. 05) , intracellular free calcium concentration in Aβ group was elevated(249% ±12% ,P <0. 05 ) ; 2) incubation with DHA attenuated the decrease in the survival rate of cortical neurons and the increase in intracellular free calcium concentration induced by amyloid beta protein 25-35. Conclusions 1) Calcium overloading induced by amyloid beta protein 25-35 might be the main neurotoxicity effect; 2)DHA could partly decrease calcium overloading induced by amyloid beta protein 25-35, which might be the important mechanism of DHA

  14. White matter changes in stroke patients. Relationship with stroke subtype and outcome

    DEFF Research Database (Denmark)

    Leys, D; Englund, E; Del Ser, T;

    1999-01-01

    or white matter lesions or leukoencephalopathy or leukoaraiosis' and 'stroke or cerebral infarct or cerebral hemorrhage or cerebrovascular disease or transient ischemic attack (TIA)'. WMC, as defined radiologically, are present in up to 44% of patients with stroke or TIA and in 50% of patients...... with vascular dementia. WMC are more frequent in patients with lacunar infarcts, deep intracerebral hemorrhages, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and cerebral amyloid angiopathy. After an acute ischemic stroke, WMC are associated with a higher risk...

  15. 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.

  16. 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.

  17. Employees with Cerebral Palsy

    Science.gov (United States)

    ... problems in the muscles or nerves. Instead, faulty development or damage to motor areas in the brain disrupt the brain's ability to adequately control movement and posture (United Cerebral Palsy, 2010). "Cerebral" refers to the ...

  18. United Cerebral Palsy

    Science.gov (United States)

    ... be sure to follow us on Twitter . United Cerebral Palsy UCP educates, advocates and provides support services to ... Partners Merz Logo Sprint Relay Copyright © 2015 United Cerebral Palsy 1825 K Street NW Suite 600 Washington, DC ...

  19. 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.

  20. How ionic strength affects the conformational behavior of human and rat beta amyloids--a computational study.

    Directory of Open Access Journals (Sweden)

    Zdeněk Kříž

    Full Text Available Progressive cerebral deposition of amyloid beta occurs in Alzheimers disease and during the aging of certain mammals (human, monkey, dog, bear, cow, cat but not others (rat, mouse. It is possibly due to different amino acid sequences at positions 5, 10 and 13. To address this issue, we performed series of 100 ns long trajectories (each trajectory was run twice with different initial velocity distribution on amyloid beta (1-42 with the human and rat amino acid sequence in three different environments: water with only counter ions, water with NaCl at a concentration of 0.15 M as a model of intracellular Na(+ concentration at steady state, and water with NaCl at a concentration of 0.30 M as a model of intracellular Na(+ concentration under stimulated conditions. We analyzed secondary structure stability, internal hydrogen bonds, and residual fluctuation. It was observed that the change in ionic strength affects the stability of internal hydrogen bonds. Increasing the ionic strength increases atomic fluctuation in the hydrophobic core of the human amyloid, and decreases the atomic fluctuation in the case of rat amyloid. The secondary structure analyses show a stable α-helix part between residues 10 and 20. However, C-terminus of investigated amyloids is much more flexible showing no stable secondary structure elements. Increasing ionic strength of the solvent leads to decreasing stability of the secondary structural elements. The difference in conformational behavior of the three amino acids at position 5, 10 and 13 for human and rat amyloids significantly changes the conformational behavior of the whole peptide.

  1. 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.

  2. Role of amyloid peptides in vascular dysfunction and platelet dysregulation in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Ilaria eCanobbio

    2015-03-01

    Full Text Available Alzheimer’s disease (AD is the most common neurodegenerative cause of dementia in the elderly. AD is accompanied by the accumulation of amyloid peptides in the brain parenchyma and in the cerebral vessels. The sporadic form of the AD accounts for about 95% of all cases. It is characterized by a late onset, typically after the age of 65, with a complex and still poorly understood aetiology. Several observations point towards a central role of cerebrovascular dysfunction in the onset of sporadic AD. According to the vascular hypothesis, AD may be initiated by vascular dysfunctions that precede and promote the neurodegenerative process. In accordance to this, AD patients show increased hemorragic or ischemic stroke risks. It is now clear that multiple bidirectional connections exist between AD and cerebrovascular disease, and in this new scenario, the effect of amyloid peptides on vascular cells and blood platelets appear to be central to AD. In this review we analyse the effect of amyloid peptides on vascular function and platelet activation and its contribution to the cerebrovascular pathology associated with AD and the progression of this disease.

  3. Selective disruption of the cerebral neocortex in Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Rahul S Desikan

    Full Text Available BACKGROUND: Alzheimer's disease (AD and its transitional state mild cognitive impairment (MCI are characterized by amyloid plaque and tau neurofibrillary tangle (NFT deposition within the cerebral neocortex and neuronal loss within the hippocampal formation. However, the precise relationship between pathologic changes in neocortical regions and hippocampal atrophy is largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study, combining structural MRI scans and automated image analysis tools with reduced cerebrospinal fluid (CSF Aβ levels, a surrogate for intra-cranial amyloid plaques and elevated CSF phosphorylated tau (p-tau levels, a surrogate for neocortical NFTs, we examined the relationship between the presence of Alzheimer's pathology, gray matter thickness of select neocortical regions, and hippocampal volume in cognitively normal older participants and individuals with MCI and AD (n = 724. Amongst all 3 groups, only select heteromodal cortical regions significantly correlated with hippocampal volume. Amongst MCI and AD individuals, gray matter thickness of the entorhinal cortex and inferior temporal gyrus significantly predicted longitudinal hippocampal volume loss in both amyloid positive and p-tau positive individuals. Amongst cognitively normal older adults, thinning only within the medial portion of the orbital frontal cortex significantly differentiated amyloid positive from amyloid negative individuals whereas thinning only within the entorhinal cortex significantly discriminated p-tau positive from p-tau negative individuals. CONCLUSIONS/SIGNIFICANCE: Cortical Aβ and tau pathology affects gray matter thinning within select neocortical regions and potentially contributes to downstream hippocampal degeneration. Neocortical Alzheimer's pathology is evident even amongst older asymptomatic individuals suggesting the existence of a preclinical phase of dementia.

  4. Presenilin-2 Mutation Causes Early Amyloid Accumulation and Memory Impairment in a Transgenic Mouse Model of Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Toshihiko Toda

    2011-01-01

    Full Text Available In order to clarify the pathophysiological role of presenilin-2 (PS2 carrying the Volga German Kindred mutation (N141I in a conventional mouse model of Alzheimer's disease (AD expressing amyloid precursor protein (APP with the Swedish mutation (Tg2576 line, we generated a double transgenic mouse (PS2Tg2576 by crossbreeding the PS2 mutant with Tg2576 mice. Here, we demonstrate that the PS2 mutation induced the early deposition of amyloid β-protein (Aβ at 2-3 months of age and progressive accumulation at 4-5 months of age in the brains of the mutant mice. The PS2 mutation also accelerated learning and memory impairment associated with Aβ accumulation at 4-5 months of age in Tg2576 mice. These results suggest that the PS2 mutation causes early cerebral amyloid accumulation and memory dysfunction. PS2Tg2576 mice are a suitable mouse model for studying amyloid-lowering therapies.

  5. Nontraumatic intracranial hemorrhage.

    Science.gov (United States)

    Fischbein, Nancy J; Wijman, Christine A C

    2010-11-01

    Nontraumatic (or spontaneous) intracranial hemorrhage most commonly involves the brain parenchyma and subarachnoid space. This entity accounts for at least 10% of strokes and is a leading cause of death and disability in adults. Important causes of spontaneous intracranial hemorrhage include hypertension, cerebral amyloid angiopathy, aneurysms, vascular malformations, and hemorrhagic infarcts (both venous and arterial). Imaging findings in common and less common causes of spontaneous intracranial hemorrhage are reviewed.

  6. Associations between white matter hyperintensities and β amyloid on integrity of projection, association, and limbic fiber tracts measured with diffusion tensor MRI.

    Directory of Open Access Journals (Sweden)

    Linda L Chao

    Full Text Available The goal of this study was to assess the relationship between Aβ deposition and white matter pathology (i.e., white matter hyperintensities, WMH on microstructural integrity of the white matter. Fifty-seven participants (mean age: 78±7 years from an ongoing multi-site research program who spanned the spectrum of normal to mild cognitive impairment (Clinical dementia rating 0-0.5 and low to high risk factors for arteriosclerosis and WMH pathology (defined as WMH volume >0.5% total intracranial volume were assessed with positron emission tomography (PET with Pittsburg compound B (PiB and magnetic resonance and diffusion tensor imaging (DTI. Multivariate analysis of covariance were used to investigate the relationship between Aβ deposition and WMH pathology on fractional anisotropy (FA from 9 tracts of interest (i.e., corona radiata, internal capsule, cingulum, parahippocampal white matter, corpus callosum, superior longitudinal, superior and inferior front-occipital fasciculi, and fornix. WMH pathology was associated with reduced FA in projection (i.e., internal capsule and corona radiate and association (i.e., superior longitudinal, superior and inferior fronto-occipital fasciculi fiber tracts. Aβ deposition (i.e., PiB positivity was associated with reduced FA in the fornix and splenium of the corpus callosum. There were interactions between PiB and WMH pathology in the internal capsule and parahippocampal white matter, where Aβ deposition reduced FA more among subjects with WMH pathology than those without. However, accounting for apoE ε4 genotype rendered these interactions insignificant. Although this finding suggests that apoE4 may increase amyloid deposition, both in the parenchyma (resulting in PiB positivity and in blood vessels (resulting in amyloid angiopathy and WMH pathology, and that these two factors together may be associated with compromised white matter microstructural integrity in multiple brain regions, additional studies

  7. Chirality and chiroptical properties of amyloid fibrils.

    Science.gov (United States)

    Dzwolak, Wojciech

    2014-09-01

    Chirality of amyloid fibrils-linear beta-sheet-rich aggregates of misfolded protein chains-often manifests in morphological traits such as helical twist visible in atomic force microscopy and in chiroptical properties accessible to vibrational circular dichroism (VCD). According to recent studies the relationship between molecular chirality of polypeptide building blocks and superstructural chirality of amyloid fibrils may be more intricate and less deterministic than previously assumed. Several puzzling experimental findings have put into question earlier intuitive ideas on: 1) the bottom-up chirality transfer upon amyloidogenic self-assembly, and 2) the structural origins of chiroptical properties of protein aggregates. For example, removal of a single amino acid residue from an amyloidogenic all-L peptide was shown to reverse handedness of fibrils. On the other hand, certain types of amyloid aggregates revealed surprisingly strong VCD spectra with the sign and shape dependent on the conditions of fibrillation. Hence, microscopic and chiroptical studies have highlighted chirality as one more aspect of polymorphism of amyloid fibrils. This brief review is intended to outline the current state of research on amyloid-like fibrils from the perspective of their structural and superstructural chirality and chiroptical properties.

  8. 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

  9. 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.)

  10. AL amyloid imaging and therapy with a monoclonal antibody to a cryptic epitope on amyloid fibrils.

    Directory of Open Access Journals (Sweden)

    Jonathan S Wall

    Full Text Available The monoclonal antibody 2A4 binds an epitope derived from a cleavage site of serum amyloid protein A (sAA containing a -Glu-Asp- amino acid pairing. In addition to its reactivity with sAA amyloid deposits, the antibody was also found to bind amyloid fibrils composed of immunoglobulin light chains. The antibody binds to synthetic fibrils and human light chain (AL amyloid extracts with high affinity even in the presence of soluble light chain proteins. Immunohistochemistry with biotinylated 2A4 demonstrated positive reaction with ALκ and ALλ human amyloid deposits in various organs. Surface plasmon resonance analyses using synthetic AL fibrils as a substrate revealed that 2A4 bound with a K(D of ∼10 nM. Binding was inhibited in the presence of the -Glu-Asp- containing immunogen peptide. Radiolabeled 2A4 specifically localized with human AL amyloid extracts implanted in mice (amyloidomas as evidenced by single photon emission (SPECT imaging. Furthermore, co-localization of the radiolabeled mAb with amyloid was shown in biodistribution and micro-autoradiography studies. Treatment with 2A4 expedited regression of ALκ amyloidomas in mice, likely mediated by the action of macrophages and neutrophils, relative to animals that received a control antibody. These data indicate that the 2A4 mAb might be of interest for potential imaging and immunotherapy in patients with AL amyloidosis.

  11. 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.

  12. Amyloid-β positron emission tomography imaging probes

    DEFF Research Database (Denmark)

    Kepe, Vladimir; Moghbel, Mateen C; Långström, Bengt;

    2013-01-01

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

  13. ImmunoPEGliposome-mediated reduction of blood and brain amyloid levels in a mouse model of Alzheimer's disease is restricted to aged animals

    DEFF Research Database (Denmark)

    Ordóñez-Gutiérrez, Lara; Posado-Fernández, Adrián; Ahmadvand, Davoud

    2016-01-01

    The accumulation of extracellular amyloid-beta (Aβ) and intracellular neurofibrillary tangles (hyper-phosphorylated Tau) in the brain are two major neuropathological hallmarks of Alzheimer's disease (AD). Active and passive immunotherapy may limit cerebral Aβ deposition and/or accelerate its clea...... treatment was superior to free monoclonal antibody administration (at an equivalent antibody dose). The potential mechanisms and significance of age-dependent immunoliposome therapy in AD is discussed....

  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. Retinal pathology of pediatric cerebral malaria in Malawi.

    Directory of Open Access Journals (Sweden)

    Valerie A White

    Full Text Available INTRODUCTION: The causes of coma and death in cerebral malaria remain unknown. Malarial retinopathy has been identified as an important clinical sign in the diagnosis and prognosis of cerebral malaria. As part of a larger autopsy study to determine causes of death in children with coma presenting to hospital in Blantyre, Malawi, who were fully evaluated clinically prior to death, we examined the histopathology of eyes of patients who died and underwent autopsy. METHODOLOGY/PRINCIPAL FINDINGS: Children with coma were admitted to the pediatric research ward, classified according to clinical definitions as having cerebral malaria or another cause of coma, evaluated and treated. The eyes were examined by direct and indirect ophthalmoscopy. If a child died and permission was given, a standardized autopsy was carried out. The patient was then assigned an actual cause of death according to the autopsy findings. The eyes were examined pathologically for hemorrhages, cystoid macular edema, parasite sequestration and thrombi. They were stained immunohistochemically for fibrin and CD61 to identify the components of thrombi, beta-amyloid precursor protein to detect axonal damage, for fibrinogen to identify vascular leakage and for glial fibrillary acidic protein to detect gliosis. Sixty-four eyes from 64 patients were examined: 35 with cerebral malaria and 29 with comas of other causes. Cerebral malaria was distinguished by sequestration of parasitized erythrocytes, the presence and severity of retinal hemorrhages, the presence of cystoid macular edema, the occurrence and number of fibrin-platelet thrombi, the presence and amount of axonal damage and vascular leakage. CONCLUSIONS/SIGNIFICANCE: We found significant differences in retinal histopathology between patients who died of cerebral malaria and those with other diagnoses. These histopathological findings offer insights into the etiology of malarial retinopathy and provide a pathological basis for

  16. Purified and synthetic Alzheimer's amyloid beta (Aβ) prions.

    Science.gov (United States)

    Stöhr, Jan; Watts, Joel C; Mensinger, Zachary L; Oehler, Abby; Grillo, Sunny K; DeArmond, Stephen J; Prusiner, Stanley B; Giles, Kurt

    2012-07-03

    The aggregation and deposition of amyloid-β (Aβ) peptides are believed to be central events in the pathogenesis of Alzheimer's disease (AD). Inoculation of brain homogenates containing Aβ aggregates into susceptible transgenic mice accelerated Aβ deposition, suggesting that Aβ aggregates are capable of self-propagation and hence might be prions. Recently, we demonstrated that Aβ deposition can be monitored in live mice using bioluminescence imaging (BLI). Here, we use BLI to probe the ability of Aβ aggregates to self-propagate following inoculation into bigenic mice. We report compelling evidence that Aβ aggregates are prions by demonstrating widespread cerebral β-amyloidosis induced by inoculation of either purified Aβ aggregates derived from brain or aggregates composed of synthetic Aβ. Although synthetic Aβ aggregates were sufficient to induce Aβ deposition in vivo, they exhibited lower specific biological activity compared with brain-derived Aβ aggregates. Our results create an experimental paradigm that should lead to identification of self-propagating Aβ conformations, which could represent novel targets for interrupting the spread of Aβ deposition in AD patients.

  17. 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.

  18. 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.

  19. 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.

  20. 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

    2014-01-07

    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.

  1. Islet amyloid polypeptide forms rigid lipid-protein amyloid fibrils on supported phospholipid bilayers.

    Science.gov (United States)

    Domanov, Yegor A; Kinnunen, Paavo K J

    2008-02-08

    Islet amyloid polypeptide (IAPP) forms fibrillar amyloid deposits in the pancreatic islets of Langerhans of patients with type 2 diabetes mellitus, and its misfolding and aggregation are thought to contribute to beta-cell death. Increasing evidence suggests that IAPP fibrillization is strongly influenced by lipid membranes and, vice versa, that the membrane architecture and integrity are severely affected by amyloid growth. Here, we report direct fluorescence microscopic observations of the morphological transformations accompanying IAPP fibrillization on the surface of supported lipid membranes. Within minutes of application in submicromolar concentrations, IAPP caused extensive remodeling of the membrane including formation of defects, vesiculation, and tubulation. The effects of IAPP concentration, ionic strength, and the presence of amyloid seeds on the bilayer perturbation and peptide aggregation were examined. Growth of amyloid fibrils was visualized using fluorescently labeled IAPP or thioflavin T staining. Two-color imaging of the peptide and membranes revealed that the fibrils were initially composed of the peptide only, and vesiculation occurred in the points where growing fibers touched the lipid membrane. Interestingly, after 2-5 h of incubation, IAPP fibers became "wrapped" by lipid membranes derived from the supported membrane. Progressive increase in molecular-level association between amyloid and membranes in the maturing fibers was confirmed by Förster resonance energy transfer spectroscopy.

  2. 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.

  3. Serum amyloid P inhibits dermal wound healing

    Science.gov (United States)

    The repair of open wounds depends on granulation tissue formation and contraction, which is primarily mediated by myofibroblasts. A subset of myofibroblasts originates from bone-marrow-derived monocytes which differentiate into fibroblast-like cells called fibrocytes. Serum amyloid P (SAP) inhibits ...

  4. 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...

  5. Fibrillar amyloid plaque formation precedes microglial activation.

    Directory of Open Access Journals (Sweden)

    Christian K E Jung

    Full Text Available In Alzheimer's disease (AD, hallmark β-amyloid deposits are characterized by the presence of activated microglia around them. Despite an extensive characterization of the relation of amyloid plaques with microglia, little is known about the initiation of this interaction. In this study, the detailed investigation of very small plaques in brain slices in AD transgenic mice of the line APP-PS1(dE9 revealed different levels of microglia recruitment. Analysing plaques with a diameter of up to 10 μm we find that only the half are associated with clear morphologically activated microglia. Utilizing in vivo imaging of new appearing amyloid plaques in double-transgenic APP-PS1(dE9xCX3CR1+/- mice further characterized the dynamic of morphological microglia activation. We observed no correlation of morphological microglia activation and plaque volume or plaque lifetime. Taken together, our results demonstrate a very prominent variation in size as well as in lifetime of new plaques relative to the state of microglia reaction. These observations might question the existing view that amyloid deposits by themselves are sufficient to attract and activate microglia in vivo.

  6. Graphene oxide strongly inhibits amyloid beta fibrillation

    NARCIS (Netherlands)

    Mahmoudi, Morteza; Akhavan, Omid; Ghavami, Mahdi; Rezaee, Farhad; Ghiasi, Seyyed Mohammad Amin

    2012-01-01

    Since amyloid beta fibrillation (AbF) plays an important role in the development of neurodegenerative diseases, we investigated the effect of graphene oxide (GO) and their protein-coated surfaces on the kinetics of Ab fibrillation in the aqueous solution. We showed that GO and their protein-covered

  7. Reversible cerebral vasoconstriction syndrome

    Directory of Open Access Journals (Sweden)

    Saini Monica

    2009-01-01

    Full Text Available Reversible cerebral vasoconstriction syndromes (RCVS are a group of disorders that have in common an acute presentation with headache, reversible vasoconstriction of cerebral arteries, with or without neurological signs and symptoms. In contrast to primary central nervous system vasculitis, they have a relatively benign course. We describe here a patient who was diagnosed with RCVS.

  8. 前列地尔对急性脑梗死患者血清β淀粉样蛋白水平及神经功能的影响%Effects of alprostadil on serum levels of β-amyloids and neurological impairment in patients with acute cerebral infarction

    Institute of Scientific and Technical Information of China (English)

    周永; 林森; 赵连东

    2015-01-01

    目的:探讨前列地尔治疗对急性脑梗死患者血清β淀粉样蛋白(1-40)、(1-42)[Aβ(1-40)、Aβ(1-42)]水平及神经功能的影响。方法选择急性脑梗死患者84例,分为前列地尔组及对照组各42例,前列地尔组给予静脉滴注前列地尔10μg/d,每日1次,共治疗14天;对照组不使用前列地尔,其他治疗相同。两组患者分别于治疗前、治疗后14天和28天测定静脉血 Aβ(1-40)、Aβ(1-42)水平并评价神经功能缺损程度。结果治疗前两组间血清 Aβ(1-40)、Aβ(1-42)及 Aβ(1-40)/Aβ(1-42)比值差异无统计学意义(P >0.05)。治疗后14天、28天,前列地尔组 Aβ(1-40)及 Aβ(1-40)/Aβ(1β-42)比值逐步降低(P <0.001),Aβ(1-42)于治疗后14天升高(P <0.05)。对照组 Aβ(1-40)和 Aβ(1-42)水平无显著改变(P >0.05)。两组神经功能缺损情况均较治疗前明显改善,与对照组相比,治疗组改善更明显(P <0.01)。结论前列地尔可以降低急性脑梗死后血清 Aβ(1-40)水平,降低血清 Aβ(1-40)/Aβ(1-42)比值。对急性脑梗死神经功能缺损有更好的改善作用。%Objective To investigate the effects of alprostadil on serum levels of A β1-40 and Aβ1-42 and neurological impair-ment in patients with acute cerebral infarction .Methods Eighty-four patients with acute cerebral infarction were enrolled within 48 h of onset.The enrolled patients were randomly divided into alprostadil and control groups .Alprostadil was infused at a dose of 10 μg, once daily for 14 days while the control group received similar treatment except alprostadil infusion .Blood samples were collected before treatment and 14 and 28 days after treatment to measure changes of serum levels of A β1-40 and Aβ1-42.Meanwhile,the degree of neu-rological impairment was estimated

  9. 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.

  10. The value of incomplete mouse models of Alzheimer's disease.

    Science.gov (United States)

    Radde, Rebecca; Duma, Cecilia; Goedert, Michel; Jucker, Mathias

    2008-03-01

    To study Alzheimer's disease (AD), a variety of mouse models has been generated through the overexpression of the amyloid precursor protein and/or the presenilins harboring one or several mutations found in familial AD. With aging, these mice develop several lesions similar to those of AD, including diffuse and neuritic amyloid deposits, cerebral amyloid angiopathy, dystrophic neurites and synapses, and amyloid-associated neuroinflammation. Other characteristics of AD, such as neurofibrillary tangles and nerve cell loss, are not satisfactorily reproduced in these models. Mouse models that recapitulate only specific aspects of AD pathogenesis are of great advantage when deciphering the complexity of the disease and can contribute substantially to diagnostic and therapeutic innovations. Incomplete mouse models have been key to the development of Abeta42-targeted therapies, as well as to the current understanding of the interrelationship between cerebral beta-amyloidosis and tau neurofibrillary lesions, and are currently being used to develop novel diagnostic agents for in vivo imaging.

  11. Unilateral cerebral polymicrogyria with ipsilateral cerebral hemiatrophy

    Energy Technology Data Exchange (ETDEWEB)

    Hayakawa, Katsumi [Department of Radiology, Kyoto City Hospital, 1-2 Higashi-Takada-cho, Mibu, Nakagyo-ku, 604-8845 Kyoto (Japan); Kanda, Toyoko; Yamori, Yuriko [Department of Pediatric Neurology, St. Joseph Hospital for Handicapped Children, 603-8323 Kyoto (Japan)

    2002-10-01

    We evaluated six children in whom MR imaging showed unilateral cerebral polymicrogyria associated with ipsilateral cerebral atrophy and ipsilateral brain stem atrophy. The aim of this study was to clarify whether this disorder based on neuroimaging constitutes a new homogeneous clinical entity. The subjects were six children whose ages at the time of MR imaging ranged from 8 months to 11 years. Their clinical and MR features were analyzed. All of the children were born between 38 and 42 weeks gestation, without any significant perinatal events. Spastic hemiplegia and epilepsy were observed in all of the patients, and mental retardation was observed in four. The MR findings included unilateral cerebral polymicrogyria associated with ipsilateral cerebral hemiatrophy and ipsilateral brain stem atrophy in all patients. The ipsilateral sylvian fissure was hypoplastic in four patients. These patients showed relatively homogeneous clinical and neuroimaging features. Although the additional clinical features varied according to the site and the extent affected by the polymicrogyria, this disorder could constitute a new relatively homogeneous clinical entity. (orig.)

  12. 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.

  13. 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.

  14. 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.

  15. Macrophage colony-stimulating factor augments beta-amyloid-induced interleukin-1, interleukin-6, and nitric oxide production by microglial cells.

    Science.gov (United States)

    Murphy, G M; Yang, L; Cordell, B

    1998-08-14

    In Alzheimer's disease (AD), a chronic cerebral inflammatory state is thought to lead to neuronal injury. Microglia, intrinsic cerebral immune effector cells, are likely to be key in the pathophysiology of this inflammatory state. We showed that macrophage colony-stimulating factor, a microglial activator found at increased levels in the central nervous system in AD, dramatically augments beta-amyloid peptide (betaAP)-induced microglial production of interleukin-1, interleukin-6, and nitric oxide. In contrast, granulocyte macrophage colony-stimulating factor, another hematopoietic cytokine found in the AD brain, did not augment betaAP-induced microglial secretory activity. These results indicate that increased macrophage colony-stimulating factor levels in AD could magnify betaAP-induced microglial inflammatory cytokine and nitric oxide production, which in turn could intensify the cerebral inflammatory state by activating astrocytes and additional microglia, as well as directly injuring neurons.

  16. Anestesia e paralisia cerebral

    OpenAIRE

    Március Vinícius M Maranhão

    2005-01-01

    JUSTIFICATIVA E OBJETIVOS: A paralisia cerebral (PC) é uma doença não progressiva decorrente de lesão no sistema nervoso central, levando a um comprometimento motor do paciente. O portador de PC freqüentemente é submetido a procedimentos cirúrgicos devido a doenças usuais e situações particulares decorrentes da paralisia cerebral. Foi objetivo deste artigo revisar aspectos da paralisia cerebral de interesse para o anestesiologista, permitindo um adequado manuseio pré, intra e pós-operatório n...

  17. Copper Promotes the Trafficking of the Amyloid Precursor Protein*

    OpenAIRE

    Acevedo, Karla M.; Hung, Ya Hui; Dalziel, Andrew H.; Li, Qiao-Xin; Laughton, Katrina; Wikhe, Krutika; Rembach, Alan; Roberts, Blaine; Masters, Colin L.; Ashley I. Bush; Camakaris, James

    2010-01-01

    Accumulation of the amyloid β peptide in the cortical and hippocampal regions of the brain is a major pathological feature of Alzheimer disease. Amyloid β peptide is generated from the sequential protease cleavage of the amyloid precursor protein (APP). We reported previously that copper increases the level of APP at the cell surface. Here we report that copper, but not iron or zinc, promotes APP trafficking in cultured polarized epithelial cells and neuronal cells. In SH-SY5Y neuronal cells ...

  18. An update on the amyloid hypothesis.

    Science.gov (United States)

    Eckman, Christopher B; Eckman, Elizabeth A

    2007-08-01

    Alzheimer's disease (AD) is a devastating neurodegenerative disease. To rationally develop novel therapeutic and/or preventative agents for AD, an understanding of the etiology and pathogenesis of this complex disease is necessary. This article examines the evidence for the amyloid hypothesis of AD pathogenesis and discusses how it relates to the neurological and neuropathological features of AD, the known genetic risk factors and causative mutations, and the heightened risk associated with advanced age.

  19. Traumatic Brain Injury, Microglia, and Beta Amyloid

    OpenAIRE

    Mannix, Rebekah C.; Whalen, Michael J

    2012-01-01

    Recently, there has been growing interest in the association between traumatic brain injury (TBI) and Alzheimer's Disease (AD). TBI and AD share many pathologic features including chronic inflammation and the accumulation of beta amyloid (A\\(\\beta\\)). Data from both AD and TBI studies suggest that microglia play a central role in A\\(\\beta\\) accumulation after TBI. This paper focuses on the current research on the role of microglia response to A\\(\\beta\\) after TBI.

  20. Amyloid-β assessed by florbetapir F 18 PET and 18-month cognitive decline

    Science.gov (United States)

    Sperling, Reisa A.; Coleman, R. Edward; Johnson, Keith A.; Reiman, Eric M.; Davis, Mat D.; Grundman, Michael; Sabbagh, Marwan N.; Sadowsky, Carl H.; Fleisher, Adam S.; Carpenter, Alan; Clark, Christopher M.; Joshi, Abhinay D.; Mintun, Mark A.; Skovronsky, Daniel M.

    2012-01-01

    Objectives: Florbetapir F 18 PET can image amyloid-β (Aβ) aggregates in the brains of living subjects. We prospectively evaluated the prognostic utility of detecting Aβ pathology using florbetapir PET in subjects at risk for progressive cognitive decline. Methods: A total of 151 subjects who previously participated in a multicenter florbetapir PET imaging study were recruited for longitudinal assessment. Subjects included 51 with recently diagnosed mild cognitive impairment (MCI), 69 cognitively normal controls (CN), and 31 with clinically diagnosed Alzheimer disease dementia (AD). PET images were visually scored as positive (Aβ+) or negative (Aβ−) for pathologic levels of β-amyloid aggregation, blind to diagnostic classification. Cerebral to cerebellar standardized uptake value ratios (SUVr) were determined from the baseline PET images. Subjects were followed for 18 months to evaluate changes in cognition and diagnostic status. Analysis of covariance and correlation analyses were conducted to evaluate the association between baseline PET amyloid status and subsequent cognitive decline. Results: In both MCI and CN, baseline Aβ+ scans were associated with greater clinical worsening on the Alzheimer's Disease Assessment Scale–Cognitive subscale (ADAS-Cog (p < 0.01) and Clinical Dementia Rating–sum of boxes (CDR-SB) (p < 0.02). In MCI Aβ+ scans were also associated with greater decline in memory, Digit Symbol Substitution (DSS), and Mini-Mental State Examination (MMSE) (p < 0.05). In MCI, higher baseline SUVr similarly correlated with greater subsequent decline on the ADAS-Cog (p < 0.01), CDR-SB (p < 0.03), a memory measure, DSS, and MMSE (p < 0.05). Aβ+ MCI tended to convert to AD dementia at a higher rate than Aβ− subjects (p < 0.10). Conclusions: Florbetapir PET may help identify individuals at increased risk for progressive cognitive decline. PMID:22786606

  1. Contrasting effects of nanoparticle-protein attraction on amyloid aggregation.

    Science.gov (United States)

    Radic, Slaven; Davis, Thomas P; Ke, Pu Chun; Ding, Feng

    2015-01-01

    Nanoparticles (NPs) have been experimentally found to either promote or inhibit amyloid aggregation of proteins, but the molecular mechanisms for such complex behaviors remain unknown. Using coarse-grained molecular dynamics simulations, we investigated the effects of varying the strength of nonspecific NP-protein attraction on amyloid aggregation of a model protein, the amyloid-beta peptide implicated in Alzheimer's disease. Specifically, with increasing NP-peptide attraction, amyloid aggregation on the NP surface was initially promoted due to increased local protein concentration on the surface and destabilization of the folded state. However, further increase of NP-peptide attraction decreased the stability of amyloid fibrils and reduced their lateral diffusion on the NP surface necessary for peptide conformational changes and self-association, thus prohibiting amyloid aggregation. Moreover, we found that the relative concentration between protein and NPs also played an important role in amyloid aggregation. With a high NP/protein ratio, NPs that intrinsically promote protein aggregation may display an inhibitive effect by depleting the proteins in solution while having a low concentration of the proteins on each NP's surface. Our coarse-grained molecular dynamics simulation study offers a molecular mechanism for delineating the contrasting and seemingly conflicting effects of NP-protein attraction on amyloid aggregation and highlights the potential of tailoring anti-aggregation nanomedicine against amyloid diseases.

  2. Functional bacterial amyloid increases Pseudomonas biofilm hydrophobicity and stiffness

    DEFF Research Database (Denmark)

    Zeng, Guanghong; Vad, Brian Stougaard; Dueholm, Morten Simonsen

    2015-01-01

    The success of Pseudomonas species as opportunistic pathogens derives in great part from their ability to form stable biofilms that offer protection against chemical and mechanical attack. The extracellular matrix of biofilms contains numerous biomolecules, and it has recently been discovered...... that in Pseudomonas one of the components includes β-sheet rich amyloid fibrils (functional amyloid) produced by the fap operon. However, the role of the functional amyloid within the biofilm has not yet been investigated in detail. Here we investigate how the fap-based amyloid produced by Pseudomonas affects biofilm...

  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. 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

  5. Brain beta-amyloid accumulation in transgenic mice expressing mutant superoxide dismutase 1.

    Science.gov (United States)

    Turner, Bradley J; Li, Qiao-Xin; Laughton, Katrina M; Masters, Colin L; Lopes, Elizabeth C; Atkin, Julie D; Cheema, Surindar S

    2004-12-01

    Oxidative stress is implicated in both the deposition and pathogenesis of beta-amyloid (Abeta) protein in Alzheimer's disease (AD). Accordingly, overexpression of the antioxidant enzyme superoxide dismutase 1 (SOD1) in neuronal cells and transgenic AD mice reduces Abeta toxicity and accumulation. In contrast, mutations in SOD1 associated with amyotrophic lateral sclerosis (ALS) confer enhanced pro-oxidative enzyme activities. We therefore examined whether ALS-linked mutant SOD1 overexpression in motor neuronal cells or transgenic ALS mice modulates Abeta toxicity or its accumulation in the brain. Aggregated, but not freshly solubilised, substrate-bound Abeta peptides induced degenerative morphology and cytotoxicity in motor neuron-like NSC-34 cells. Transfection of NSC-34 cells with human wild-type SOD1 attenuated Abeta-induced toxicity, however this neuroprotective effect was also observed for ALS-linked mutant SOD1. Analysis of the cerebral cortex, brainstem, cerebellum and olfactory bulb from transgenic SOD1G93A mice using enzyme-linked immunosorbent assay of acid-guanidine extracts revealed age-dependent elevations in Abeta levels, although not significantly different from wild-type mouse brain. In addition, brain amyloid protein precursor (APP) levels remained unaltered as a consequence of mutant SOD1 expression. We therefore conclude that mutant SOD1 overexpression promotes neither Abeta toxicity nor brain accumulation in these ALS models.

  6. The role of metallobiology and amyloid-β peptides in Alzheimer's disease.

    Science.gov (United States)

    Roberts, Blaine R; Ryan, Timothy M; Bush, Ashley I; Masters, Colin L; Duce, James A

    2012-01-01

    The biggest risk factor for Alzheimer's disease is the process of ageing, but the mechanisms that lead to the manifestation of the disease remain to be elucidated. Why age triggers the disease is unclear but an emerging theme is the inability for a cell to efficiently maintain many key processes such as energy production, repair, and regenerative mechanisms. Metal ions are essential to the metabolic function of every cell. This review will explore the role and reported changes in metal ions in Alzheimer disease, particularly the brain, blood and cerebral spinal fluid, emphasizing how iron, copper and zinc may be involved through the interactions with amyloid precursor protein, the proteolytically cleaved peptide amyloid-beta (Aβ), and other related metalloproteins. Finally, we explore the monomeric makeup of possible Aβ dimers, what a dimeric Aβ species from Alzheimer's disease brain tissue is likely to be composed of, and discuss how metals may influence Aβ production and toxicity via a copper catalyzed dityrosine cross-link.

  7. 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.

  8. Demonstration of cerebral vessels by multiplane computed cerebral angiotomography

    Energy Technology Data Exchange (ETDEWEB)

    Asari S.; Satch, T.; Sakurai, M.; Yamamoto, Y. (Matsuyama Shimin Hospital, Matsuyama (Japan)); Sadamoto, K.

    1981-06-01

    1. Cerebral arteries and veins were demonstrated by multiplane computed cerebral angiotomography (combination of axial, modified coronal, half axial (Towne), and semisagittal planes). The vessels which were demonstrated by various planes were as follows: Axial plane: Willis ring, middle cerebral arteries (horizontal and insular portions), anterior cerebral arteries (Horizontal and ascending portions), posterior cerebral arteries, basal vein of Rosenthal, internal cerebral veins (and the subependymal veins which join the ICV), and vein of Galen. Coronal plane: intermal carotid arteries (supraclinoid portion), anterior cerebral arteries (horizontal portion), middle cerebral arteries (horizontal and insular portions), lenticulostriate arteries, basal vein of Rosenthal (and the subependymal veins which join this vessel), internal cerebral veins, and vein of Galen. Half axial plane (Towne projection): basilar artery, vertebral arteries, posterior cerebral arteries, superior cerebellar arteries, middle cerebral arteries (horizontal portion), and anterior cerebral arteries (horizontal and ascending portions). Semisagittal plane: internal carotid artery (supraclinoid portion), posterior communicating artery, posterior carebral artery, superior cerebellar artery, internal cerebral vein, basal vein of Rosenthal, vein of Galen, and straight shinus. 2. A detailed knowledge of normal cerebrovascular structures acquired by computed tomography (CT) is essential in detecting and more precisely localizing lesions such as cerebrovascular disease, neoplasm or abscess, in differentiating these lesions from the normal contrast-enhanced structures, and in understanding the spatial relationship between the mass lesion and the neighboring vessels. In addition, it will be possible to discover such asymptomatic cerebrovascular diseases as non-ruptured aneurysms, arteriovenous malformations, and Moyamoya disease by means of computed cerebral angiotomography.

  9. Cerebral venous sinus thrombosis

    Energy Technology Data Exchange (ETDEWEB)

    Renowden, Shelley [Frenchay Hospital, Bristol BS16 1LE (United Kingdom)

    2004-02-01

    A comprehensive synopsis on cerebral venous thrombosis is presented. It emphasizes the various aetiologies, the wide clinical spectrum and the unpredictable outcome. Imaging techniques and pitfalls are reported and the therapeutic options are discussed. (orig.)

  10. Acute ischemic cerebral attack

    OpenAIRE

    Franco-Garcia Samir; Barreiro-Pinto Belis

    2010-01-01

    The decrease of the cerebral blood flow below the threshold of autoregulation led to changes of cerebral ischemia and necrosis that traduce in signs and symtoms of focal neurologic dysfunction called acute cerebrovascular symdrome (ACS) or stroke. Two big groups according to its etiology are included in this category the hemorragic that constitue a 20% and the ischemic a 80% of cases. Great interest has wom the ischemic ACS because of its high social burden, being the third cause of no violen...

  11. Cerebral palsy and congenital malformations

    DEFF Research Database (Denmark)

    Garne, Ester; Dolk, Helen; Krägeloh-Mann, Inge;

    2007-01-01

    AIM: To determine the proportion of children with cerebral palsy (CP) who have cerebral and non-cerebral congenital malformations. METHODS: Data from 11 CP registries contributing to the European Cerebral Palsy Database (SCPE), for children born in the period 1976-1996. The malformations were...... classified as recognized syndromes, chromosomal anomalies, cerebral malformations or non-cerebral malformations. Prevalence of malformations was compared to published data on livebirths from a European database of congenital malformations (EUROCAT). RESULTS: Overall 547 out of 4584 children (11.9%) with CP...... were reported to have a congenital malformation. The majority (8.6% of all children) were diagnosed with a cerebral malformation. The most frequent types of cerebral malformations were microcephaly and hydrocephaly. Non-cerebral malformations were present in 97 CP children and in further 14 CP children...

  12. Regional brain hypometabolism is unrelated to regional amyloid plaque burden

    Science.gov (United States)

    Altmann, Andre; Ng, Bernard; Landau, Susan M.; Jagust, William J.

    2015-01-01

    See Sorg and Grothe (doi:10.1093/brain/awv302) for a scientific commentary on this article. In its original form, the amyloid cascade hypothesis of Alzheimer’s disease holds that fibrillar deposits of amyloid are an early, driving force in pathological events leading ultimately to neuronal death. Early clinicopathological investigations highlighted a number of inconsistencies leading to an updated hypothesis in which amyloid plaques give way to amyloid oligomers as the driving force in pathogenesis. Rather than focusing on the inconsistencies, amyloid imaging studies have tended to highlight the overlap between regions that show early amyloid plaque signal on positron emission tomography and that also happen to be affected early in Alzheimer’s disease. Recent imaging studies investigating the regional dependency between metabolism and amyloid plaque deposition have arrived at conflicting results, with some showing regional associations and other not. We extracted multimodal neuroimaging data from the Alzheimer’s disease neuroimaging database for 227 healthy controls and 434 subjects with mild cognitive impairment. We analysed regional patterns of amyloid deposition, regional glucose metabolism and regional atrophy using florbetapir (18F) positron emission tomography, 18F-fluordeoxyglucose positron emission tomography and T1-weighted magnetic resonance imaging, respectively. Specifically, we derived grey matter density and standardized uptake value ratios for both positron emission tomography tracers in 404 functionally defined regions of interest. We examined the relation between regional glucose metabolism and amyloid plaques using linear models. For each region of interest, correcting for regional grey matter density, age, education and disease status, we tested the association of regional glucose metabolism with (i) cortex-wide florbetapir uptake; (ii) regional (i.e. in the same region of interest) florbetapir uptake; and (iii) regional florbetapir uptake

  13. CLINICAL ANALYSIS OF 84 PATIENTS WITH CEREBRAL WATERSHED INFARCTION%脑分水岭梗死84例临床分析

    Institute of Scientific and Technical Information of China (English)

    孔德权

    2012-01-01

    Objective To analyze the clinical feature and relevant factors of cerebral watershed infarction( CWI) in order to provide the reference for treatment and prevention. Methods The medical history, physical examination, auxiliary examination and prognosis of 84 patients with CWI were reviewed. Results The onset of 47 cases( 55. 95% )was during rest,26 cases( 30. 95% )during sleep, llcases ( 13. 10% ) during activity. Of all the patients, 61. 90% ,38. 09%, 21. 43%, 16. 67% and 35. 71% respectively were combined with hypertension,dyslipidemia,coronary heart disease,hyperhomocysteinemia and diabetes mellitus. Seventy point two four percent and 54. 76% of all had smoking and drinking history. 84. 52%of all were detected with vascular narrowing or block,and mild,moderate and severe level accounted for 14. 94% ,40. 23% and 44. 83%. Middle cerebral artery stenosis or occlusion, internal carotid stenosis or occlusion accounted for 43. 68% and 42. 53%. S - CWI angiopathy rate was the highest, thereinto, middle cerebral artery angiopathy was the most( P < 0. 01 ). The internal carotid angiopathy rate of C - CWI was the highest( P <0. 01 ). The cure rate was 41. 67% , obvious effective rate was 51. 19% , effective rate was 7. 14%. Conclusion CWI was related to systemic circulation, middle cerebral artery and internal carotid stenosis or occlusion. If treated earlier, the serious injure can be prevented.%目的 分析脑分水岭梗死(cerebral watershed infarction,CWI)临床特征及相关因素,为临床预防和治疗提供依据.方法 回顾性分析CWI患者84例的病史、体格检查、辅助检查及预后转归等临床资料.结果 安静时起病47例(55.95%),睡眠时起病26例(30.95%),活动时起病11例(13.10%).合并高血压、血脂异常、冠状动脉粥样硬化性心脏病、高同型半胱氨酸血症、糖尿病分别为52例(61.90%)、18例(38.09%)、18例(21.43%)、14例(16.67%)、30例(35.71%);既往有吸烟、饮酒史占59例(70.24%)、46例(54

  14. St. John's Wort reduces beta-amyloid accumulation in a double transgenic Alzheimer's disease mouse model-role of P-glycoprotein.

    Science.gov (United States)

    Brenn, Anja; Grube, Markus; Jedlitschky, Gabriele; Fischer, Andrea; Strohmeier, Barbara; Eiden, Martin; Keller, Markus; Groschup, Martin H; Vogelgesang, Silke

    2014-01-01

    The adenosine triphosphate-binding cassette transport protein P-glycoprotein (ABCB1) is involved in the export of beta-amyloid from the brain into the blood, and there is evidence that age-associated deficits in cerebral P-glycoprotein content may be involved in Alzheimer's disease pathogenesis. P-glycoprotein function and expression can be pharmacologically induced by a variety of compounds including extracts of Hypericum perforatum (St. John's Wort). To clarify the effect of St. John's Wort on the accumulation of beta-amyloid and P-glycoprotein expression in the brain, St. John's Wort extract (final hyperforin concentration 5%) was fed to 30-day-old male C57BL/6J-APP/PS1(+/-) mice over a period of 60 or 120 days, respectively. Age-matched male C57BL/6J-APP/PS1(+/-) mice receiving a St. John's Wort-free diet served as controls. Mice receiving St. John's Wort extract showed (i) significant reductions of parenchymal beta-amyloid 1-40 and 1-42 accumulation; and (ii) moderate, but statistically significant increases in cerebrovascular P-glycoprotein expression. Thus, the induction of cerebrovascular P-glycoprotein may be a novel therapeutic strategy to protect the brain from beta-amyloid accumulation, and thereby impede the progression of Alzheimer's disease.

  15. 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.

  16. The effects of beta-amyloid protein and presenilin on potassium channel%淀粉样蛋白及早老素对钾通道的影响

    Institute of Scientific and Technical Information of China (English)

    佟晓永; 王晓良

    2001-01-01

    Alzheimer病目前是痴呆的最常见原因,病理学特征是:神经纤维缠结,神经斑块,神经元丢失,淀粉样血管改变。临床上最显著的特点是学习记忆障碍。钾通道在学习记忆中起着重要作用。Alzheimer病人成纤维细胞以及嗅成纤维细胞113pS四已胺敏感的钾通道缺失。记忆相关蛋白Cp20以及与Alzheimer病遗传密切相关的淀粉样蛋白前体蛋白及早老素均能调节钾通道活性。Alzheimer病时钾通道亚型的改变尚需进一步的理论研究。钾通道在Alzhe imer病治疗方面有可能成为重要靶点。%Alzheimer disease(AD) is the most common cau se of dementia today. Th e characteristic histopathologic changes include neurofibrillary tangles, neurit ic plaques, neuronal loss, and amyloid angiopathy. The noted Alzheimer symptom is the dysfunction of learning a nd memory. Potassium channels play a key role in it. A 113-pS tetraethylammoniu m-sensitive potassium channel was consistently absent from AD fibroblasts and o lfactory neuroblasts. Cp20, a memory-associated protein, amyloid precuror prote in and presenilin which are all tightly associated with genetic Alzheimer diseas e can regulate the activities of potassium channels. The changes of potassium ch annels subtype need further study. Potassium channels are maybe the important dr ug targets in the treatment of Alzheimer disease.

  17. Monitoring of cerebral haemodynamics in newborn infants

    DEFF Research Database (Denmark)

    Liem, K Djien; Greisen, Gorm

    2010-01-01

    The most important cerebrovascular injuries in newborn infants, particularly in preterm infants, are cerebral haemorrhage and ischemic injury. The typical cerebral vascular anatomy and the disturbance of cerebral haemodynamics play important roles in the pathophysiology. The term 'cerebral...

  18. Nanomedicine in cerebral palsy

    Directory of Open Access Journals (Sweden)

    Balakrishnan B

    2013-11-01

    Full Text Available Bindu Balakrishnan,1 Elizabeth Nance,1 Michael V Johnston,2 Rangaramanujam Kannan,3 Sujatha Kannan1 1Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University; Baltimore, MD, USA; 2Department of Neurology and Pediatrics, Kennedy Krieger Institute, Baltimore, MD, USA; 3Department of Ophthalmology, Center for Nanomedicine, Johns Hopkins University, Baltimore, MD, USA Abstract: Cerebral palsy is a chronic childhood disorder that can have diverse etiologies. Injury to the developing brain that occurs either in utero or soon after birth can result in the motor, sensory, and cognitive deficits seen in cerebral palsy. Although the etiologies for cerebral palsy are variable, neuroinflammation plays a key role in the pathophysiology of the brain injury irrespective of the etiology. Currently, there is no effective cure for cerebral palsy. Nanomedicine offers a new frontier in the development of therapies for prevention and treatment of brain injury resulting in cerebral palsy. Nanomaterials such as dendrimers provide opportunities for the targeted delivery of multiple drugs that can mitigate several pathways involved in injury and can be delivered specifically to the cells that are responsible for neuroinflammation and injury. These materials also offer the opportunity to deliver agents that would promote repair and regeneration in the brain, resulting not only in attenuation of injury, but also enabling normal growth. In this review, the current advances in nanotechnology for treatment of brain injury are discussed with specific relevance to cerebral palsy. Future directions that would facilitate clinical translation in neonates and children are also addressed. Keywords: dendrimer, cerebral palsy, neuroinflammation, nanoparticle, neonatal brain injury, G4OH-PAMAM

  19. Cardiac resynchronization therapy in a patient with amyloid cardiomyopathy.

    Science.gov (United States)

    Zizek, David; Cvijić, Marta; Zupan, Igor

    2013-06-01

    Cardiac involvement in systemic light chain amyloidosis carries poor prognosis. Amyloid deposition in the myocardium can alter regional left ventricular contraction and cause dyssynchrony. Cardiac resynchronization therapy (CRT) is an effective treatment strategy for patients with advanced heart failure and echocardiographic dyssynchrony. We report a clinical and echocardiographic response of a patient with amyloid cardiomyopathy, treated with a combination of chemotherapy and CRT.

  20. The Effect of Glycosaminoglycans (GAGs on Amyloid Aggregation and Toxicity

    Directory of Open Access Journals (Sweden)

    Clara Iannuzzi

    2015-02-01

    Full Text Available Amyloidosis is a protein folding disorder in which normally soluble proteins are deposited extracellularly as insoluble fibrils, impairing tissue structure and function. Charged polyelectrolytes such as glycosaminoglycans (GAGs are frequently found associated with the proteinaceous deposits in tissues of patients affected by amyloid diseases. Experimental evidence indicate that they can play an active role in favoring amyloid fibril formation and stabilization. Binding of GAGs to amyloid fibrils occurs mainly through electrostatic interactions involving the negative polyelectrolyte charges and positively charged side chains residues of aggregating protein. Similarly to catalyst for reactions, GAGs favor aggregation, nucleation and amyloid fibril formation functioning as a structural templates for the self-assembly of highly cytotoxic oligomeric precursors, rich in β-sheets, into harmless amyloid fibrils. Moreover, the GAGs amyloid promoting activity can be facilitated through specific interactions via consensus binding sites between amyloid polypeptide and GAGs molecules. We review the effect of GAGs on amyloid deposition as well as proteins not strictly related to diseases. In addition, we consider the potential of the GAGs therapy in amyloidosis.

  1. Native human serum amyloid P component is a single pentamer

    DEFF Research Database (Denmark)

    Sørensen, Inge Juul; Andersen, Ove; Nielsen, EH;

    1995-01-01

    Serum amyloid P component (SAP) and C-reactive protein (CRP) are members of the pentraxin protein family. SAP is the precursor protein to amyloid P component present in all forms of amyloidosis. The prevailing notion is that SAP in circulation has the form of a double pentameric molecule (decamer...

  2. Specific Triazine Herbicides Induce Amyloid-beta(42) Production

    NARCIS (Netherlands)

    Portelius, Erik; Durieu, Emilie; Bodin, Marion; Cam, Morgane; Pannee, Josef; Leuxe, Charlotte; Mabondzo, Aloise; Oumata, Nassima; Galons, Herve; Lee, Jung Yeol; Chang, Young-Tae; Stuber, Kathrin; Koch, Philipp; Fontaine, Gaelle; Potier, Marie-Claude; Manousopoulou, Antigoni; Garbis, Spiros D.; Covaci, Adrian; Van Dam, Debby; De Deyn, Peter; Karg, Frank; Flajolet, Marc; Omori, Chiori; Hata, Saori; Suzuki, Toshiharu; Blennow, Kaj; Zetterberg, Henrik; Meijer, Laurent

    2016-01-01

    Proteolytic cleavage of the amyloid-beta protein precursor (A beta PP) ecretases leads to extracellular release of amyloid-beta (A beta) peptides. Increased production of A beta(42) over A beta(40) and aggregation into oligomers and plaques constitute an Alzheimer's disease (AD) hallmark. Identifyin

  3. Unraveling the mystery of protein-amyloid binding mechanisms

    NARCIS (Netherlands)

    Beringer, D.

    2013-01-01

    There are several diseases which are caused by amyloid, a deposit of aggregated protein. Examples of these diseases are Alzheimer’s disease, caused by the aggregation of the peptide Aβ, and Diabetes type 2, caused by hIAPP aggregates. A large number of proteins interact with these amyloid fibrils, s

  4. Clinical Neuroimaging of cerebral ischemia

    Energy Technology Data Exchange (ETDEWEB)

    Nakagawara, Jyoji [Nakamura Memorial Hospital, Sapporo (Japan)

    1999-06-01

    Notice points in clinical imaging of cerebral ischemia are reviewed. When cerebral blood flow is determined in acute stage of cerebral embolism (cerebral blood flow SPECT), it is important to find area of ischemic core and ischemic penumbra. When large cortex area is assigned to ischemic penumbra, thrombolytic therapy is positively adapted, but cautious correspondence is necessary when ischemic core is recognized. DWI is superior in the detection of area equivalent to ischemic core of early stage, but, in imaging of area equivalent to ischemic penumbra, perfusion image or distribution image of cerebral blood volume (CBV) by MRI need to be combined. Luxury perfusion detected by cerebral blood flow SPECT in the cases of acute cerebral embolism suggests vascular recanalization, but a comparison with CT/MRI and continuous assessment of cerebral circulation dynamics were necessary in order to predict brain tissue disease (metabolic abnormality). In hemodynamic cerebral ischemia, it is important to find stage 2 equivalent to misery perfusion by quantification of cerebral blood flow SPECT. Degree of diaschisis can indicate seriousness of brain dysfunction for lacuna infarct. Because cerebral circulation reserve ability (perfusion pressure) is normal in all areas of the low cerebral blood flow by diaschisis mechanism, their areas are easily distinguished from those of hemodynamic cerebral ischemia. (K.H.)

  5. Laser-induced propagation and destruction of amyloid beta fibrils.

    Science.gov (United States)

    Yagi, Hisashi; Ozawa, Daisaku; Sakurai, Kazumasa; Kawakami, Toru; Kuyama, Hiroki; Nishimura, Osamu; Shimanouchi, Toshinori; Kuboi, Ryoichi; Naiki, Hironobu; Goto, Yuji

    2010-06-18

    The amyloid deposition of amyloid beta (Abeta) peptides is a critical pathological event in Alzheimer disease (AD). Preventing the formation of amyloid deposits and removing preformed fibrils in tissues are important therapeutic strategies against AD. Previously, we reported the destruction of amyloid fibrils of beta(2)-microglobulin K3 fragments by laser irradiation coupled with the binding of amyloid-specific thioflavin T. Here, we studied the effects of a laser beam on Abeta fibrils. As was the case for K3 fibrils, extensive irradiation destroyed the preformed Abeta fibrils. However, irradiation during spontaneous fibril formation resulted in only the partial destruction of growing fibrils and a subsequent explosive propagation of fibrils. The explosive propagation was caused by an increase in the number of active ends due to breakage. The results not only reveal a case of fragmentation-induced propagation of fibrils but also provide insights into therapeutic strategies for AD.

  6. Amyloid-like protein inclusions in tobacco transgenic plants.

    Directory of Open Access Journals (Sweden)

    Anna Villar-Piqué

    Full Text Available The formation of insoluble protein deposits in human tissues is linked to the onset of more than 40 different disorders, ranging from dementia to diabetes. In these diseases, the proteins usually self-assemble into ordered β-sheet enriched aggregates known as amyloid fibrils. Here we study the structure of the inclusions formed by maize transglutaminase (TGZ in the chloroplasts of tobacco transplastomic plants and demonstrate that they have an amyloid-like nature. Together with the evidence of amyloid structures in bacteria and fungi our data argue that amyloid formation is likely a ubiquitous process occurring across the different kingdoms of life. The discovery of amyloid conformations inside inclusions of genetically modified plants might have implications regarding their use for human applications.

  7. Development of [F-18]-Labeled Amyloid Imaging Agents for PET

    Energy Technology Data Exchange (ETDEWEB)

    Mathis, CA

    2007-05-09

    The applicant proposes to design and synthesize a series of fluorine-18-labeled radiopharmaceuticals to be used as amyloid imaging agents for positron emission tomography (PET). The investigators will conduct comprehensive iterative in vitro and in vivo studies based upon well defined acceptance criteria in order to identify lead agents suitable for human studies. The long term goals are to apply the selected radiotracers as potential diagnostic agents of Alzheimer's disease (AD), as surrogate markers of amyloid in the brain to determine the efficacy of anti-amyloid therapeutic drugs, and as tools to help address basic scientific questions regarding the progression of the neuropathology of AD, such as testing the "amyloid cascade hypothesis" which holds that amyloid accumulation is the primary cause of AD.

  8. Cerebral phaeohyphomycosis by Exophiala dermatitidis

    Directory of Open Access Journals (Sweden)

    S Sood

    2014-01-01

    Full Text Available Cerebral phaeohyphomycosis is a rare and frequently fatal disease. We report a case of cerebral phaeohyphomycosis caused by Exophiala dermatitidis in a young immuno competent male presenting to a tertiary care hospital in Jaipur.

  9. Cerebral phaeohyphomycosis by Exophiala dermatitidis.

    Science.gov (United States)

    Sood, S; Vaid, V K; Sharma, M; Bhartiya, H

    2014-01-01

    Cerebral phaeohyphomycosis is a rare and frequently fatal disease. We report a case of cerebral phaeohyphomycosis caused by Exophiala dermatitidis in a young immuno competent male presenting to a tertiary care hospital in Jaipur.

  10. Stability and cytotoxicity of crystallin amyloid nanofibrils

    Science.gov (United States)

    Kaur, Manmeet; Healy, Jackie; Vasudevamurthy, Madhusudan; Lassé, Moritz; Puskar, Ljiljana; Tobin, Mark J.; Valery, Celine; Gerrard, Juliet A.; Sasso, Luigi

    2014-10-01

    Previous work has identified crystallin proteins extracted from fish eye lenses as a cheap and readily available source for the self-assembly of amyloid nanofibrils. However, before exploring potential applications, the biophysical aspects and safety of this bionanomaterial need to be assessed so as to ensure that it can be effectively and safely used. In this study, crude crystallin amyloid fibrils are shown to be stable across a wide pH range, in a number of industrially relevant solvents, at both low and high temperatures, and in the presence of proteases. Crystallin nanofibrils were compared to well characterised insulin and whey protein fibrils using Thioflavin T assays and TEM imaging. Cell cytotoxicity assays suggest no adverse impact of both mature and fragmented crystallin fibrils on cell viability of Hec-1a endometrial cells. An IR microspectroscopy study supports long-term structural integrity of crystallin nanofibrils.Previous work has identified crystallin proteins extracted from fish eye lenses as a cheap and readily available source for the self-assembly of amyloid nanofibrils. However, before exploring potential applications, the biophysical aspects and safety of this bionanomaterial need to be assessed so as to ensure that it can be effectively and safely used. In this study, crude crystallin amyloid fibrils are shown to be stable across a wide pH range, in a number of industrially relevant solvents, at both low and high temperatures, and in the presence of proteases. Crystallin nanofibrils were compared to well characterised insulin and whey protein fibrils using Thioflavin T assays and TEM imaging. Cell cytotoxicity assays suggest no adverse impact of both mature and fragmented crystallin fibrils on cell viability of Hec-1a endometrial cells. An IR microspectroscopy study supports long-term structural integrity of crystallin nanofibrils. Electronic supplementary information (ESI) available: ThT fluorescence graphs of buffers and solvents used for

  11. [Cerebral ischemia and histamine].

    Science.gov (United States)

    Adachi, Naoto

    2002-10-01

    Cerebral ischemia induces excess release of glutamate and an increase in the intracellular Ca2+ concentration, which provoke catastrophic enzymatic processes leading to irreversible neuronal injury. Histamine plays the role of neurotransmitter in the central nervous system, and histaminergic fibers are widely distributed in the brain. In cerebral ischemia, release of histamine from nerve endings has been shown to be enhanced by facilitation of its activity. An inhibition of the histaminergic activity in ischemia aggravates the histologic outcome. In contrast, intracerebroventricular administration of histamine improves the aggravation, whereas blockade of histamine H2 receptors aggravates ischemic injury. Furthermore, H2 blockade enhances ischemic release of glutamate and dopamine. These findings suggest that central histamine provides beneficial effects against ischemic neuronal damage by suppressing release of excitatory neurotransmitters. However, histaminergic H2 action facilitates the permeability of the blood-brain barrier and shows deleterious effects on cerebral edema.

  12. Cerebral hemodynamics in migraine

    DEFF Research Database (Denmark)

    Hachinski, V C; Olesen, Jes; Norris, J W

    1977-01-01

    Clinical and angiographic findings in migraine are briefly reviewed in relation to cerebral hemodynamic changes shown by regional cerebral blood flow (rCBF) studies. Three cases of migraine studied by the intracarotid xenon 133 method during attacks are reported. In classic migraine, with typical...... prodromal symptoms, a decrease in cerebral blood flow has been demonstrated during the aura. Occasionally, this flow decrease persists during the headache phase. In common migraine, where such prodromata are not seen, a flow decrease has not been demonstrated. During the headache phase of both types...... of migraine, rCBF has usually been found to be normal or in the high range of normal values. The high values may represent postischemic hyperemia, but are probably more frequently secondary to arousal caused by pain. Thus, during the headache phase rCBF may be subnormal, normal or high. These findings do...

  13. Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain.

    Science.gov (United States)

    Iliff, Jeffrey J; Wang, Minghuan; Zeppenfeld, Douglas M; Venkataraman, Arun; Plog, Benjamin A; Liao, Yonghong; Deane, Rashid; Nedergaard, Maiken

    2013-11-13

    CSF from the subarachnoid space moves rapidly into the brain along paravascular routes surrounding penetrating cerebral arteries, exchanging with brain interstitial fluid (ISF) and facilitating the clearance of interstitial solutes, such as amyloid β, in a pathway that we have termed the "glymphatic" system. Prior reports have suggested that paravascular bulk flow of CSF or ISF may be driven by arterial pulsation. However, cerebral arterial pulsation could not be directly assessed. In the present study, we use in vivo two-photon microscopy in mice to visualize vascular wall pulsatility in penetrating intracortical arteries. We observed that unilateral ligation of the internal carotid artery significantly reduced arterial pulsatility by ~50%, while systemic administration of the adrenergic agonist dobutamine increased pulsatility of penetrating arteries by ~60%. When paravascular CSF-ISF exchange was evaluated in real time using in vivo two-photon and ex vivo fluorescence imaging, we observed that internal carotid artery ligation slowed the rate of paravascular CSF-ISF exchange, while dobutamine increased the rate of paravascular CSF-ISF exchange. These findings demonstrate that cerebral arterial pulsatility is a key driver of paravascular CSF influx into and through the brain parenchyma, and suggest that changes in arterial pulsatility may contribute to accumulation and deposition of toxic solutes, including amyloid β, in the aging brain.

  14. Cutaneous Manifestations of Familial Transthyretin Amyloid Polyneuropathy.

    Science.gov (United States)

    Lanoue, Julien; Wei, Nancy; Gorevic, Peter; Phelps, Robert G

    2016-10-01

    Familial amyloid polyneuropathy (FAP) is a rare inherited autosomal dominant form of systemic amyloidosis, which classically presents with severe motor, sensory, and autonomic dysfunction. Cutaneous involvement does not become clinically apparent until late stage symptomatic disease and is rarely reported in modern literature. Here, the authors review the clinical and histologic cutaneous findings of FAP previously described in the literature and report on 3 patients with unique genetic mutations (Thr60Ala and Gly6Ser; Trp41Leu; Glu89Gln) for which cutaneous involvement has not previously been described. Histologically, our patients showed variable amyloid deposition in the subcutaneous adipose tissue, papillary dermis, and dermal blood vessel walls. A review of the literature suggests cutaneous transthyretin deposition is an underrecognized feature of FAP that occurs early on in disease, even before neural involvement and related symptoms as seen in one of our patients. As such, a cutaneous punch biopsy can serve as quick, easy, and relatively noninvasive diagnostic tool in suspected cases.

  15. Copernicus revisited: amyloid beta in Alzheimer's disease.

    Science.gov (United States)

    Joseph, J; Shukitt-Hale, B; Denisova, N A; Martin, A; Perry, G; Smith, M A

    2001-01-01

    The beta-amyloid hypothesis of Alzheimer's Disease (AD) has dominated the thinking and research in this area for over a decade and a half. While there has been a great deal of effort in attempting to prove its centrality in this devastating disease, and while an enormous amount has been learned about its properties (e.g., putative toxicity, processing and signaling), Abeta has not proven to be both necessary and sufficient for the development, neurotoxicity, and cognitive deficits associated with this disease. Instead, the few treatments that are available have emerged from aging research and are primarily directed toward modification of acetylcholine levels. Clearly, it is time to rethink this position and to propose instead that future approaches should focus upon altering the age-related sensitivity of the neuronal environment to insults involving such factors as inflammation and oxidative stress. In other words "solve the problems of aging and by extension those of AD will also be reduced." This review is being submitted as a rather Lutherian attempt to "nail an alternative thesis" to the gate of the Church of the Holy Amyloid to open its doors to the idea that aging is the most pervasive element in this disease and Abeta is merely one of the planets.

  16. Magnetite nanoparticle interactions with insulin amyloid fibrils

    Science.gov (United States)

    Chen, Yun-Wen; Chang, Chiung-Wen; Hung, Huey-Shan; Kung, Mei-Lang; Yeh, Bi-Wen; Hsieh, Shuchen

    2016-10-01

    Accumulation of amyloid fibrils is one of the likely key factors leading to the development of Alzheimer’s disease and other amyloidosis associated diseases. Magnetic nanoparticles (NPs) have been developed as promising medical materials for many medical applications. In this study, we have explored the effects of Fe3O4 NPs on the fibrillogenesis process of insulin fibrils. When Fe3O4 NPs were co-incubated with insulin, Fe3O4 NPs had no effect on the structural transformation into amyloid-like fibrils but had higher affinity toward insulin fibrils. We demonstrated that the zeta potential of insulin fibrils and Fe3O4 NPs were both positive, suggesting the binding forces between Fe3O4 NPs and insulin fibrils were van der Waals forces but not surface charge. Moreover, a different amount of Fe3O4 NPs added had no effect on secondary structural changes of insulin fibrils. These results propose the potential use of Fe3O4 NPs as therapeutic agents against diseases related to protein aggregation or contrast agents for magnetic resonance imaging.

  17. Immune functions of serum amyloid A.

    Science.gov (United States)

    Eklund, Kari K; Niemi, K; Kovanen, P T

    2012-01-01

    Serum amyloid A (SAA) is a highly conserved, acute-phase protein synthesized predominantly by the liver. After secretion into the circulation, it associates with high-density lipoprotein (HDL) particles. During acute inflammation, serum SAA levels may rise up to 1000-fold, and under these conditions, SAA displaces apolipoprotein A-I from HDL, thus becoming the major apolipoprotein of circulating HDL3. SAA exhibits significant immunological activity by, for example, inducing the synthesis of several cytokines and by being chemotactic for neutrophils and mast cells. It exerts many of its immunological activities by binding and activating cell-surface receptors, including Toll-like receptor (TLR) 2 and TLR4, formyl peptide receptor-like 1 (FPRL1), class B scavenger receptor CD36, and the ATP receptor P2X7. SAA also recently has been shown to activate the inflammasome cascade, which has a key role in immune activation, thus further stressing the unique role of SAA in immunomodulation. Traditionally, SAA has been considered to have a key role in the pathogenesis of amyloid A-type amyloidosis, but we now understand that it may also participate in the pathogenesis of chronic inflammatory diseases, such as rheumatoid arthritis and atherosclerosis. Thus, SAA is one potential target in the treatment of diseases associated with chronic inflammation. The purpose of this review is to shed light on SAA as an immunologically active protein. We also focus on the recent findings implicating SAA in the regulation of the inflammasome cascade.

  18. 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

  19. SERF Protein Is a Direct Modifier of Amyloid Fiber Assembly

    Directory of Open Access Journals (Sweden)

    S. Fabio Falsone

    2012-08-01

    Full Text Available The inherent cytotoxicity of aberrantly folded protein aggregates contributes substantially to the pathogenesis of amyloid diseases. It was recently shown that a class of evolutionary conserved proteins, called MOAG-4/SERF, profoundly alter amyloid toxicity via an autonomous but yet unexplained mode. We show that the biological function of human SERF1a originates from its atypical ability to specifically distinguish between amyloid and nonamyloid aggregation. This inherently unstructured protein directly affected the aggregation kinetics of a broad range of amyloidogenic proteins in vitro, while being inactive against nonamyloid aggregation. A representative biophysical analysis of the SERF1a:α-synuclein (aSyn complex revealed that the amyloid-promoting activity resulted from an early and transient interaction, which was sufficient to provoke a massive increase of soluble aSyn amyloid nucleation templates. Therefore, the autonomous amyloid-modifying activity of SERF1a observed in living organisms relies on a direct and dedicated manipulation of the early stages in the amyloid aggregation pathway.

  20. 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.)

  1. Using bacterial inclusion bodies to screen for amyloid aggregation inhibitors

    Directory of Open Access Journals (Sweden)

    Villar-Piqué Anna

    2012-05-01

    Full Text Available Abstract Background The amyloid-β peptide (Aβ42 is the main component of the inter-neuronal amyloid plaques characteristic of Alzheimer's disease (AD. The mechanism by which Aβ42 and other amyloid peptides assemble into insoluble neurotoxic deposits is still not completely understood and multiple factors have been reported to trigger their formation. In particular, the presence of endogenous metal ions has been linked to the pathogenesis of AD and other neurodegenerative disorders. Results Here we describe a rapid and high-throughput screening method to identify molecules able to modulate amyloid aggregation. The approach exploits the inclusion bodies (IBs formed by Aβ42 when expressed in bacteria. We have shown previously that these aggregates retain amyloid structural and functional properties. In the present work, we demonstrate that their in vitro refolding is selectively sensitive to the presence of aggregation-promoting metal ions, allowing the detection of inhibitors of metal-promoted amyloid aggregation with potential therapeutic interest. Conclusions Because IBs can be produced at high levels and easily purified, the method overcomes one of the main limitations in screens to detect amyloid modulators: the use of expensive and usually highly insoluble synthetic peptides.

  2. The amyloid stretch hypothesis: Recruiting proteins toward the dark side

    Science.gov (United States)

    Esteras-Chopo, Alexandra; Serrano, Luis; de la Paz, Manuela López

    2005-01-01

    A detailed understanding of the molecular events underlying the conversion and self-association of normally soluble proteins into amyloid fibrils is fundamental to the identification of therapeutic strategies to prevent or cure amyloid-related disorders. Recent investigations indicate that amyloid fibril formation is not just a general property of the polypeptide backbone depending on external factors, but that it is strongly modulated by amino acid side chains. Here, we propose and address the validation of the premise that the amyloidogenicity of a protein is indeed localized in short protein stretches (amyloid stretch hypothesis). We demonstrate that the conversion of a soluble nonamyloidogenic protein into an amyloidogenic prone molecule can be triggered by a nondestabilizing six-residue amyloidogenic insertion in a particular structural environment. Interestingly enough, although the inserted amyloid sequences clearly cause the process, the protease-resistant core of the fiber also includes short adjacent sequences from the otherwise soluble globular domain. Thus, short amyloid stretches accessible for intermolecular interactions trigger the self-assembly reaction and pull the rest of the protein into the fibrillar aggregate. The reliable identification of such amyloidogenic stretches in proteins opens the possibility of using them as targets for the inhibition of the amyloid fibril formation process. PMID:16263932

  3. Acute ischaemic brain lesions in intracerebral haemorrhage: multicentre cross-sectional magnetic resonance imaging study.

    Science.gov (United States)

    Gregoire, Simone M; Charidimou, Andreas; Gadapa, Naveen; Dolan, Eamon; Antoun, Nagui; Peeters, Andre; Vandermeeren, Yves; Laloux, Patrice; Baron, Jean-Claude; Jäger, Hans R; Werring, David J

    2011-08-01

    Subclinical acute ischaemic lesions on brain magnetic resonance imaging have recently been described in spontaneous intracerebral haemorrhage, and may be important to understand pathophysiology and guide treatment. The underlying mechanisms are uncertain. We tested the hypothesis that ischaemic lesions are related to magnetic resonance imaging markers of the severity and type of small-vessel disease (hypertensive arteriopathy or cerebral amyloid angiopathy) in a multicentre, cross-sectional study. We studied consecutive patients with intracerebral haemorrhage from four specialist stroke centres, and age-matched stroke service referrals without intracerebral haemorrhage. Acute ischaemic lesions were assessed on magnetic resonance imaging (imaging. White matter changes and cerebral microbleeds were rated with validated scales. We investigated associations between diffusion-weighted imaging lesions, clinical and radiological characteristics. We included 114 patients with intracerebral haemorrhage (39 with clinically probable cerebral amyloid angiopathy) and 47 age-matched controls. The prevalence of diffusion-weighted imaging lesions was 9/39 (23%) in probable cerebral amyloid angiopathy-related intracerebral haemorrhage versus 6/75 (8%) in the remaining patients with intracerebral haemorrhage (P = 0.024); no diffusion-weighted imaging lesions were found in controls. Diffusion-weighted imaging lesions were mainly cortical and were associated with mean white matter change score (odds ratio 1.14 per unit increase, 95% confidence interval 1.02-1.28, P = 0.024) and the presence of strictly lobar cerebral microbleeds (odds ratio 3.85, 95% confidence interval 1.15-12.93, P = 0.029). Acute, subclinical ischaemic brain lesions are frequent but previously underestimated after intracerebral haemorrhage, and are three times more common in cerebral amyloid angiopathy-related intracerebral haemorrhage than in other intracerebral haemorrhage types. Ischaemic brain lesions are

  4. Mechanical deformation mechanisms and properties of amyloid fibrils.

    Science.gov (United States)

    Choi, Bumjoon; Yoon, Gwonchan; Lee, Sang Woo; Eom, Kilho

    2015-01-14

    Amyloid fibrils have recently received attention due to their remarkable mechanical properties, which are highly correlated with their biological functions. We have studied the mechanical deformation mechanisms and properties of amyloid fibrils as a function of their length scales by using atomistic simulations. It is shown that the length of amyloid fibrils plays a role in their deformation and fracture mechanisms in such a way that the competition between shear and bending deformations is highly dependent on the fibril length, and that as the fibril length increases, so does the bending strength of the fibril while its shear strength decreases. The dependence of rupture force for amyloid fibrils on their length is elucidated using the Bell model, which suggests that the rupture force of the fibril is determined from the hydrogen bond rupture mechanism that critically depends on the fibril length. We have measured the toughness of amyloid fibrils, which is shown to depend on the fibril length. In particular, the toughness of the fibril with its length of ∼3 nm is estimated to be ∼30 kcal mol(-1) nm(-3), comparable to that of a spider silk crystal with its length of ∼2 nm. Moreover, we have shown the important effect of the pulling rate on the mechanical deformation mechanisms and properties of amyloid fibril. It is found that as the pulling rate increases, so does the contribution of the shear effect to the elastic deformation of the amyloid fibril with its length of deformation mechanism of the amyloid fibril with its length of >15 nm is almost independent of the pulling rate. Our study sheds light on the role of the length scale of amyloid fibrils and the pulling rate in their mechanical behaviors and properties, which may provide insights into how the excellent mechanical properties of protein fibrils can be determined.

  5. Experimental Focal Cerebral Ischemia

    DEFF Research Database (Denmark)

    Christensen, Thomas

    2007-01-01

    of the middle cerebral artery (MCAO) was used as an experimental model of ischemic stroke. MCAO produces an acute lesion consisting of an ischemic core or focus with severely reduced blood flow surrounded by a borderzone or ischemic penumbra with less pronounced blood flow reduction. Cells in the ischemic focus...

  6. Ligand-binding sites in human serum amyloid P component

    DEFF Research Database (Denmark)

    Heegaard, N.H.H.; Heegaard, Peter M. H.; Roepstorff, P.;

    1996-01-01

    Amyloid P component (AP) is a naturally occurring glycoprotein that is found in serum and basement membranes, AP is also a component of all types of amyloid, including that found in individuals who suffer from Alzheimer's disease and Down's syndrome. Because AP has been found to bind strongly...... of 25 mu M, while the IC50 of AP-(27-38)-peptide and AP-(33-38)-peptide are 10 mu M and 2 mu M, respectively, The understanding of the structure and function of active AP peptides will be useful for development of amyloid-targeted diagnostics and therapeutics....

  7. Aluminium, beta-amyloid and non-enzymatic glycosylation.

    Science.gov (United States)

    Exley, C; Schley, L; Murray, S; Hackney, C M; Birchall, J D

    1995-05-08

    The non-enzymatic glycosylation of beta-amyloid is implicated in the aetiology of Alzheimer's disease. However, controversy surrounds the nature of any involvement and a potential mechanism has not been fully elucidated. We present evidence of an aluminium-induced aggregation of the A beta P(25-35) peptide and speculate that the mechanism of formation of our ordered beta-amyloid aggregates might involve non-enzymatic glycosylation and/or site-specific crosslinking of beta-amyloid fibrils by atomic aluminium.

  8. Eugenol prevents amyloid formation of proteins and inhibits amyloid-induced hemolysis

    Science.gov (United States)

    Dubey, Kriti; Anand, Bibin G.; Shekhawat, Dolat Singh; Kar, Karunakar

    2017-02-01

    Eugenol has attracted considerable attention because of its potential for many pharmaceutical applications including anti-inflammatory, anti-tumorigenic and anti-oxidant properties. Here, we have investigated the effect of eugenol on amyloid formation of selected globular proteins. We find that both spontaneous and seed-induced aggregation processes of insulin and serum albumin (BSA) are significantly suppressed in the presence of eugenol. Isothermal titration calorimetric data predict a single binding site for eugenol-insulin complex confirming the affinity of eugenol for native soluble insulin species. We also find that eugenol suppresses amyloid-induced hemolysis. Our findings reveal the inherent ability of eugenol to stabilize native proteins and to delay the conversion of protein species of native conformation into β-sheet assembled mature fibrils, which seems to be crucial for its inhibitory effect.

  9. Interaction of amyloid inhibitor proteins with amyloid beta peptides: insight from molecular dynamics simulations.

    Directory of Open Access Journals (Sweden)

    Payel Das

    Full Text Available Knowledge of the detailed mechanism by which proteins such as human αB- crystallin and human lysozyme inhibit amyloid beta (Aβ peptide aggregation is crucial for designing treatment for Alzheimer's disease. Thus, unconstrained, atomistic molecular dynamics simulations in explicit solvent have been performed to characterize the Aβ17-42 assembly in presence of the αB-crystallin core domain and of lysozyme. Simulations reveal that both inhibitor proteins compete with inter-peptide interaction by binding to the peptides during the early stage of aggregation, which is consistent with their inhibitory action reported in experiments. However, the Aβ binding dynamics appear different for each inhibitor. The binding between crystallin and the peptide monomer, dominated by electrostatics, is relatively weak and transient due to the heterogeneous amino acid distribution of the inhibitor surface. The crystallin-bound Aβ oligomers are relatively long-lived, as they form more extensive contact surface with the inhibitor protein. In contrast, a high local density of arginines from lysozyme allows strong binding with Aβ peptide monomers, resulting in stable complexes. Our findings not only illustrate, in atomic detail, how the amyloid inhibitory mechanism of human αB-crystallin, a natural chaperone, is different from that of human lysozyme, but also may aid de novo design of amyloid inhibitors.

  10. Yeast and Fungal Prions: Amyloid-Handling Systems, Amyloid Structure, and Prion Biology.

    Science.gov (United States)

    Wickner, R B; Edskes, H K; Gorkovskiy, A; Bezsonov, E E; Stroobant, E E

    2016-01-01

    Yeast prions (infectious proteins) were discovered by their outré genetic properties and have become important models for an array of human prion and amyloid diseases. A single prion protein can become any of many distinct amyloid forms (called prion variants or strains), each of which is self-propagating, but with different biological properties (eg, lethal vs mild). The folded in-register parallel β sheet architecture of the yeast prion amyloids naturally suggests a mechanism by which prion variant information can be faithfully transmitted for many generations. The yeast prions rely on cellular chaperones for their propagation, but can be cured by various chaperone imbalances. The Btn2/Cur1 system normally cures most variants of the [URE3] prion that arise. Although most variants of the [PSI+] and [URE3] prions are toxic or lethal, some are mild in their effects. Even the most mild forms of these prions are rare in the wild, indicating that they too are detrimental to yeast. The beneficial [Het-s] prion of Podospora anserina poses an important contrast in its structure, biology, and evolution to the yeast prions characterized thus far.

  11. Interaction between amyloid beta peptide and an aggregation blocker peptide mimicking islet amyloid polypeptide.

    Directory of Open Access Journals (Sweden)

    Nasrollah Rezaei-Ghaleh

    Full Text Available Assembly of amyloid-beta peptide (Aβ into cytotoxic oligomeric and fibrillar aggregates is believed to be a major pathologic event in Alzheimer's disease (AD and interfering with Aβ aggregation is an important strategy in the development of novel therapeutic approaches. Prior studies have shown that the double N-methylated analogue of islet amyloid polypeptide (IAPP IAPP-GI, which is a conformationally constrained IAPP analogue mimicking a non-amyloidogenic IAPP conformation, is capable of blocking cytotoxic self-assembly of Aβ. Here we investigate the interaction of IAPP-GI with Aβ40 and Aβ42 using NMR spectroscopy. The most pronounced NMR chemical shift changes were observed for residues 13-20, while residues 7-9, 15-16 as well as the C-terminal half of Aβ--that is both regions of the Aβ sequence that are converted into β-strands in amyloid fibrils--were less accessible to solvent in the presence of IAPP-GI. At the same time, interaction of IAPP-GI with Aβ resulted in a concentration-dependent co-aggregation of Aβ and IAPP-GI that was enhanced for the more aggregation prone Aβ42 peptide. On the basis of the reduced toxicity of the Aβ peptide in the presence of IAPP-GI, our data are consistent with the suggestion that IAPP-GI redirects Aβ into nontoxic "off-pathway" aggregates.

  12. Tensile deformation and failure of amyloid and amyloid-like protein fibrils

    Science.gov (United States)

    Solar, Max; Buehler, Markus J.

    2014-03-01

    Here we report a series of full atomistic molecular dynamics simulations of six amyloid or amyloid-like protein fibrils in order to systematically understand the effect of different secondary structure motifs on the mechanical tensile and failure response of cross-\\beta protein fibrils. We find a similar failure behavior across the six structures; an initial failure event occurs at small strains involving cooperative rupture of a group of hydrogen bonds, followed by a slow one-by-one hydrogen bond rupture process as the remaining \\beta -sheets peel off with very low applied stress. We also find that the ultimate tensile strength of the protein fibrils investigated scales directly with the number of hydrogen bonds per unit area which break in the initial rupture event. Our results provide insights into structure-property relationships in protein fibrils important for disease and engineering applications and lay the groundwork for the development of materials selection criteria for the design of de novo amyloid-based functional biomaterials.

  13. Parálisis cerebral Cerebral palsy

    OpenAIRE

    Jorge Malagon Valdez

    2007-01-01

    El término parálisis cerebral (PC) engloba a un gran número de síndromes neurológicos clínicos, de etiología diversa. Estos síndromes se caracterizan por tener una sintomatología común: los trastornos motores. Algunos autores prefieren manejar términos como "encefalopatía fija", "encefalopatías no evolutivas". Se mencionan la utilidad de programas de intervención temprana y métodos especiales de rehabilitación, así como el manejo de las deficiencias asociadas como la epilepsia, deficiencia me...

  14. Parálisis cerebral Cerebral palsy

    Directory of Open Access Journals (Sweden)

    Jorge Malagon Valdez

    2007-01-01

    Full Text Available El término parálisis cerebral (PC engloba a un gran número de síndromes neurológicos clínicos, de etiología diversa. Estos síndromes se caracterizan por tener una sintomatología común: los trastornos motores. Algunos autores prefieren manejar términos como "encefalopatía fija", "encefalopatías no evolutivas". Se mencionan la utilidad de programas de intervención temprana y métodos especiales de rehabilitación, así como el manejo de las deficiencias asociadas como la epilepsia, deficiencia mental, trastornos del lenguaje, audición, visión, déficit de la atención que mejoran el pronóstico de manera significativa. El pronóstico también depende de la gravedad del padecimiento y de las manifestaciones asociadas.The term cerebral palsy (CP, is used for a great number of clinical neurological syndromes. The syndromes are characterized by having a common cause, motor defects. It is important, because they can cause a brain damage by presenting motor defects and some associated deficiencies, such as mental deficiency, epilepsy, language and visual defects and pseudobulbar paralysis, with the nonevolving fact. Some authors prefer using terms such as "non-evolving encephalopathies". In the treatment the utility of prevention programs of early stimulation and special rehabilitation methods, and treatment of associated deficiencies such as epilepsy, mental deficiency, language, audition and visual problems, and the attention deficit improve the prognosis in an important way. The prognosis depends on the severity of the disease and the associated manifestations.

  15. Minocycline alleviates beta-amyloid protein and tau pathology via restraining neuroinflammation induced by diabetic metabolic disorder

    Directory of Open Access Journals (Sweden)

    Cai Z

    2013-08-01

    Full Text Available Zhiyou Cai,1 Yong Yan,2 Yonglong Wang2 1Department of Neurology, the Lu’an Affiliated Hospital of Anhui Medical University, Lu’an People’s Hospital, Lu’an, Anhui Province, People’s Republic of China; 2Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, People’s Republic of China Background: Compelling evidence has shown that diabetic metabolic disorder plays a critical role in the pathogenesis of Alzheimer’s disease, including increased expression of β-amyloid protein (Aβ and tau protein. Evidence has supported that minocycline, a tetracycline derivative, protects against neuroinflammation induced by neurodegenerative disorders or cerebral ischemia. This study has evaluated minocycline influence on expression of Aβ protein, tau phosphorylation, and inflammatory cytokines (interleukin-1β and tumor necrosis factor-α in the brain of diabetic rats to clarify neuroprotection by minocycline under diabetic metabolic disorder. Method: An animal model of diabetes was established by high fat diet and intraperitoneal injection of streptozocin. In this study, we investigated the effect of minocycline on expression of Aβ protein, tau phosphorylation, and inflammatory cytokines (interleukin-1β and tumor necrosis factor-α in the hippocampus of diabetic rats via immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay. Results: These results showed that minocycline decreased expression of Aβ protein and lowered the phosphorylation of tau protein, and retarded the proinflammatory cytokines, but not amyloid precursor protein. Conclusion: On the basis of the finding that minocycline had no influence on amyloid precursor protein and beta-site amyloid precursor protein cleaving enzyme 1 which determines the speed of Aβ generation, the decreases in Aβ production and tau hyperphosphorylation by minocycline are through inhibiting

  16. New progress in brain aging and its related neurological diseases

    Directory of Open Access Journals (Sweden)

    Ming-wei ZHU

    2014-03-01

    Full Text Available Brain aging-related neurological diseases including Alzheimer's disease (AD, Parkinson's disease (PD and cerebral amyloid angiopathy (CAA have become one of the major diseases endangering the health of old people in China. Although the mechanism of brain aging and pathogenesis of its related neurodegenerative diseases remain unclear, protein pathological studies such as tau, α-synuclein (α-Syn, TDP-43 and amyloid-β protein (Aβ based on brain tissue bank and case registration database are opening the door to solve the mystery in the brain aging process and unlock pathogenesis of aging-related neurodegenerative diseases. Research on functional neuroimaging including 11C-PIB PET and 18F-FDDNP PET in Alzheimer's disease and 18F-FDG PET in Parkinson's disease, and biomarkers such as total-tau, phosphorylated-tau, and the 42 amino acid fragment of β-amyloid in cerebrospinal fluid (CSF in the preclinical stages of Alzheimer's disease now become hot topics in the field of elderly dementia and movement disorders. Clinicopathological correlation research of Alzheimer's disease, Parkinson's disease and cerebral amyloid angiopathy is also one of focuses in the geriatric neurological diseases. doi: 10.3969/j.issn.1672-6731.2014.03.004

  17. 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.

  18. Cerebral microbleeds in early Alzheimer's disease.

    Science.gov (United States)

    Poliakova, T; Levin, O; Arablinskiy, A; Vasenina, E; Zerr, I

    2016-10-01

    We hypothesize that cerebral microbleeds (CMB) in patients with different neuropsychological profiles (amnestic or non-amnestic) and MRI features of vascular damage could provide important information on the underlying pathological process in early Alzheimer's disease. The study was performed at two trial sites. We studied 136 outpatients with cognitive decline. MRI was performed using a magnetic field of 1.5 and 3 T. Neuropsychological assessment included Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment scale (MoCA), Addenbrooke's Cognitive Examination (ACE-R), Cambridge Cognitive Examination battery (CAMCOG) (Part 3), Clock Drawing Test, fluency test and the visual memory test (SCT). CSF was examined for standard parameters such as tau, phosphorylated tau, amyloid-β 1-40 and 42 and Qalbumin, in accordance with established protocols and genotype. In 61 patients (45 %), at least 1 CMB was found. Most of the CMBs were described in the amnestic profile (67 %). In 86 % of the cases, multiple CMB were observed. The ratio of Aβ1-40/42 in non-amnestic patients with CMB was significantly lower (mean 0.6) than in patients without CMB (mean 1.2). A notable difference in the albumin ratio as an indicator of the BBB was observed between groups with and without CMB. In the CMP-positive group, the E2 genotype was observed more frequently, and the E4 genotype less frequently, than in the CMB-negative group. Based on the cerebrospinal fluid-serum albumin ratio, we were able to show that patients with CMB present several features of BBB dysfunction. According to logistic regression, the predictive factors for CMB in patients with cognitive decline were age, WMHs score and albumin ratio. We found a significant reduction in the Aβ-amyloid ratio in the non-amnestic profile group with CMB (particularly in the cortical region) in comparison to those without CMB. While this is an interesting finding, its significance needs to be assessed in a prospective follow-up.

  19. Amyloid A amyloidosis secondary to rheumatoid arthritis: pathophysiology and treatments.

    Science.gov (United States)

    Nakamura, Tadashi

    2011-01-01

    The introduction of biological therapies targeting specific inflammatory mediators revolutionised the treatment of rheumatoid arthritis (RA). Targeting key components of the immune system allows efficient suppression of the pathological inflammatory cascade that leads to RA symptoms and subsequent joint destruction. Reactive amyloid A (AA) amyloidosis, one of the most severe complications of RA, is a serious, potentially life-threatening disorder caused by deposition of AA amyloid fibrils in multiple organs. These AA amyloid fibrils derive from the circulatory acute-phase reactant serum amyloid A protein (SAA), and may be controlled by treatment. New biologics may permit AA amyloidosis secondary to RA to become a treatable, manageable disease. Rheumatologists, when diagnosing and treating patients with AA amyloidosis secondary to RA, must understand the pathophysiology and clinical factors related to development and progression of the disease, including genetic predisposition and biological versatility of SAA.

  20. Amyloid detection using a Peltier-based device.

    Science.gov (United States)

    Cabrera, Miguel A; Ferreyra, Martin G; Cortez, Leonardo; Grupalli, Silvina A; Alvarez, L Leguina; Chehin, Rosana

    2012-01-01

    Amyloid aggregation of polypeptides is related to a growing number of pathologic states known as amyloid disorders. At present, it is clear that any proteins submitted to appropriate physicochemical environment can acquire fibrilar conformation. Fourier transform infrared spectroscopy (FTIR) has been a widely used technique to study temperature- induced amyloid-fibrils formation in vitro. In this way, strict changes and temperature controls are required to characterize the physicochemical basis of the amyloid-fibrils formation. In this article, the development of a highly efficient and accurate Peltier-based system to improve FTIR measurements is presented (see An Old Physics Phenomenon Applied to a Serious Biomedical Pathology. The accuracy of the thermostatic control was tested with biophysical parameters on biological samples probing its reproducibility. The design of the present device contributes to maintain the FTIR environment stable, which represents a real contribution to improve the spectral quality and thus, the reliability of the results.

  1. Tau/Amyloid Beta 42 Peptide Test (Alzheimer Biomarkers)

    Science.gov (United States)

    ... Was this page helpful? Also known as: Alzheimer Biomarkers Formal name: Tau Protein and Amyloid Beta 42 ... being researched for their potential use as AD biomarkers. If someone has symptoms of dementia , a health ...

  2. Phosphorylation modifies the molecular stability of β-amyloid deposits

    Science.gov (United States)

    Rezaei-Ghaleh, Nasrollah; Amininasab, Mehriar; Kumar, Sathish; Walter, Jochen; Zweckstetter, Markus

    2016-04-01

    Protein aggregation plays a crucial role in neurodegenerative diseases. A key feature of protein aggregates is their ubiquitous modification by phosphorylation. Little is known, however, about the molecular consequences of phosphorylation of protein aggregates. Here we show that phosphorylation of β-amyloid at serine 8 increases the stability of its pathogenic aggregates against high-pressure and SDS-induced dissociation. We further demonstrate that phosphorylation results in an elevated number of hydrogen bonds at the N terminus of β-amyloid, the region that is critically regulated by a variety of post-translational modifications. Because of the increased lifetime of phosphorylated β-amyloid aggregates, phosphorylation can promote the spreading of β-amyloid in Alzheimer pathogenesis. Our study suggests that regulation of the molecular stability of protein aggregates by post-translational modifications is a crucial factor for disease progression in the brain.

  3. Binuclear ruthenium(II) complexes for amyloid fibrils recognition

    Energy Technology Data Exchange (ETDEWEB)

    Hanczyc, Piotr, E-mail: piotr.hanczyc@chalmers.se

    2014-12-05

    Highlights: • Interactions of binuclear ruthenium(II) complexes with amyloid fibrils. • Dimer ruthenium(II) compounds are sensitive amyloid fibrils biomarkers. • Recognition of amyloid-chromophore adducts by two-photon excited emission. - Abstract: Metal–organic compounds represent a unique class of biomarkers with promising photophysical properties useful for imaging. Here interactions of insulin fibrils with two binuclear complexes [μ-(11,11′-bidppz)(phen){sub 4}Ru{sub 2}]{sup 4+} (1) and [μ-C4(cpdppz)(phen){sub 4}Ru{sub 2}]{sup 4+} (2) are studied by linear dichroism (LD) and fluorescence. These ruthenium(II) compounds could provide a new generation of amyloid binding chromophores with long lived lifetimes, good luminescence quantum yields for the bound molecules and photo-stability useful in multiphoton luminescence imaging.

  4. Prion Diseases of Yeast: Amyloid Structure and Biology

    OpenAIRE

    Reed B Wickner; Edskes, Herman K.; Kryndushkin, Dmitry; McGlinchey, Ryan; Bateman, David; Kelly, Amy

    2011-01-01

    Prion “variants” or “strains” are prions with the identical protein sequence, but different characteristics of the prion infection: e.g. different incubation period for scrapie strains or different phenotype intensity for yeast prion variants. We have shown that infectious amyloids of the yeast prions [PSI+], [URE3] and [PIN+] each have an in-register parallel β-sheet architecture. Moreover, we have pointed out that this amyloid architecture can explain how one protein can faithfully transmit...

  5. An unusual case of cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy with occipital lobe involvement

    Directory of Open Access Journals (Sweden)

    Bhavesh Trikamji

    2016-01-01

    Full Text Available Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL is an autosomal dominant angiopathy caused by a mutation in the notch 3 gene on chromosome 19. Clinically, patients may be asymptomatic or can present with recurrent ischemic episodes and strokes leading to dementia, depression, pseudobulbar palsy, and hemi- or quadraplegia. Additional manifestations that have been described include migraine (mostly with aura, psychiatric disturbances, and epileptic seizures. Neuroimaging is essential to the diagnosis of CADASIL. On imaging CADASIL is characterized by symmetric involvement by confluent lesions located subcortically in the frontal and temporal lobes as well as in the insula, periventricularly, in the centrum semiovale, in the internal and external capsule, basal ganglia, and brain stem; with relative sparing of the fronto-orbital and the occipital subcortical regions. We describe a 49 year old male with CADASIL with absence of temporal lobe findings on MRI but predominant lesions within the periventricular white matter, occipital lobes with extension into the subcortical frontal lobes, corpus callosum and cerebellar white matter. Although CADASIL characteristically presents with anterior temporal lobe involvement, these findings may be absent and our case addresses the atypical imaging findings in CADASIL.

  6. Face-name associative memory performance is related to amyloid burden in normal elderly.

    Science.gov (United States)

    Rentz, Dorene M; Amariglio, Rebecca E; Becker, J Alex; Frey, Meghan; Olson, Lauren E; Frishe, Katherine; Carmasin, Jeremy; Maye, Jacqueline E; Johnson, Keith A; Sperling, Reisa A

    2011-07-01

    Cerebral amyloid beta (Aβ) deposition occurs in a substantial fraction of cognitively normal (CN) older individuals. However, it has been difficult to reliably detect evidence of amyloid-related cognitive alterations in CN using standard neuropsychological measures. We sought to determine whether a highly demanding face-name associative memory exam (FNAME) could detect evidence of Aβ-related memory impairment in CN. We studied 45 CN subjects (mean age=71.7 ± 8.8) with Clinical Dementia Rating (CDR) scores=0 and MMSE ≥ 28, using Positron Emission Tomography with Pittsburgh Compound B (PiB PET). Memory factor scores were derived from a principal components analysis for FNAME name retrieval (FN-N), FNAME occupation retrieval (FN-O) and the 6-Trial Selective Reminding Test (SRT). Using multiple linear and logistic regression analyses, we related the memory factor scores to PiB distribution volume ratios (DVR, cerebellar reference) as either a continuous or a dichotomous variable in frontal cortex and a posterior cortical region representing the precuneus, posterior cingulate and lateral parietal cortices (PPCLP), co-varying for age and AMNART IQ (a proxy of cognitive reserve (CR)). A significant inverse relationship for FN-N was found with Aβ deposition in frontal (R(2)=0.29, β=-2.2, p=0.02) and PPCLP cortices (R(2)=0.26, β=-2.4, p=0.05). In contrast, neither FN-O nor the SRT were significantly related to Aβ deposition. Performance on a demanding test of face-name associative memory was related to Aβ burden in brain regions associated with memory systems. Associative memory for faces and names, a common complaint among older adults, may be a sensitive marker of early Aβ-related impairment.

  7. Inhibition of tau hyperphosphorylation and beta amyloid production in rat brain by oral administration of atorvastatin

    Institute of Scientific and Technical Information of China (English)

    LU Fen; LI Xu; SUO Ai-qin; ZHANG Jie-wen

    2010-01-01

    Background Alzheimer's disease (AD) is a neurodegenerative disorder and the leading cause of dementia in the elderly. The two hallmark lesions in AD brain are deposition of amyloid plaques and neurofibrillary tangles (NFTs).Hypercholesteremia is one of the risk factors of AD. But its role in the pathogenesis of AD is largely unknown. The aim of this study was to investigate the relationship between hypercholesteremia and tau phosphorylation or β-amyloid (Aβ),and evaluate the effect of atorvastatin on the level of tau phosphorylation and Aβ in the brains of rats fed with high cholesterol diet.Methods Sprague-Dawley (SD) rats were randomly divided into normal diet control group, high cholesterol diet group,and high cholesterol diet plus atorvastatin (Lipitor, 15 mg·kg-1·d-1) treated group. Blood from caudal vein was collected to measure total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL) and high-density lipoprotein (HDL) at the end of the 3th and the 6th months by an enzymatic method. The animals were sacrificed 6 months later and brains were removed. All left brain hemispheres were fixed for immunohistochemistry. Hippocampus and cerebral cortex were separated from right hemispheres and homogenized separately. Tau phosphorylation and Aβ in the brain tissue were determined by Western blotting (using antibodies PHF-1 and Tau-1) and anti-Aβ40/anti-Aβ42, respectively.Results We found that high cholesterol diet led to hypercholesteremia of rats as well as hyperphosphorylation of tau and increased Aβ level in the brains. Treatment of the high cholesterol diet fed rats with atorvastatin prevented the changes of both tau phosphorylation and Aβ level induced by high cholesterol diet.Conclusions Hypercholesteremia could induce tau hyperphosphorylation and Aβ production in rat brain. Atorvastatin could inhibit tau hyperphosphorylation and decrease Aβ generation. It may play a protective role in the patho-process of hypercholesteremia

  8. Face-name Associative Memory Performance is Related To Amyloid Burden in Normal Elderly

    Science.gov (United States)

    Rentz, Dorene M.; Amariglio, Rebecca. E.; Becker, J. Alex; Frey, Meghan; Olson, Lauren E.; Frishe, Katherine; Carmasin, Jeremy; Maye, Jacqueline E.; Johnson, Keith A.; Sperling, Reisa A.

    2011-01-01

    Cerebral amyloid beta (Aβ) deposition occurs in a substantial fraction of cognitively normal (CN) older individuals. However, it has been difficult to reliably detect evidence of amyloid-related cognitive alterations in CN using standard neuropsychological measures. We sought to determine whether a highly demanding face-name associative memory exam (FNAME) could detect evidence of Aβ-related memory impairment in CN. We studied 45 CN subjects (mean age = 71.7 ± 8.8) with Clinical Dementia Rating (CDR) scores = 0 and MMSE ≥ 28, using Positron Emission Tomography with Pittsburgh Compound B (PiB PET). Memory factor scores were derived from a principal components analysis for FNAME name retrieval (FN-N), FNAME occupation retrieval (FN-O) and the 6-Trial Selective Reminding Test (SRT). Using multiple linear and logistic regression analyses, we related the memory factor scores to PiB distribution volume ratios (DVR, cerebellar reference) as either a continuous or a dichotomous variable in frontal cortex and a posterior cortical region representing the precuneus, posterior cingulate and lateral parietal cortices (PPCLP), co-varying for age and AMNART IQ (a proxy of cognitive reserve (CR)). A significant inverse relationship for FN-N was found with Aβ deposition in frontal (R2 = .29, β = −2.2, p = 0.02) and PPCLP cortices (R2 = .26, β = −2.4, p = 0.05). In contrast, neither FN-O nor the SRT were significantly related to Aβ deposition. Performance on a demanding test of face-name associative memory was related to Aβ burden in brain regions associated with memory systems. Associative memory for faces and names, a common complaint among older adults, may be a sensitive marker of early Aβ-related impairment. PMID:21689670

  9. Applications of cerebral SPECT

    Energy Technology Data Exchange (ETDEWEB)

    McArthur, C., E-mail: claire.mcarthur@nhs.net [Department of Neuroradiology, Institute of Neurological Sciences, Glasgow (United Kingdom); Jampana, R.; Patterson, J.; Hadley, D. [Department of Neuroradiology, Institute of Neurological Sciences, Glasgow (United Kingdom)

    2011-07-15

    Single-photon emission computed tomography (SPECT) can provide three-dimensional functional images of the brain following the injection of one of a series of radiopharmaceuticals that crosses the blood-brain barrier and distributes according to cerebral perfusion, neurotransmitter, or cell density. Applications include differentiating between the dementias, evaluating cerebrovascular disease, preoperative localization of epileptogenic foci, diagnosing movement disorders, and evaluation of intracerebral tumours, while also proving a useful research tool. Unlike positronemission tomography (PET), SPECT imaging is widely available and can be performed in any department that has access to a rotating gamma camera. The purpose of this review is to demonstrate the utility of cerebral SPECT and increase awareness of its role in the investigation of neurological and psychiatric disorders.

  10. Amyloid fibrils composed of hexameric peptides attenuate neuroinflammation.

    Science.gov (United States)

    Kurnellas, Michael P; Adams, Chris M; Sobel, Raymond A; Steinman, Lawrence; Rothbard, Jonathan B

    2013-04-03

    The amyloid-forming proteins tau, αB crystallin, and amyloid P protein are all found in lesions of multiple sclerosis (MS). Our previous work established that amyloidogenic peptides from the small heat shock protein αB crystallin (HspB5) and from amyloid β fibrils, characteristic of Alzheimer's disease, were therapeutic in experimental autoimmune encephalomyelitis (EAE), reflecting aspects of the pathology of MS. To understand the molecular basis for the therapeutic effect, we showed a set of amyloidogenic peptides composed of six amino acids, including those from tau, amyloid β A4, major prion protein (PrP), HspB5, amylin, serum amyloid P, and insulin B chain, to be anti-inflammatory and capable of reducing serological levels of interleukin-6 and attenuating paralysis in EAE. The chaperone function of the fibrils correlates with the therapeutic outcome. Fibrils composed of tau 623-628 precipitated 49 plasma proteins, including apolipoprotein B-100, clusterin, transthyretin, and complement C3, supporting the hypothesis that the fibrils are active biological agents. Amyloid fibrils thus may provide benefit in MS and other neuroinflammatory disorders.

  11. Structural properties of Gerstmann-Straussler-Scheinker disease amyloid protein.

    Science.gov (United States)

    Salmona, Mario; Morbin, Michela; Massignan, Tania; Colombo, Laura; Mazzoleni, Giulia; Capobianco, Raffaella; Diomede, Luisa; Thaler, Florian; Mollica, Luca; Musco, Giovanna; Kourie, Joseph J; Bugiani, Orso; Sharma, Deepak; Inouye, Hideyo; Kirschner, Daniel A; Forloni, Gianluigi; Tagliavini, Fabrizio

    2003-11-28

    Prion protein (PrP) amyloid formation is a central feature of genetic and acquired forms of prion disease such as Gerstmann-Sträussler-Scheinker disease (GSS) and variant Creutzfeldt-Jakob disease. The major component of GSS amyloid is a PrP fragment spanning residues approximately 82-146. To investigate the determinants of the physicochemical properties of this fragment, we synthesized PrP-(82-146) and variants thereof, including entirely and partially scrambled peptides. PrP-(82-146) readily formed aggregates that were partially resistant to protease digestion. Peptide assemblies consisted of 9.8-nm-diameter fibrils having a parallel cross-beta-structure. Second derivative of infrared spectra indicated that PrP-(82-146) aggregates are primarily composed of beta-sheet (54%) and turn (24%) which is consistent with their amyloid-like properties. The peptide induced a remarkable increase in plasma membrane microviscosity of primary neurons. Modification of the amino acid sequence 106-126 caused a striking increase in aggregation rate, with formation of large amount of protease-resistant amorphous material and relatively few amyloid fibrils. Alteration of the 127-146 region had even more profound effects, with the inability to generate amyloid fibrils. These data indicate that the intrinsic properties of PrP-(82-146) are dependent upon the integrity of the C-terminal region and account for the massive deposition of PrP amyloid in GSS.

  12. Complexation of amyloid fibrils with charged conjugated polymers.

    Science.gov (United States)

    Ghosh, Dhiman; Dutta, Paulami; Chakraborty, Chanchal; Singh, Pradeep K; Anoop, A; Jha, Narendra Nath; Jacob, Reeba S; Mondal, Mrityunjoy; Mankar, Shruti; Das, Subhadeep; Malik, Sudip; Maji, Samir K

    2014-04-01

    It has been suggested that conjugated charged polymers are amyloid imaging agents and promising therapeutic candidates for neurological disorders. However, very less is known about their efficacy in modulating the amyloid aggregation pathway. Here, we studied the modulation of Parkinson's disease associated α-synuclein (AS) amyloid assembly kinetics using conjugated polyfluorene polymers (PF, cationic; PFS, anionic). We also explored the complexation of these charged polymers with the various AS aggregated species including amyloid fibrils and oligomers using multidisciplinary biophysical techniques. Our data suggests that both polymers irrespective of their different charges in the side chains increase the fibrilization kinetics of AS and also remarkably change the morphology of the resultant amyloid fibrils. Both polymers were incorporated/aligned onto the AS amyloid fibrils as evident from electron microscopy (EM) and atomic force microscopy (AFM), and the resultant complexes were structurally distinct from their pristine form of both polymers and AS supported by FTIR study. Additionally, we observed that the mechanism of interactions between the polymers with different species of AS aggregates were markedly different.

  13. Amyloid diseases of yeast: prions are proteins acting as genes.

    Science.gov (United States)

    Wickner, Reed B; Edskes, Herman K; Bateman, David A; Kelly, Amy C; Gorkovskiy, Anton; Dayani, Yaron; Zhou, Albert

    2014-01-01

    The unusual genetic properties of the non-chromosomal genetic elements [URE3] and [PSI+] led to them being identified as prions (infectious proteins) of Ure2p and Sup35p respectively. Ure2p and Sup35p, and now several other proteins, can form amyloid, a linear ordered polymer of protein monomers, with a part of each molecule, the prion domain, forming the core of this β-sheet structure. Amyloid filaments passed to a new cell seed the conversion of the normal form of the protein into the same amyloid form. The cell's phenotype is affected, usually from the deficiency of the normal form of the protein. Solid-state NMR studies indicate that the yeast prion amyloids are in-register parallel β-sheet structures, in which each residue (e.g. Asn35) forms a row along the filament long axis. The favourable interactions possible for aligned identical hydrophilic and hydrophobic residues are believed to be the mechanism for propagation of amyloid conformation. Thus, just as DNA mediates inheritance by templating its own sequence, these proteins act as genes by templating their conformation. Distinct isolates of a given prion have different biological properties, presumably determined by differences between the amyloid structures. Many lines of evidence indicate that the Saccharomyces cerevisiae prions are pathological disease agents, although the example of the [Het-s] prion of Podospora anserina shows that a prion can have beneficial aspects.

  14. Switchable photooxygenation catalysts that sense higher-order amyloid structures

    Science.gov (United States)

    Taniguchi, Atsuhiko; Shimizu, Yusuke; Oisaki, Kounosuke; Sohma, Youhei; Kanai, Motomu

    2016-10-01

    Proteins can misfold into amyloid structures that are associated with diseases; however, the same proteins often have important biological roles. To degrade selectively the amyloid form without affecting the fraction of functional protein is, therefore, an attractive goal. Here we report target-state-dependent photooxygenation catalysts that are active only when bound to the cross-β-sheet structure that is characteristic of pathogenic aggregated amyloid proteins. We show these catalysts can selectively oxygenate the amyloid form of amyloid β-protein (Aβ) 1-42 in the presence of non-amyloid off-target substrates. Furthermore, photooxygenation with a catalyst that bears an Aβ-binding peptide attenuated the Aβ pathogenicity in the presence of cells. We also show that selective photooxygenation is generally applicable to other amyloidogenic proteins (amylin, insulin, β2-microglobulin, transthyretin and α-synuclein) and does not affect the physiologically functional non-aggregate states of these proteins. This is the first report of an artificial catalyst that can be selectively and reversibly turned on and off depending on the structure and aggregation state of the substrate protein.

  15. Force generation by the growth of amyloid aggregates.

    Science.gov (United States)

    Herling, Therese W; Garcia, Gonzalo A; Michaels, Thomas C T; Grentz, Wolfgang; Dean, James; Shimanovich, Ulyana; Gang, Hongze; Müller, Thomas; Kav, Batuhan; Terentjev, Eugene M; Dobson, Christopher M; Knowles, Tuomas P J

    2015-08-01

    The generation of mechanical forces are central to a wide range of vital biological processes, including the function of the cytoskeleton. Although the forces emerging from the polymerization of native proteins have been studied in detail, the potential for force generation by aberrant protein polymerization has not yet been explored. Here, we show that the growth of amyloid fibrils, archetypical aberrant protein polymers, is capable of unleashing mechanical forces on the piconewton scale for individual filaments. We apply microfluidic techniques to measure the forces released by amyloid growth for two systems: insulin and lysozyme. The level of force measured for amyloid growth in both systems is comparable to that observed for actin and tubulin, systems that have evolved to generate force during their native functions and, unlike amyloid growth, rely on the input of external energy in the form of nucleotide hydrolysis for maximum force generation. Furthermore, we find that the power density released from growing amyloid fibrils is comparable to that of high-performance synthetic polymer actuators. These findings highlight the potential of amyloid structures as active materials and shed light on the criteria for regulation and reversibility that guide molecular evolution of functional polymers.

  16. Toxic species in amyloid disorders: Oligomers or mature fibrils

    Directory of Open Access Journals (Sweden)

    Meenakshi Verma

    2015-01-01

    Full Text Available Protein aggregation is the hallmark of several neurodegenerative disorders. These protein aggregation (fibrillization disorders are also known as amyloid disorders. The mechanism of protein aggregation involves conformation switch of the native protein, oligomer formation leading to protofibrils and finally mature fibrils. Mature fibrils have long been considered as the cause of disease pathogenesis; however, recent evidences suggest oligomeric intermediates formed during fibrillization to be toxic. In this review, we have tried to address the ongoing debate for these toxic amyloid species. We did an extensive literature search and collated information from Pubmed (http://www.ncbi.nlm.nih.gov and Google search using various permutations and combinations of the following keywords: Neurodegeneration, amyloid disorders, protein aggregation, fibrils, oligomers, toxicity, Alzheimer′s Disease, Parkinson′s Disease. We describe different instances showing the toxicity of mature fibrils as well as oligomers in Alzheimer′s Disease and Parkinson′s Disease. Distinct structural framework and morphology of amyloid oligomers suggests difference in toxic effect between oligomers and fibrils. We highlight the difference in structure and proposed toxicity pathways for fibrils and oligomers. We also highlight the evidences indicating that intermediary oligomeric species can act as potential diagnostic biomarker. Since the formation of these toxic species follow a common structural switch among various amyloid disorders, the protein aggregation events can be targeted for developing broad-range therapeutics. The therapeutic trials based on the understanding of different protein conformers (monomers, oligomers, protofibrils and fibrils in amyloid cascade are also described.

  17. Insulin amyloid at injection sites of patients with diabetes.

    Science.gov (United States)

    Nilsson, Melanie R

    2016-09-01

    The formation of insulin amyloid can dramatically impact glycemic control in patients with diabetes, making it an important therapeutic consideration. In addition, the cost associated with the excess insulin required by patients with amyloid is estimated to be $3K per patient per year, which adds to the growing financial burden of this disease. Insulin amyloid has been observed with every mode of therapeutic insulin administration (infusion, injection and inhalation), and the number of reported cases has increased significantly since 2002. The new cases represent a much broader demographic, and include many patients who have used exclusively human insulin and human insulin analogs. The reason for the increase in case reports is unknown, but this review explores the possibility that changes in patient care, improved differential diagnosis and/or changes in insulin type and insulin delivery systems may be important factors. The goal of this review is to raise key questions that will inspire proactive measures to prevent, identify and treat insulin amyloid. Furthermore, this comprehensive examination of insulin amyloid can provide insight into important considerations for other injectable drugs that are prone to form amyloid deposits.

  18. Phenylpropanolamine and cerebral hemorrhage

    Energy Technology Data Exchange (ETDEWEB)

    McDowell, J.R.; LeBlanc, H.J.

    1985-05-01

    Computerized tomography, carotid angiograms, and arteriography were used to diagnose several cases of cerebral hemorrhage following the use of phenylpropanolamine. The angiographic picture in one of the three cases was similar to that previously described in association with amphetamine abuse and pseudoephedrine overdose, both substances being chemically and pharmacologically similar to phenylpropanolamine. The study suggests that the arterial change responsible for symptoms may be due to spasm rather than arteriopathy. 14 references, 5 figures.

  19. Analysis the Cell for Invigorating Blood Circulation and the Subcellular Angiology of Cardio Cerebral Angiopathy%心脑血管病人的活血细胞及亚细胞成分分析

    Institute of Scientific and Technical Information of China (English)

    孙春霞; 王友宁

    2004-01-01

    目的:探讨超高倍显微系统活血分析在缺血性心脑血管性疾病早期诊断中的应用价值.方法:从398例患者及200例健康志愿者中采集手指末梢血制成活血涂片,以超高倍显微系统快速进行检测.将红细胞活力、红细胞聚集、血小板聚集及异源性斑块检测结果进行比较,评价病人组与健康对照组之间的差异.结果:病人组阳性率明显高于健康组(P<0.05).结论: 超高倍检查是一种快速、直观、方便、比较准确的早期发现人体机能异常的手段,在缺血性心脑血管性疾病早期诊断中具有积极作用.

  20. Cerebral salt wasting syndrome

    Directory of Open Access Journals (Sweden)

    Harshal Dholke

    2016-01-01

    Full Text Available Traumatic brain injury (TBI is on the rise, especially in today′s fast-paced world. TBI requires not only neurosurgical expertise but also neurointensivist involvement for a better outcome. Disturbances of sodium balance are common in patients with brain injury, as the central nervous system plays a major role in sodium regulation. Hyponatraemia, defined as serum sodium <135 meq/L is commonly seen and is especially deleterious as it can contribute to cerebral oedema in these patients. Syndrome of inappropriate antidiuretic hormone secretion (SIADH, is the most well-known cause of hyponatraemia in this subset of patients. Cerebral Salt Wasting Syndrome (CSWS, leading to renal sodium loss is an important cause of hyponatraemia in patients with TBI. Although incompletely studied, decreased renal sympathetic responses and cerebral natriuretic factors play a role in the pathogenesis of CSWS. Maintaining a positive sodium balance and adequate hydration can help in the treatment. It is important to differentiate between SIADH and CSWS when trying to ascertain a case for patients with acute brain injury, as the treatment of the two are diametrically opposite.

  1. Cerebral oxygenation and hyperthermia

    Directory of Open Access Journals (Sweden)

    Anthony Richard Bain

    2014-03-01

    Full Text Available Hyperthermia is associated with marked reductions in cerebral blood flow (CBF. Increased distribution of cardiac output to the periphery, increases in alveolar ventilation and resultant hypocapnia each contribute to the fall in CBF during passive hyperthermia; however, their relative contribution remains a point of contention, and probably depends on the experimental condition (e.g. posture and degree of hyperthermia. The hyperthermia-induced hyperventilatory response reduces arterial CO2 pressure (PaCO2 causing cerebral vasoconstriction and subsequent reductions in flow. During supine passive hyperthermia, the majority of recent data indicate that reductions in PaCO2 may be the primary, if not sole, culprit for reduced CBF. On the other hand, during more dynamic conditions (e.g. hemorrhage or orthostatic challenges, an inability to appropriately decrease peripheral vascular conductance presents a condition whereby adequate cerebral perfusion pressure may be compromised secondary to reductions in systemic blood pressure. Although studies have reported maintenance of pre-frontal cortex oxygenation (assessed by near-infrared spectroscopy during exercise and severe heat stress, the influence of cutaneous blood flow is known to contaminate this measure. This review discusses the governing mechanisms associated with changes in CBF and oxygenation during moderate to severe (i.e. 1.0°C to 2.0°C increase in body core temperature levels of hyperthermia. Future research directions are provided.

  2. Cerebral malformations without antenatal diagnosis

    Energy Technology Data Exchange (ETDEWEB)

    Girard, Nadine J. [Diagnostic Neuroradiology, Hopital Timone, Marseille (France)

    2010-06-15

    Cerebral malformations are usually described following the different steps in development. Disorders of neurulation (dysraphisms), or diverticulation (holoprosencephalies and posterior fossa cysts), and total commissural agenesis are usually diagnosed in utero. In contrast, disorders of histogenesis (proliferation-differentiation, migration, organization) are usually discovered in infants and children. The principal clinical symptoms that may be a clue to cerebral malformation include congenital hemiparesis, epilepsy and mental or psychomotor retardation. MRI is the imaging method of choice to assess cerebral malformations. (orig.)

  3. Cerebral Autoregulation in Normal Pregnancy and Preeclampsia

    NARCIS (Netherlands)

    van Veen, Teelkien R.; Panerai, Ronney B.; Haeri, Sina; Griffioen, Annemiek C.; Zeeman, Gerda; Belfort, Michael A.

    2013-01-01

    OBJECTIVE: To test the hypothesis that preeclampsia is associated with impaired dynamic cerebral autoregulation. METHODS: In a prospective cohort analysis, cerebral blood flow velocity of the middle cerebral artery (determined by transcranial Doppler), blood pressure (determined by noninvasive arter

  4. Molecular pathophysiology of cerebral edema.

    Science.gov (United States)

    Stokum, Jesse A; Gerzanich, Volodymyr; Simard, J Marc

    2016-03-01

    Advancements in molecular biology have led to a greater understanding of the individual proteins responsible for generating cerebral edema. In large part, the study of cerebral edema is the study of maladaptive ion transport. Following acute CNS injury, cells of the neurovascular unit, particularly brain endothelial cells and astrocytes, undergo a program of pre- and post-transcriptional changes in the activity of ion channels and transporters. These changes can result in maladaptive ion transport and the generation of abnormal osmotic forces that, ultimately, manifest as cerebral edema. This review discusses past models and current knowledge regarding the molecular and cellular pathophysiology of cerebral edema.

  5. ETAS, an enzyme-treated asparagus extract, attenuates amyloid beta-induced cellular disorder in PC12 cells.

    Science.gov (United States)

    Ogasawara, Junetsu; Ito, Tomohiro; Wakame, Koji; Kitadate, Kentaro; Sakurai, Takuya; Sato, Shogo; Ishibashi, Yoshinaga; Izawa, Tetsuya; Takahashi, Kazuto; Ishida, Hitoshi; Takabatake, Ichiro; Kizaki, Takako; Ohno, Hideki

    2014-04-01

    One of the pathological characterizations of Alzheimer's disease (AD) is the deposition of amyloid beta peptide (Abeta) in cerebral cortical cells. The deposition of Abeta in neuronal cells leads to an increase in the production of free radicals that are typified by reactive oxygen species (ROS), thereby inducing cell death. A growing body of evidence now suggests that several plant-derived food ingredients are capable of scavenging ROS in mammalian cells. The purpose of the present study was to investigate whether enzyme-treated asparagus extract (ETAS), which is rich in antioxidants, is one of these ingredients. The pre-incubation of differentiated PC 12 cells with ETAS significantly recovered Abeta-induced reduction of cell viability, which was accompanied by reduced levels of ROS. These results suggest that ETAS may be one of the functional food ingredients with anti-oxidative capacity to help prevent AD.

  6. siRNA against presenilin 1 (PS1 down regulates amyloid β42 production in IMR-32 cells

    Directory of Open Access Journals (Sweden)

    Kandimalla Ramesh JL

    2012-01-01

    Full Text Available Abstract Background One of the pathological hallmarks of Alzheimer's disease (AD is the deposition of the ~4 kDa amyloid β protein (Aβ within lesions known as senile plaques. Aβ is also deposited in the walls of cerebral blood vessels in many cases of AD. A substantial proportion of the Aβ that accumulates in the AD brain is deposited as Amyloid, which is highly insoluble, proteinaceous material with a β-pleated-sheet conformation and deposited extracellularly in the form of 5-10 nm wide straight fibrils. As γ-secretase catalyzes the final cleavage that releases the Aβ42 or 40 from amyloid β -protein precursor (APP, therefore, it is a potential therapeutic target for the treatment of AD. γ-Secretase cleavage is performed by a high molecular weight protein complex containing presenilins (PSs, nicastrin, Aph-1 and Pen-2. Previous studies have demonstrated that the presenilins (PS1 and PS2 are critical components of a large enzyme complex that performs γ-secretase cleavage. Methods In this study we used RNA interference (RNAi technology to examine the effects of small-interfering RNA (siRNA against PS1 on expression levels of PS1 and Aβ42 in IMR-32 Cells using RTPCR, western blotting and immunofluorescence techniques. Results The results of the present study showed down regulation of PS1 and Aβ42 in IMR32 cells transfected with siRNA against PS1. Conclusion Our results substantiate the concept that PS1 is involved in γ-secretase activity and provides the rationale for therapeutic strategies aimed at influencing Aβ42 production.

  7. The epsilon isoform of 14-3-3 protein is a component of the prion protein amyloid deposits of Gerstmann-Sträussler-Scheinker disease.

    Science.gov (United States)

    Di Fede, Giuseppe; Giaccone, Giorgio; Limido, Lucia; Mangieri, Michela; Suardi, Silvia; Puoti, Gianfranco; Morbin, Michela; Mazzoleni, Giulia; Ghetti, Bernardino; Tagliavini, Fabrizio

    2007-02-01

    The 14-3-3 proteins are highly conserved, ubiquitous molecules involved in a variety of biologic events, such as transduction pathway modulation, cell cycle control, and apoptosis. Seven isoforms have been identified that are abundant in the brain, preferentially localized in neurons. Remarkable increases in 14-3-3 are seen in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease (CJD), and it has been found in pathologic inclusions of several neurodegenerative diseases. Moreover, the zeta isoform has been detected in prion protein (PrP) amyloid deposits of CJD patients. To further investigate the cerebral distribution of 14-3-3 in prion-related encephalopathies, we carried out an immunohistochemical and biochemical analysis of brain tissue from patients with Gerstmann-Sträussler-Scheinker disease (GSS) and sporadic, familial and acquired forms of CJD, using specific antibodies against the seven 14-3-3 isoforms. The study showed a strong immunoreactivity of PrP amyloid plaques of GSS patients for the 14-3-3 epsilon isoform, but not for the other isoforms. The epsilon isoform of 14-3-3 was not found in PrP deposits of CJD. These results indicate that the epsilon isoform of 14-3-3 is a component of PrP amyloid deposits of GSS and suggest that this is the sole 14-3-3 isoform specifically involved in the neuropathologic changes associated with this disorder.

  8. Interactions between amyloid-β and hemoglobin: implications for amyloid plaque formation in Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Jia-Ying Chuang

    Full Text Available Accumulation of amyloid-β (Aβ peptides in the brain is one of the central pathogenic events in Alzheimer's disease (AD. However, why and how Aβ aggregates within the brain of AD patients remains elusive. Previously, we demonstrated hemoglobin (Hb binds to Aβ and co-localizes with the plaque and vascular amyloid deposits in post-mortem AD brains. In this study, we further characterize the interactions between Hb and Aβ in vitro and in vivo and report the following observations: 1 the binding of Hb to Aβ required iron-containing heme; 2 other heme-containing proteins, such as myoglobin and cytochrome C, also bound to Aβ; 3 hemin-induced cytotoxicity was reduced in neuroblastoma cells by low levels of Aβ; 4 Hb was detected in neurons and glial cells of post-mortem AD brains and was up-regulated in aging and APP/PS1 transgenic mice; 5 microinjection of human Hb into the dorsal hippocampi of the APP/PS1 transgenic mice induced the formation of an envelope-like structure composed of Aβ surrounding the Hb droplets. Our results reveal an enhanced endogenous expression of Hb in aging brain cells, probably serving as a compensatory mechanism against hypoxia. In addition, Aβ binds to Hb and other hemoproteins via the iron-containing heme moiety, thereby reducing Hb/heme/iron-induced cytotoxicity. As some of the brain Hb could be derived from the peripheral circulation due to a compromised blood-brain barrier frequently observed in aged and AD brains, our work also suggests the genesis of some plaques may be a consequence of sustained amyloid accretion at sites of vascular injury.

  9. Magnetic resonance Q mapping reveals a decrease in microvessel density in the arcAβ mouse model of cerebral amyloidosis

    Directory of Open Access Journals (Sweden)

    Giovanna eIelacqua

    2016-01-01

    arcAβ mice. We further demonstrated a region-specific association between parenchymal and vascular deposition of β-amyloid and decreased vascular density, without a correlation with the amount of Aβ deposition. We found that Q mapping was more suitable than the hemodynamic read-outs to detect amyloid-related degeneration of the cerebral microvasculature.

  10. Magnetic Resonance Q Mapping Reveals a Decrease in Microvessel Density in the arcAβ Mouse Model of Cerebral Amyloidosis.

    Science.gov (United States)

    Ielacqua, Giovanna D; Schlegel, Felix; Füchtemeier, Martina; Xandry, Jael; Rudin, Markus; Klohs, Jan

    2015-01-01

    reduction of microvessel density in the old arcAβ mice. We further demonstrated a region-specific association between parenchymal and vascular deposition of β-amyloid and decreased vascular density, without a correlation with the amount of Aβ deposition. We found that Q mapping was more suitable than the hemodynamic read-outs to detect amyloid-related degeneration of the cerebral microvasculature.

  11. Neuroprotection via matrix-trophic coupling between cerebral endothelial cells and neurons.

    Science.gov (United States)

    Guo, Shuzhen; Kim, Woo Jean; Lok, Josephine; Lee, Sun-Ryung; Besancon, Elaine; Luo, Bing-Hao; Stins, Monique F; Wang, Xiaoying; Dedhar, Shoukat; Lo, Eng H

    2008-05-27

    The neurovascular unit is an emerging concept that emphasizes homeostatic interactions between endothelium and cerebral parenchyma. Here, we show that cerebral endothelium are not just inert tubes for delivering blood, but they also secrete trophic factors that can be directly neuroprotective. Conditioned media from cerebral endothelial cells broadly protects neurons against oxygen-glucose deprivation, oxidative damage, endoplasmic reticulum stress, hypoxia, and amyloid neurotoxicity. This phenomenon is largely mediated by endothelial-produced brain-derived neurotrophic factor (BDNF) because filtering endothelial-conditioned media with TrkB-Fc eliminates the neuroprotective effect. Endothelial production of BDNF is sustained by beta-1 integrin and integrin-linked kinase (ILK) signaling. Noncytotoxic levels of oxidative stress disrupts ILK signaling and reduces endothelial levels of neuroprotective BDNF. These data suggest that cerebral endothelium provides a critical source of homeostatic support for neurons. Targeting these signals of matrix and trophic coupling between endothelium and neurons may provide new therapeutic opportunities for stroke and other CNS disorders.

  12. An autopsy case of hemiconvulsion-hemiplegia-epilepsy syndrome manifesting as cerebral hemiatrophy in an elderly man.

    Science.gov (United States)

    Iwase, Tamaki; Yoshida, Mari; Mizuno, Tomoyuki; Sato, Shinya; Nokura, Kazuya

    2015-12-01

    We report an autopsy case of hemiconvulsion-hemiplegia-epilepsy (HHE) syndrome in a 79-year-old man. HHE syndrome usually occurs in children younger than 4 years of age. Although most HHE syndrome patients live into adult life, only a few cases of the syndrome have been reported in the elderly. In our case, cerebral hemiatrophy, left mesial temporal sclerosis and crossed cerebellar atrophy were observed. Because this is the oldest case ever reported, we further investigated age-related neuropathological changes and found an interhemispheric difference in amyloid-β-related neuropathologic changes. There were almost no senile plaques or amyloid-laden vessels in the left hemisphere. As far as we know, this is the first report of age-related neuropathology in a brain manifesting HHE syndrome.

  13. Endogenously generated amyloid β increases membrane fluidity in neural 2a cells

    Institute of Scientific and Technical Information of China (English)

    NIU Ying; SHENG BaiYang; SONG Bo; LIU LingLing; ZHANG XiuFang; ZHAO NanMing; GONG YanDao

    2009-01-01

    The effect of endogenously generated amyloid β on membrane fluidity was investigated in Neural 2a cells stably expressing Swedish mutant amyloid precursor protein (APPswe). Membrane fluidity was studied by fluorescence polarizability using 1,6-Diphenyl-1,3,5-Hexatriene (DPH) as the fluorescence probe. It was found that the membrane fluidity in APPswe cells was significantly higher than that in its wild type counterparts. Alleviating the effect of amyloid β either by y secretase activity inhibition or by amyloid antibody treatment decreased membrane fluidity, which indicated an important role of amyloid β in increasing membrane fluidity. Treatment using amyloid β channel blocker, tromethamine and NA4 suggested that channel formed by amyloid β on the cell membrane is a way through which amyloid β takes its membrane fluidizing effect.

  14. Identification of a Common Binding Mode for Imaging Agents to Amyloid Fibrils from Molecular Dynamics Simulations

    DEFF Research Database (Denmark)

    Skeby, Katrine Kirkeby; Sørensen, Jesper; Schiøtt, Birgit

    2013-01-01

    Amyloid diseases are characterized by the misfolding and deposition of proteins in the body in the form of insoluble amyloid fibrils. Alzheimer’s disease and type 2 diabetes mellitus are two examples of amyloid diseases which are closely related both with respect to the atomic structures of the a......Amyloid diseases are characterized by the misfolding and deposition of proteins in the body in the form of insoluble amyloid fibrils. Alzheimer’s disease and type 2 diabetes mellitus are two examples of amyloid diseases which are closely related both with respect to the atomic structures...... of the amyloid fibrils and the disease pathology. Alzheimer’s disease is very difficult to diagnose, and much research is being performed to develop noninvasive diagnostic methods, such as imaging with small-molecule agents. The interactions between amyloid fibrils and imaging agents are challenging to examine...

  15. Characterizing Structural Stability of Amyloid Motif Fibrils Mediated by Water Molecules.

    Science.gov (United States)

    Choi, Hyunsung; Chang, Hyun Joon; Lee, Myeongsang; Na, Sungsoo

    2017-02-04

    In biological systems, structural confinements of amyloid fibrils can be mediated by the role of water molecules. However, the underlying effect of the dynamic behavior of water molecules on structural stabilities of amyloid fibrils is still unclear. By performing molecular dynamics simulations, we investigate the dynamic features and the effect of interior water molecules on conformations and mechanical characteristics of various amyloid fibrils. We find that a specific mechanism induced by the dynamic properties of interior water molecules can affect diffusion of water molecules inside amyloid fibrils, inducing their different structural stabilities. The conformation of amyloid fibrils induced by interior water molecules show the fibrils' different mechanical features. We elucidate the role of confined and movable interior water molecules in structural stabilities of various amyloid fibrils. Our results offer insights not only in further understanding of mechanical features of amyloids as mediated by water molecules, but also in the fine-tuning of the functional abilities of amyloid fibrils for applications.

  16. Nonequilibrium and generalized-ensemble molecular dynamics simulations for amyloid fibril

    Energy Technology Data Exchange (ETDEWEB)

    Okumura, Hisashi [Research Center for Computational Science, Institute for Molecular Science, Okazaki, Aichi 444-8585 (Japan); Department of Structural Molecular Science, The Graduate University for Advanced Studies, Okazaki, Aichi 444-8585 (Japan)

    2015-12-31

    Amyloids are insoluble and misfolded fibrous protein aggregates and associated with more than 20 serious human diseases. We perform all-atom molecular dynamics simulations of amyloid fibril assembly and disassembly.

  17. Hyperventilation, cerebral perfusion, and syncope

    DEFF Research Database (Denmark)

    Immink, R V; Pott, F C; Secher, N H

    2014-01-01

    dioxide (PaCO2) and oxygen (PaO2) partial pressures so that hypercapnia/hypoxia increases and hypocapnia/hyperoxia reduces global cerebral blood flow. Cerebral hypoperfusion and TLOC have been associated with hypocapnia related to HV. Notwithstanding pronounced cerebrovascular effects of PaCO2...

  18. Resting cerebral blood flow

    Science.gov (United States)

    Ances, B M.; Sisti, D; Vaida, F; Liang, C L.; Leontiev, O; Perthen, J E.; Buxton, R B.; Benson, D; Smith, D M.; Little, S J.; Richman, D D.; Moore, D J.; Ellis, R J.

    2009-01-01

    Objective: HIV enters the brain soon after infection causing neuronal damage and microglial/astrocyte dysfunction leading to neuropsychological impairment. We examined the impact of HIV on resting cerebral blood flow (rCBF) within the lenticular nuclei (LN) and visual cortex (VC). Methods: This cross-sectional study used arterial spin labeling MRI (ASL-MRI) to measure rCBF within 33 HIV+ and 26 HIV− subjects. Nonparametric Wilcoxon rank sum test assessed rCBF differences due to HIV serostatus. Classification and regression tree (CART) analysis determined optimal rCBF cutoffs for differentiating HIV serostatus. The effects of neuropsychological impairment and infection duration on rCBF were evaluated. Results: rCBF within the LN and VC were significantly reduced for HIV+ compared to HIV− subjects. A 2-tiered CART approach using either LN rCBF ≤50.09 mL/100 mL/min or LN rCBF >50.09 mL/100 mL/min but VC rCBF ≤37.05 mL/100 mL/min yielded an 88% (29/33) sensitivity and an 88% (23/26) specificity for differentiating by HIV serostatus. HIV+ subjects, including neuropsychologically unimpaired, had reduced rCBF within the LN (p = 0.02) and VC (p = 0.001) compared to HIV− controls. A temporal progression of brain involvement occurred with LN rCBF significantly reduced for both acute/early (<1 year of seroconversion) and chronic HIV-infected subjects, whereas rCBF in the VC was diminished for only chronic HIV-infected subjects. Conclusion: Resting cerebral blood flow (rCBF) using arterial spin labeling MRI has the potential to be a noninvasive neuroimaging biomarker for assessing HIV in the brain. rCBF reductions that occur soon after seroconversion possibly reflect neuronal or vascular injury among HIV+ individuals not yet expressing neuropsychological impairment. GLOSSARY AEH = acute/early HIV infection; ANOVA = analysis of variance; ASL-MRI = arterial spin labeling MRI; CART = classification and regression tree; CBF = cerebral blood flow; CH = chronic HIV

  19. Odontogenic fibroma, including amyloid and ossifying variants.

    Science.gov (United States)

    Eversole, Lewis R

    2011-12-01

    Sixty-five cases of odontogenic fibroma (OdonF) are herein presented having been segregated into peripheral, extra bony tumors (n = 40) and tumors arising in bone or centrally (n = 25). All cases were characterized microscopically by a fibrous proliferation that varied within and between cases in cellularity and collagen fibril diameter, with intermixed odontogenic epithelial islands and cords. All central lesions presented as well demarcated radiolucencies and resorption of contiguous tooth roots was a common finding. These intraosseous lesions were of the WHO type; the so-called nonWHO type was excluded as all lesions with this diagnosis were devoid of an epithelial component and could be reclassified as other soft tissue fibrogenic tumors. Neither the central tumors nor the peripheral lesions recurred following enucleation/curettage, with a mean follow-up of 4 and 3.4 years respectively. Three distinct microscopic variations were encountered in this series: (1) two cases of OdonF with giant cell reaction, (2) two instances of OdonF with ossifying fibroma; and (3) four instances of OdonF with odontogenic ameloblast-associated protein (ODAM), an amyloid-like protein found deposited adjacent to epithelial cords plus CD1a+/S-100+ Langerhans dendritic cells entwined around the epithelial element. A single instance of the odontogenic fibroma-like hamartoma/enamel hypoplasia syndrome has been included in this series.

  20. Amyloid PET in European and North American cohorts; and exploring age as a limit to clinical use of amyloid imaging

    Energy Technology Data Exchange (ETDEWEB)

    Chiotis, Konstantinos [Karolinska Institutet, Department of NVS, Center for Alzheimer Research, Translational Alzheimer Neurobiology, Stockholm (Sweden); Carter, Stephen F. [Karolinska Institutet, Department of NVS, Center for Alzheimer Research, Translational Alzheimer Neurobiology, Stockholm (Sweden); University of Manchester, Wolfson Molecular Imaging Centre, Institute of Brain, Behaviour and Mental Health, Manchester (United Kingdom); Farid, Karim [Karolinska Institutet, Department of NVS, Center for Alzheimer Research, Translational Alzheimer Neurobiology, Stockholm (Sweden); APHP, Hotel-Dieu Hospital, Department of Nuclear Medicine, Paris (France); Savitcheva, Irina [Karolinska University Hospital Huddinge, Department of Radiology, Stockholm (Sweden); Nordberg, Agneta [Karolinska Institutet, Department of NVS, Center for Alzheimer Research, Translational Alzheimer Neurobiology, Stockholm (Sweden); Karolinska University Hospital Huddinge, Department of Geriatric Medicine, Stockholm (Sweden); Collaboration: for the Diagnostic Molecular Imaging (DiMI) network and the Alzheimer' s Disease Neuroimaging Initiative

    2015-09-15

    Several radiotracers that bind to fibrillar amyloid-beta in the brain have been developed and used in various patient cohorts. This study aimed to investigate the comparability of two amyloid positron emission tomography (PET) tracers as well as examine how age affects the discriminative properties of amyloid PET imaging. Fifty-one healthy controls (HCs), 72 patients with mild cognitive impairment (MCI) and 90 patients with Alzheimer's disease (AD) from a European cohort were scanned with [11C]Pittsburgh compound-B (PIB) and compared with an age-, sex- and disease severity-matched population of 51 HC, 72 MCI and 84 AD patients from a North American cohort who were scanned with [18F]Florbetapir. An additional North American population of 246 HC, 342 MCI and 138 AD patients with a Florbetapir scan was split by age (55-75 vs 76-93 y) into groups matched for gender and disease severity. PET template-based analyses were used to quantify regional tracer uptake. The mean regional uptake patterns were similar and strong correlations were found between the two tracers across the regions of interest in HC (ρ = 0.671, p = 0.02), amyloid-positive MCI (ρ = 0.902, p < 0.001) and AD patients (ρ = 0.853, p < 0.001). The application of the Florbetapir cut-off point resulted in a higher proportion of amyloid-positive HC and a lower proportion of amyloid-positive AD patients in the older group (28 and 30 %, respectively) than in the younger group (19 and 20 %, respectively). These results illustrate the comparability of Florbetapir and PIB in unrelated but matched patient populations. The role of amyloid PET imaging becomes increasingly important with increasing age in the diagnostic assessment of clinically impaired patients. (orig.)

  1. Polymerizing the fibre between bacteria and host cells: the biogenesis of functional amyloid fibres

    OpenAIRE

    2008-01-01

    Amyloid fibres are proteinaceous aggregates associated with several human diseases, including Alzheimer’s, Huntington’s and Creutzfeldt Jakob’s. Disease-associated amyloid formation is the result of proteins that misfold and aggregate into β sheet-rich fibre polymers. Cellular toxicity is readily associated with amyloidogenesis, although the molecular mechanism of toxicity remains unknown. Recently, a new class of ‘functional’ amyloid fibres was discovered that demonstrates that amyloids can ...

  2. Amyloid Structure and Assembly: Insights from Scanning Transmission Electron Microscopy

    Energy Technology Data Exchange (ETDEWEB)

    Goldsbury, C.; Wall, J.; Baxa, U.; Simon, M. N.; Steven, A. C.; Engel, A.; Aebi, U.; Muller, S. A.

    2011-01-01

    Amyloid fibrils are filamentous protein aggregates implicated in several common diseases such as Alzheimer's disease and type II diabetes. Similar structures are also the molecular principle of the infectious spongiform encephalopathies such as Creutzfeldt-Jakob disease in humans, scrapie in sheep, and of the so-called yeast prions, inherited non-chromosomal elements found in yeast and fungi. Scanning transmission electron microscopy (STEM) is often used to delineate the assembly mechanism and structural properties of amyloid aggregates. In this review we consider specifically contributions and limitations of STEM for the investigation of amyloid assembly pathways, fibril polymorphisms and structural models of amyloid fibrils. This type of microscopy provides the only method to directly measure the mass-per-length (MPL) of individual filaments. Made on both in vitro assembled and ex vivo samples, STEM mass measurements have illuminated the hierarchical relationships between amyloid fibrils and revealed that polymorphic fibrils and various globular oligomers can assemble simultaneously from a single polypeptide. The MPLs also impose strong constraints on possible packing schemes, assisting in molecular model building when combined with high-resolution methods like solid-state nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR).

  3. Prediction of Peptide and Protein Propensity for Amyloid Formation.

    Directory of Open Access Journals (Sweden)

    Carlos Família

    Full Text Available Understanding which peptides and proteins have the potential to undergo amyloid formation and what driving forces are responsible for amyloid-like fiber formation and stabilization remains limited. This is mainly because proteins that can undergo structural changes, which lead to amyloid formation, are quite diverse and share no obvious sequence or structural homology, despite the structural similarity found in the fibrils. To address these issues, a novel approach based on recursive feature selection and feed-forward neural networks was undertaken to identify key features highly correlated with the self-assembly problem. This approach allowed the identification of seven physicochemical and biochemical properties of the amino acids highly associated with the self-assembly of peptides and proteins into amyloid-like fibrils (normalized frequency of β-sheet, normalized frequency of β-sheet from LG, weights for β-sheet at the window position of 1, isoelectric point, atom-based hydrophobic moment, helix termination parameter at position j+1 and ΔG° values for peptides extrapolated in 0 M urea. Moreover, these features enabled the development of a new predictor (available at http://cran.r-project.org/web/packages/appnn/index.html capable of accurately and reliably predicting the amyloidogenic propensity from the polypeptide sequence alone with a prediction accuracy of 84.9 % against an external validation dataset of sequences with experimental in vitro, evidence of amyloid formation.

  4. Lipid raft disruption protects mature neurons against amyloid oligomer toxicity.

    Science.gov (United States)

    Malchiodi-Albedi, Fiorella; Contrusciere, Valentina; Raggi, Carla; Fecchi, Katia; Rainaldi, Gabriella; Paradisi, Silvia; Matteucci, Andrea; Santini, Maria Teresa; Sargiacomo, Massimo; Frank, Claudio; Gaudiano, Maria Cristina; Diociaiuti, Marco

    2010-04-01

    A specific neuronal vulnerability to amyloid protein toxicity may account for brain susceptibility to protein misfolding diseases. To investigate this issue, we compared the effects induced by oligomers from salmon calcitonin (sCTOs), a neurotoxic amyloid protein, on cells of different histogenesis: mature and immature primary hippocampal neurons, primary astrocytes, MG63 osteoblasts and NIH-3T3 fibroblasts. In mature neurons, sCTOs increased apoptosis and induced neuritic and synaptic damages similar to those caused by amyloid beta oligomers. Immature neurons and the other cell types showed no cytotoxicity. sCTOs caused cytosolic Ca(2+) rise in mature, but not in immature neurons and the other cell types. Comparison of plasma membrane lipid composition showed that mature neurons had the highest content in lipid rafts, suggesting a key role for them in neuronal vulnerability to sCTOs. Consistently, depletion in gangliosides protected against sCTO toxicity. We hypothesize that the high content in lipid rafts makes mature neurons especially vulnerable to amyloid proteins, as compared to other cell types; this may help explain why the brain is a target organ for amyloid-related diseases.

  5. On the adsorption of magnetite nanoparticles on lysozyme amyloid fibrils.

    Science.gov (United States)

    Majorosova, Jozefina; Petrenko, Viktor I; Siposova, Katarina; Timko, Milan; Tomasovicova, Natalia; Garamus, Vasil M; Koralewski, Marceli; Avdeev, Mikhail V; Leszczynski, Błażej; Jurga, Stefan; Gazova, Zuzana; Hayryan, Shura; Hu, Chin-Kun; Kopcansky, Peter

    2016-10-01

    An adsorption of magnetic nanoparticles (MNP) from electrostatically stabilized aqueous ferrofluids on amyloid fibrils of hen egg white lysozyme (HEWL) in 2mg/mL acidic dispersions have been detected for the MNP concentration range of 0.01-0.1vol.%. The association of the MNP with amyloid fibrils has been characterized by transmission electron microscopy (TEM), small-angle X-ray scattering (SAXS) and magneto-optical measurements. It has been observed that the extent of adsorption is determined by the MNP concentration. When increasing the MNP concentration the formed aggregates of magnetic particles repeat the general rod-like structure of the fibrils. The effect is not observed when MNP are mixed with the solution of lysozyme monomers. The adsorption has been investigated with the aim to clarify previously found disaggregation activity of MNP in amyloid fibrils dispersions and to get deeper insight into interaction processes between amyloids and MNP. The observed effect is also discussed with respect to potential applications for ordering lysozyme amyloid fibrils in a liquid crystal phase under external magnetic fields.

  6. New Insights in the Amyloid-Beta Interaction with Mitochondria

    Directory of Open Access Journals (Sweden)

    Carlos Spuch

    2012-01-01

    Full Text Available 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 proteins are known to localize to mitochondrial membranes, block the transport of nuclear-encoded mitochondrial proteins to mitochondria, interact with mitochondrial proteins, disrupt the electron transport chain, increase reactive oxygen species production, cause mitochondrial damage, and prevent neurons from functioning normally. In this paper, we will outline current knowledge of the intracellular localization of amyloid-beta. Moreover, we summarize evidence from AD postmortem brain as well as animal AD models showing that amyloid-beta triggers mitochondrial dysfunction through a number of pathways such as impairment of oxidative phosphorylation, elevation of reactive oxygen species production, alteration of mitochondrial dynamics, and interaction with mitochondrial proteins. Thus, this paper supports the Alzheimer cascade mitochondrial hypothesis such as the most important early events in this disease, and probably one of the future strategies on the therapy of this neurodegenerative disease.

  7. Cerebral sinus venous thrombosis

    Directory of Open Access Journals (Sweden)

    Hernando Raphael Alvis-Miranda

    2013-01-01

    Full Text Available Cerebral sinus venous thrombosis (CSVT is a rare phenomenon that can be seen with some frequency in young patients. CSVT is a multifactorial condition with gender-related specific causes, with a wide clinical presentation, the leading causes differ between developed and developing countries, converting CSVT in a condition characterized by a highly variable clinical spectra, difficult diagnosis, variable etiologies and prognosis that requires fine medical skills and a high suspicious index. Patients who presents with CSVT should underwent to CT-scan venography (CVT and to the proper inquiry of the generating cause. This disease can affect the cerebral venous drainage and related anatomical structure. The symptoms may appear in relation to increased intracranial pressure imitating a pseudotumorcerebri. Prognosis depends on the early detection. Correcting the cause, generally the complications can be prevented. Mortality trends have diminished, and with the new technologies, surely it will continue. This work aims to review current knowledge about CSVT including its pathogenesis, etiology, clinical manifestations, diagnosis, and treatment.

  8. Cerebral imaging in pediatrics

    Energy Technology Data Exchange (ETDEWEB)

    Gordon, I. [London, Great Ormond Street Hospital for Children (United Kingdom)

    1998-06-01

    Radioisotope brain imaging has focused mainly on regional cerebral blood flow (rCBF). However the use of ligand which go to specific receptor sites is being introduced in pediatrics, mainly psychiatry. rCBF is potentially available in many institutions, especially with the availability of multi-headed gamma cameras. The use of this technique in pediatrics requires special attention to detail in the manner of data acquisition and handling the child. The interpretation of the rCBF study in a child requires knowledge of normal brain maturation. The major clinical use in pediatrics is epilepsy because of the advances in surgery and the frequency of complex partial seizures. Other indications in pediatric neurology include brain death, acute neurological loss including stroke, language disorders, cerebral palsy, hypertension due to renovascular disease, traumatic brain injury and migraine. There are pediatric physiological conditions in which rCBF has been undertaken, these include anorexia nervosa, autism, Gilles de la Tourette syndrome (GTS) and attention deficit disorder-hyperactivity (ADHD). Research using different ligands to specific receptor sites will also be reviewed in pediatrics.

  9. Cerebral cartography and connectomics.

    Science.gov (United States)

    Sporns, Olaf

    2015-05-19

    Cerebral cartography and connectomics pursue similar goals in attempting to create maps that can inform our understanding of the structural and functional organization of the cortex. Connectome maps explicitly aim at representing the brain as a complex network, a collection of nodes and their interconnecting edges. This article reflects on some of the challenges that currently arise in the intersection of cerebral cartography and connectomics. Principal challenges concern the temporal dynamics of functional brain connectivity, the definition of areal parcellations and their hierarchical organization into large-scale networks, the extension of whole-brain connectivity to cellular-scale networks, and the mapping of structure/function relations in empirical recordings and computational models. Successfully addressing these challenges will require extensions of methods and tools from network science to the mapping and analysis of human brain connectivity data. The emerging view that the brain is more than a collection of areas, but is fundamentally operating as a complex networked system, will continue to drive the creation of ever more detailed and multi-modal network maps as tools for on-going exploration and discovery in human connectomics.

  10. Cerebral sinus venous thrombosis

    Science.gov (United States)

    Alvis-Miranda, Hernando Raphael; Milena Castellar-Leones, Sandra; Alcala-Cerra, Gabriel; Rafael Moscote-Salazar, Luis

    2013-01-01

    Cerebral sinus venous thrombosis (CSVT) is a rare phenomenon that can be seen with some frequency in young patients. CSVT is a multifactorial condition with gender-related specific causes, with a wide clinical presentation, the leading causes differ between developed and developing countries, converting CSVT in a condition characterized by a highly variable clinical spectra, difficult diagnosis, variable etiologies and prognosis that requires fine medical skills and a high suspicious index. Patients who presents with CSVT should underwent to CT-scan venography (CVT) and to the proper inquiry of the generating cause. This disease can affect the cerebral venous drainage and related anatomical structure. The symptoms may appear in relation to increased intracranial pressure imitating a pseudotumorcerebri. Prognosis depends on the early detection. Correcting the cause, generally the complications can be prevented. Mortality trends have diminished, and with the new technologies, surely it will continue. This work aims to review current knowledge about CSVT including its pathogenesis, etiology, clinical manifestations, diagnosis, and treatment. PMID:24347950

  11. Gene expression analysis reveals early changes in several molecular pathways in cerebral malaria-susceptible mice versus cerebral malaria-resistant mice

    Directory of Open Access Journals (Sweden)

    Grau Georges E

    2007-12-01

    Full Text Available Abstract Background Microarray analyses allow the identification and assessment of molecular signatures in whole tissues undergoing pathological processes. To better understand cerebral malaria pathogenesis, we investigated intra-cerebral gene-expression profiles in well-defined genetically cerebral malaria-resistant (CM-R and CM-susceptible (CM-S mice, upon infection by Plasmodium berghei ANKA (PbA. We investigated mouse transcriptional responses at early and late stages of infection by use of cDNA microarrays. Results Through a rigorous statistical approach with multiple testing corrections, we showed that PbA significantly altered brain gene expression in CM-R (BALB/c, and in CM-S (CBA/J and C57BL/6 mice, and that 327 genes discriminated between early and late infection stages, between mouse strains, and between CM-R and CM-S mice. We further identified 104, 56, 84 genes with significant differential expression between CM-R and CM-S mice on days 2, 5, and 7 respectively. The analysis of their functional annotation indicates that genes involved in metabolic energy pathways, the inflammatory response, and the neuroprotection/neurotoxicity balance play a major role in cerebral malaria pathogenesis. In addition, our data suggest that cerebral malaria and Alzheimer's disease may share some common mechanisms of pathogenesis, as illustrated by the accumulation of β-amyloid proteins in brains of CM-S mice, but not of CM-R mice. Conclusion Our microarray analysis highlighted marked changes in several molecular pathways in CM-S compared to CM-R mice, particularly at early stages of infection. This study revealed some promising areas for exploration that may both provide new insight into the knowledge of CM pathogenesis and the development of novel therapeutic strategies.

  12. Modeling the Aggregation Propensity and Toxicity of Amyloid-β Variants

    DEFF Research Database (Denmark)

    Tiwari, Manish Kumar; Kepp, Kasper Planeta

    2015-01-01

    Protein aggregation is a hallmark of many neurodegenerative disorders. Alzheimer’s disease (AD) is directly linked to deposits of amyloid-β (Aβ) derived from the amyloid-β protein precursor (AβPP), and multiple experimental studies have investigated the aggregation behavior of these amyloids...

  13. 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

  14. Trifluoroethanol modulates α-synuclein amyloid-like aggregate formation, stability and dissolution

    DEFF Research Database (Denmark)

    Di Carlo, Maria Giovanna; Vetri, Valeria; Buscarino, Gianpiero

    2016-01-01

    The conversion of proteins into amyloid fibrils and other amyloid-like aggregates is closely connected to the onset of a series of age-related pathologies. Upon changes in environmental conditions, amyloid-like aggregates may also undergo disassembly into oligomeric aggregates, the latter being r...

  15. Whole body amyloid deposition imaging by 123I-SAP scintigraphy

    NARCIS (Netherlands)

    van Rheenen, Ronald; Glaudemans, Andor; Hazenberg, Bouke

    2011-01-01

    Amyloidosis is the name of a group of diseases characterized by extracellular deposition of amyloid fibrils. Deposition of amyloid can be localized or systemic. The 123I-SAP-scan can be used to image extent and distribution of amyloid deposition in patients with systemic AA, AL and ATTR amyloidosis.

  16. Analysis of amyloid fibrils in the cheetah (Acinonyx jubatus).

    Science.gov (United States)

    Bergström, Joakim; Ueda, Mitsuharu; Une, Yumi; Sun, Xuguo; Misumi, Shogo; Shoji, Shozo; Ando, Yukio

    2006-06-01

    Recently, a high prevalence of amyloid A (AA) amyloidosis has been documented among captive cheetahs worldwide. Biochemical analysis of amyloid fibrils extracted from the liver of a Japanese captive cheetah unequivocally showed that protein AA was the main fibril constituent. Further characterization of the AA fibril components by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot analysis revealed three main protein AA bands with approximate molecular weights of 8, 10 and 12 kDa. Mass spectrometry analysis of the 12-kDa component observed in SDS-PAGE and Western blotting confirmed the molecular weight of a 12,381-Da peak. Our finding of a 12-kDa protein AA component provides evidence that the cheetah SAA sequence is longer than the previously reported 90 amino acid residues (approximately 10 kDa), and hence SAA is part of the amyloid fibril.

  17. Alzheimer's disease: the amyloid hypothesis and the Inverse Warburg effect

    KAUST Repository

    Demetrius, Lloyd A.

    2015-01-14

    Epidemiological and biochemical studies show that the sporadic forms of Alzheimer\\'s disease (AD) are characterized by the following hallmarks: (a) An exponential increase with age; (b) Selective neuronal vulnerability; (c) Inverse cancer comorbidity. The present article appeals to these hallmarks to evaluate and contrast two competing models of AD: the amyloid hypothesis (a neuron-centric mechanism) and the Inverse Warburg hypothesis (a neuron-astrocytic mechanism). We show that these three hallmarks of AD conflict with the amyloid hypothesis, but are consistent with the Inverse Warburg hypothesis, a bioenergetic model which postulates that AD is the result of a cascade of three events—mitochondrial dysregulation, metabolic reprogramming (the Inverse Warburg effect), and natural selection. We also provide an explanation for the failures of the clinical trials based on amyloid immunization, and we propose a new class of therapeutic strategies consistent with the neuroenergetic selection model.

  18. Atomic-resolution structures of prion AGAAAAGA amyloid fibrils

    CERN Document Server

    Zhang, Jiapu

    2011-01-01

    To the best of the author's knowledge, there is little structural data available on the AGAAAAGA palindrome in the hydrophobic region (113-120) of prion proteins due to the unstable, noncrystalline and insoluble nature of the amyloid fibril, although many experimental studies have shown that this region has amyloid fibril forming properties and plays an important role in prion diseases. In view of this, the present study is devoted to address this problem from computational approaches such as local optimization steepest descent, conjugate gradient, discrete gradient and Newton methods, global optimization simulated annealing and genetic algorithms, canonical dual optimization theory, and structural bioinformatics. The optimal atomic-resolution structures of prion AGAAAAGA amyloid fibils reported in this Chapter have a value to the scientific community in its drive to find treatments for prion diseases or at least be useful for the goals of medicinal chemistry.

  19. Molecular dynamics simulations of amyloid fibrils: an in silico approach

    Institute of Scientific and Technical Information of China (English)

    Wei Ye; Wei Wang; Cheng Jiang; Qingfen Yu; Haifeng Chen

    2013-01-01

    Amyloid fibrils play causal roles in the pathogenesis of amyloid-related degenerative diseases such as Alzheimer's disease,type Ⅱ diabetes mellitus,and the prion-related transmissible spongiform encephalopathies.The mechanism of fibril formation and protein aggregation is still hotly debated and remains an important open question in order to develop therapeutic method of these diseases.However,traditional molecular biological and crystallographic experiments could hardly observe atomic details and aggregation process.Molecular dynamics (MD) simulations could provide explanations for experimental results and detailed pathway of protein aggregation.In this review,we focus on the applications of MD simulations on several amyloidogenic protein systems.Furthermore,MD simulations could help us to understand the mechanism of amyloid aggregation and how to design the inhibitors.

  20. Destroying activity of magnetoferritin on lysozyme amyloid fibrils

    Energy Technology Data Exchange (ETDEWEB)

    Kopcansky, Peter; Siposova, Katarina [Institute of Experimental Physics, SAS, Watsonova 47, 040 01 Kosice (Slovakia); Melnikova, Lucia, E-mail: melnikova@saske.sk [Institute of Experimental Physics, SAS, Watsonova 47, 040 01 Kosice (Slovakia); Bednarikova, Zuzana [Institute of Experimental Physics, SAS, Watsonova 47, 040 01 Kosice (Slovakia); Institute of Chemical Sciences, Faculty of Sciences, Safarik University, Kosice (Slovakia); Timko, Milan; Mitroova, Zuzana; Antosova, Andrea [Institute of Experimental Physics, SAS, Watsonova 47, 040 01 Kosice (Slovakia); Garamus, Vasil M. [Helmholtz-Zentrum Geesthacht: Centre for Materials and Coastal Research, Max-Planck-Street 1, 21502 Geesthacht (Germany); Petrenko, Viktor I. [Joint Institute for Nuclear Research, Joliot-Curie 6, Dubna, 141980 Moscow Region (Russian Federation); Kyiv Taras Shevchenko National University, Volodymyrska Street 64, Kyiv 01033 (Ukraine); Avdeev, Mikhail V. [Joint Institute for Nuclear Research, Joliot-Curie 6, Dubna, 141980 Moscow Region (Russian Federation); Gazova, Zuzana [Institute of Experimental Physics, SAS, Watsonova 47, 040 01 Kosice (Slovakia); Department of Medical and Clinical Biochemistry and LABMED, Tr. SNP 1, 040 11 Kosice (Slovakia)

    2015-03-01

    Presence of protein amyloid aggregates (oligomers, protofilaments, fibrils) is associated with many diseases as diabetes mellitus or Alzheimer's disease. The interaction between lysozyme amyloid fibrils and magnetoferritin loaded with different amount of iron atoms (168 or 532 atoms) has been investigated by small-angle X-rays scattering and thioflavin T fluorescence measurements. Results suggest that magnetoferritin caused an iron atom-concentration dependent reduction of lysozyme fibril size. - Highlights: • The interaction between lysozyme amyloid fibrils and magnetoferritin loaded with different amount of iron atoms (168 or 532 atoms) has been investigated by small-angle X-rays scattering and thioflavin T fluorescence measurements. • Results suggest that magnetoferritin caused an iron atom-concentration dependent reduction of lysozyme fibril size.

  1. Cerebrovascular hemodynamics in patients with cerebral arteriosclerosis

    Institute of Scientific and Technical Information of China (English)

    Jianbo Yang; Changcong Cui; Chengbin Wu

    2011-01-01

    The present study observed hemodynamic changes in 26 patients with cerebral arteriosclerosis using a cerebral circulation dynamics detector and transcranial Doppler.In patients with cerebral arteriosclerosis the blood supply and flow rate in the bilateral carotid arteries and the blood flow rate in the anterior cerebral and middle cerebral arteries were similar to normal controls, but the cerebral vascular resistance, critical pressure and pulsatility index were increased, and cerebral arterial elasticity and cerebral blood flow autoregulation were decreased.Compared with the lesioned hemisphere of patients with cerebral infarction, the total blood supply and blood flow rate of patients with cerebral arteriosclerosis were higher.Compared with normal subjects, patients with cerebral arteriosclerosis exhibited cognitive disturbances, mainly in short-term memory, attention, abstract capability, and spatial and executive dysfunction.Results showed that cerebral arteriosclerosis does not directly affect the blood supply of a cerebral hemisphere, but affects cognitive function.The increased cerebral vascular resistance and reduced autoregulation of cerebral blood vessels may be important hemodynamic mechanisms of arteriosclerosis-induced cerebral infarction.

  2. Gene expression profile of amyloid beta protein-injected mouse model for Alzheimer disease

    Institute of Scientific and Technical Information of China (English)

    Ling-na KONG; Ping-ping ZUO; Liang MU; Yan-yong LIU; Nan YANG

    2005-01-01

    Aim: To investigate the gene expression profile changes in the cerebral cortex of mice injected icv with amyloid beta-protein (Aβ) fragment 25-35 using cDNA microarray. Methods: Balb/c mice were randomly divided into a control group and Aβ-treated group. The Morris water maze test was performed to detect the effect of Aβ-injection on the learning and memory of mice. Atlas Mouse 1.2 Expression Arrays containing 1176 genes were used to investigate the gene expression pattern of each group. Results: The gene expression profiles showed that 19 genes including TBX1, NF-κB, AP-1/c-Jun, cadherin, integrin, erb-B2, and FGFR1 were up-regulated after 2 weeks oficv administration of Aβ; while 12 genes were downregulated, including NGF, glucose phosphate isomerase 1, AT motif binding factor 1, Na+/K+-ATPase, and Akt. Conclusions: The results provide important leads for pursuing a more complete understanding of the molecular events of Aβ-injection into mice with Alzheimer disease.

  3. Dynamic changes in PET amyloid and FDG imaging at different stages of Alzheimer's disease.

    Science.gov (United States)

    Kadir, Ahmadul; Almkvist, Ove; Forsberg, Anton; Wall, Anders; Engler, Henry; Långström, Bengt; Nordberg, Agneta

    2012-01-01

    In this study 5 patients with mild cognitive impairment (MCI) and 9 Alzheimer's disease (AD) patients underwent respectively 3- and 5-year follow-up positron emission tomography (PET) studies with N-methyl [(11)C] 2-(4-methylaminophenyl)-6-hydroxy-benzothiazole ((11)C-PIB) and (18)F-fluorodeoxyglucose ((18)F-FDG) to understand the time courses in AD disease processes. Significant increase in PIB retention as well as decrease in regional cerebral metabolic rate of glucose (rCMRglc) was observed at group level in the MCI patients while no significant change was observed in cognitive function. At group level the AD patients showed unchanged high PIB retention at 5-year follow-up compared with baseline. At the individual level, increased, stable, and decreased PIB retention were observed while disease progression was reflected in significant decrease in rCMRglc and cognition. In conclusion, after a long-term follow-up with PET, we observed an increase in fibrillar amyloid load in MCI patients followed by more stable level in clinical AD patients. The rCMRglc starts to decline in MCI patients and became more pronounced in clinical stage which related to continuous decline in cognition.

  4. ANTIAMNESIC POTENTIAL OF SOLASODINE AGAINST β-AMYLOID PROTEIN INDUCED AMNESIA IN MICE

    Directory of Open Access Journals (Sweden)

    Desai Alpesh B

    2011-05-01

    Full Text Available Alzheimer’s disease (AD, the most common form of dementia in the elderly population, is characterized by an insidious onset with memory impairment and an inexorable progression of cognitive decline. Nootropic agents are a heterogeneous groups of drugs developed for use in dementia and other cerebral disorders. Nootropics agents are being primarily used to improve memory, mood and behavior. However, the resulting adverse effects associated with these agents have limited their use. Therefore, it is worthwhile to explore the utility of traditional medicines for the treatment of various cognitive disorders. The present study was undertaken to assess the potential of solasodine on β-amyloid induced amnesia in mice. Elevated plus maze (EPM and Morris water maze (MWM was employed to evaluate learning and memory parameters. Piracetam was used as the standard drug. Solasodine (1, 2 and 4 mg/kg, p.o. was screened for claimed potential in mice. Solasodine improved both short term memory and long term memory when assessed on Elevated pluz maze and Morris Water maze respectively. Hence, solasodine might prove to be a useful memory restorative agent in the treatment of dementia seen in the Alzheimer’s disease.

  5. Atomic Resolution Structure of Monomorphic Aβ42 Amyloid Fibrils.

    Science.gov (United States)

    Colvin, Michael T; Silvers, Robert; Ni, Qing Zhe; Can, Thach V; Sergeyev, Ivan; Rosay, Melanie; Donovan, Kevin J; Michael, Brian; Wall, Joseph; Linse, Sara; Griffin, Robert G

    2016-08-03

    Amyloid-β (Aβ) is a 39-42 residue protein produced by the cleavage of the amyloid precursor protein (APP), which subsequently aggregates to form cross-β amyloid fibrils that are a hallmark of Alzheimer's disease (AD). The most prominent forms of Aβ are Aβ1-40 and Aβ1-42, which differ by two amino acids (I and A) at the C-terminus. However, Aβ42 is more neurotoxic and essential to the etiology of AD. Here, we present an atomic resolution structure of a monomorphic form of AβM01-42 amyloid fibrils derived from over 500 (13)C-(13)C, (13)C-(15)N distance and backbone angle structural constraints obtained from high field magic angle spinning NMR spectra. The structure (PDB ID: 5KK3 ) shows that the fibril core consists of a dimer of Aβ42 molecules, each containing four β-strands in a S-shaped amyloid fold, and arranged in a manner that generates two hydrophobic cores that are capped at the end of the chain by a salt bridge. The outer surface of the monomers presents hydrophilic side chains to the solvent. The interface between the monomers of the dimer shows clear contacts between M35 of one molecule and L17 and Q15 of the second. Intermolecular (13)C-(15)N constraints demonstrate that the amyloid fibrils are parallel in register. The RMSD of the backbone structure (Q15-A42) is 0.71 ± 0.12 Å and of all heavy atoms is 1.07 ± 0.08 Å. The structure provides a point of departure for the design of drugs that bind to the fibril surface and therefore interfere with secondary nucleation and for other therapeutic approaches to mitigate Aβ42 aggregation.

  6. BETASCAN: probable beta-amyloids identified by pairwise probabilistic analysis.

    Directory of Open Access Journals (Sweden)

    Allen W Bryan

    2009-03-01

    Full Text Available Amyloids and prion proteins are clinically and biologically important beta-structures, whose supersecondary structures are difficult to determine by standard experimental or computational means. In addition, significant conformational heterogeneity is known or suspected to exist in many amyloid fibrils. Recent work has indicated the utility of pairwise probabilistic statistics in beta-structure prediction. We develop here a new strategy for beta-structure prediction, emphasizing the determination of beta-strands and pairs of beta-strands as fundamental units of beta-structure. Our program, BETASCAN, calculates likelihood scores for potential beta-strands and strand-pairs based on correlations observed in parallel beta-sheets. The program then determines the strands and pairs with the greatest local likelihood for all of the sequence's potential beta-structures. BETASCAN suggests multiple alternate folding patterns and assigns relative a priori probabilities based solely on amino acid sequence, probability tables, and pre-chosen parameters. The algorithm compares favorably with the results of previous algorithms (BETAPRO, PASTA, SALSA, TANGO, and Zyggregator in beta-structure prediction and amyloid propensity prediction. Accurate prediction is demonstrated for experimentally determined amyloid beta-structures, for a set of known beta-aggregates, and for the parallel beta-strands of beta-helices, amyloid-like globular proteins. BETASCAN is able both to detect beta-strands with higher sensitivity and to detect the edges of beta-strands in a richly beta-like sequence. For two proteins (Abeta and Het-s, there exist multiple sets of experimental data implying contradictory structures; BETASCAN is able to detect each competing structure as a potential structure variant. The ability to correlate multiple alternate beta-structures to experiment opens the possibility of computational investigation of prion strains and structural heterogeneity of amyloid

  7. [Carpal tunnel syndrome, amyloid tenosynovitis and periodic hemodialysis].

    Science.gov (United States)

    Clanet, M; Mansat, M; Durroux, R; Testut, M F; Guiraud, B; Rascol, A; Conte, J

    1981-01-01

    Since 1975, various entrapment neuropathies have been reported in patients undergoing periodic haemodialysis, the most frequent being the carpal tunnel syndrome. Ten patients on chronic haemodialysis developing 15 carpal tunnel syndromes (5 unilateral and 5 bilateral) are reported. Various causes for the renal failure were present and clinical signs of the carpal tunnel syndrome developed at a late stage. The arteriovenous fistula required for extrarenal epuration was antebrachial and of the laterolateral type, except in one case when it was lateroterminal. The carpal tunnel syndrome was always on the same side as the fistula, developing at a later stage on th contralateral side in the 5 cases of bilateral disorders. Lesions were severe, in 11 of the 15 cases. Some patients noted fluctuations in pain symptoms during haemodialysis, either improving or becoming worse. Gross pathological findings during operation (13 cases) were tenosynovitis with epineural hypervascularisation on the opposite side. In 9 cases, however, atypical hypertrophic tenosynovitis was observed. Histological examination in 12 cases demonstrated typical tenosynovitis in 3 patients, but granulomatous tenosynovitis with amyloid deposits was reported in 9 patients. Lesions were bilateral in 2 cases thus present, on the side opposite to the fistula. Ultrastructural study confirmed the amyloid nature of the deposits in 3 cases, the microfibrillary appearance (80 to 100 A) being characteristic of amyloid substance. This rare complication does not represent a common carpal tunnel syndrome, and three mechanisms may be involved in its induction : peripheral uraemic neuropathy, haemodynamic modifications resulting from the antebrachial arteriovenous shunt, and amyloid formation in the flexor synovial sheaths. In the latter case, the type of amyloid disease may be a primary systemic amyloidosis not previously detected, or an elective amyloid process localised to the tenosynovial and periarticular tissues.

  8. Quantitative amyloid imaging using image-derived arterial input function.

    Directory of Open Access Journals (Sweden)

    Yi Su

    Full Text Available Amyloid PET imaging is an indispensable tool widely used in the investigation, diagnosis and monitoring of Alzheimer's disease (AD. Currently, a reference region based approach is used as the mainstream quantification technique for amyloid imaging. This approach assumes the reference region is amyloid free and has the same tracer influx and washout kinetics as the regions of interest. However, this assumption may not always be valid. The goal of this work is to evaluate an amyloid imaging quantification technique that uses arterial region of interest as the reference to avoid potential bias caused by specific binding in the reference region. 21 participants, age 58 and up, underwent Pittsburgh compound B (PiB PET imaging and MR imaging including a time-of-flight (TOF MR angiography (MRA scan and a structural scan. FreeSurfer based regional analysis was performed to quantify PiB PET data. Arterial input function was estimated based on coregistered TOF MRA using a modeling based technique. Regional distribution volume (VT was calculated using Logan graphical analysis with estimated arterial input function. Kinetic modeling was also performed using the estimated arterial input function as a way to evaluate PiB binding (DVRkinetic without a reference region. As a comparison, Logan graphical analysis was also performed with cerebellar cortex as reference to obtain DVRREF. Excellent agreement was observed between the two distribution volume ratio measurements (r>0.89, ICC>0.80. The estimated cerebellum VT was in line with literature reported values and the variability of cerebellum VT in the control group was comparable to reported variability using arterial sampling data. This study suggests that image-based arterial input function is a viable approach to quantify amyloid imaging data, without the need of arterial sampling or a reference region. This technique can be a valuable tool for amyloid imaging, particularly in population where reference

  9. Quantitative amyloid imaging using image-derived arterial input function.

    Science.gov (United States)

    Su, Yi; Blazey, Tyler M; Snyder, Abraham Z; Raichle, Marcus E; Hornbeck, Russ C; Aldea, Patricia; Morris, John C; Benzinger, Tammie L S

    2015-01-01

    Amyloid PET imaging is an indispensable tool widely used in the investigation, diagnosis and monitoring of Alzheimer's disease (AD). Currently, a reference region based approach is used as the mainstream quantification technique for amyloid imaging. This approach assumes the reference region is amyloid free and has the same tracer influx and washout kinetics as the regions of interest. However, this assumption may not always be valid. The goal of this work is to evaluate an amyloid imaging quantification technique that uses arterial region of interest as the reference to avoid potential bias caused by specific binding in the reference region. 21 participants, age 58 and up, underwent Pittsburgh compound B (PiB) PET imaging and MR imaging including a time-of-flight (TOF) MR angiography (MRA) scan and a structural scan. FreeSurfer based regional analysis was performed to quantify PiB PET data. Arterial input function was estimated based on coregistered TOF MRA using a modeling based technique. Regional distribution volume (VT) was calculated using Logan graphical analysis with estimated arterial input function. Kinetic modeling was also performed using the estimated arterial input function as a way to evaluate PiB binding (DVRkinetic) without a reference region. As a comparison, Logan graphical analysis was also performed with cerebellar cortex as reference to obtain DVRREF. Excellent agreement was observed between the two distribution volume ratio measurements (r>0.89, ICC>0.80). The estimated cerebellum VT was in line with literature reported values and the variability of cerebellum VT in the control group was comparable to reported variability using arterial sampling data. This study suggests that image-based arterial input function is a viable approach to quantify amyloid imaging data, without the need of arterial sampling or a reference region. This technique can be a valuable tool for amyloid imaging, particularly in population where reference normalization may

  10. CEREBRAL PALSY AND MUSIC ACHIEVEMENT

    Directory of Open Access Journals (Sweden)

    Miodrag L. STOSHLJEVIKJ

    2008-12-01

    Full Text Available Pupils with cerebral palsy attend elementary education accordind to a regular and special teaching plan and program. Regular school curriculum was reformed in 1992, while special plan and program has not been changed and adapted according to pupil’s needs and capacities. Music is one of the best means of expressing oneself and plays a very important role in the development of every child, the child with cerebral palsy in particular.In order to test the possibility of pupils with cerebral palsy, with and without mental retardation, to apprehend the actual program content, we have conducted research on musical achievement of children with cerebral palsy. During 2007 a research was carried out, on the sample of 27 pupils with cerebral palsy and mild mental retardation who attended classes in the school “Miodrag Matikj”, and a sample of16 students with cerebral palsy without mental retardation who attended the school “Dr. Dragan Hercog” in Belgrade.Results of the research, as well as analysis of music curriculum content, indicated that the capacities of students with cerebral palsy to carry out the curriculum tasks require special approach and methodology. Therefore, we introduced some proposals to overcome the difficulties in fulfilling music curriculum demands of those pupils. We made special emphasis on the use of computer based Assistive technology which facilitates the whole process to a large extent.

  11. CEREBRAL PALSY : ANTENATAL RISK FACTORS

    Directory of Open Access Journals (Sweden)

    Srinivasa Rao

    2015-05-01

    Full Text Available INTRODUCTION: Cerebral palsy (CP is a group of permanent movement disorders that appear in early childhood. Cerebral palsy is caused by abnormal development or damage to the parts of the brain that control movement, balance, and posture. Most often the problems occur during pregnancy; however, they may also occur during childbirth, or shortly after birth. Often the cause is unknown. AIM: To study the different antenatal maternal risk factors associated with cerebral palsy in the study group. MATERIA LS AND METHODS: Retrospective study was done to assess possible associated antenatal risk factors for cerebral palsy. Mothers of 100 cerebral palsy children were selected who are treated in Rani Chandramani Devi Hospital, a Government hospital in Visakhapa tn am, Andhra Pradesh State, India , from 2012 to 2014 and 100 controls, mothers of normal children were studied. Detailed antenatal history was obtained from the mothers of the children in both affected and control group. RESULTS: From the data, we conclude that the association of maternal anaemia with cerebral palsy is 7.3 times higher; association of maternal hypertension with cerebral palsy is 6.6 time higher, association with Pre - eclampsia is 6 times higher; association with Eclampsia is 8.6 times higher ; with antepartum haemorrhage, the association is 8.6 times higher and association of multiple pregnancy with cerebral palsy is 4.8 times higher than with controls. CONCLUSION: From this study of the role of antenatal risk factors, in the occurrence of cer ebral palsy in children it is concluded that the most common risk factor associated with cerebral palsy is the maternal anaemia and the other important risk factors associated being hypertension, pre eclampsia, eclampsia, antepartum haemorrhage and multipl e births.

  12. Biotechnologically engineered protein binders for applications in amyloid diseases.

    Science.gov (United States)

    Haupt, Christian; Fändrich, Marcus

    2014-10-01

    The aberrant self-assembly of polypeptide chains into amyloid structures is a common phenomenon in several neurodegenerative diseases, systemic amyloidosis, and 'normal' aging. Improvements in laboratory-scale detection of these structures, their clinical diagnosis, and the treatment of disease likely depend on the advent of new molecules that recognize particular states or induce their clearance in vivo. This review will describe what biotechnology can do to generate proteinaceous amyloid-binders, explain their molecular recognition mechanisms, and summarize possibilities to functionalize further these ligands for specific applications.

  13. Native human serum amyloid P component is a single pentamer

    DEFF Research Database (Denmark)

    Sørensen, Inge Juul; Andersen, Ove; Nielsen, EH;

    1995-01-01

    Serum amyloid P component (SAP) and C-reactive protein (CRP) are members of the pentraxin protein family. SAP is the precursor protein to amyloid P component present in all forms of amyloidosis. The prevailing notion is that SAP in circulation has the form of a double pentameric molecule (decamer...... by rocket immunoelectrophoresis and electron microscopy. Thus, electron micrographs of purified SAP showed a predominance of decamers. However, the decamer form of SAP reversed to single pentamers when purified SAP was incorporated into SAP-depleted serum....

  14. [Salmon-pink colored conjunctival tumor with amyloid deposits].

    Science.gov (United States)

    Müller, P L; Loeffler, K U; Holz, F G; Fischer, H-P; Herwig, M C

    2016-07-01

    An 82-year-old male patient presented with a salmon-pink colored conjunctival tumor of the left eye. A circumscribed, dense and whitish portion was detected by clinical examination. The histophological and immunhistochemical examination of the biopsy tissue revealed a CD20+ marginal zone lymphoma of the conjunctiva with amyloid deposits. Extranodal marginal zone lymphoma at this site is the most common lymphoma of the ocular adnexa and accounts for 5-10% of malignant diseases. An association with amyloid production is very rare and according to the current state of knowledge has no known impact on the outcome.

  15. Rust on the Brain from Microbleeds and Its Relevance to Alzheimer Studies: Invited Commentary on Cacciottolo Neurobiology of Aging, 2016

    Science.gov (United States)

    Cacciottolo, M; Morgan, TE; Finch, CE

    2016-01-01

    Cerebral microbleeds (MB) and small vessel disease (SVD) with congophilic arterial angiopathy (CAA) are increasingly recognized as a variable factor in AD cognitive impairments. This commentary on our recent report on sex-ApoE interactions in MBs published this February, briefly explores three aspects of MBs that could not be fully discussed therein: I, A possible gap between the prevalence of MBs as detected by MRI and post mortem analysis; II, The role of hemoglobin-degradation products in amyloid-attributed neurodegenerative changes; and III, Possible assessment of MB by cerebrospinal fluid (CSF) assays for iron-related markers to better screen patient subgroups for AD interventions. PMID:28042517

  16. Lobar microbleeds are associated with decline in executive functioning in older adults

    Science.gov (United States)

    Meier, Irene B.; Gu, Yian; Guzman, Vanessa A.; Wiegman, Anne F.; Schupf, Nicole; Manly, Jennifer J.; Luchsinger, José A.; Viswanathan, Anand; Martinez-Ramirez, Sergi; Greenberg, Steven M.; Mayeux, Richard; Brickman, Adam M.

    2014-01-01

    Background Normal aging is associated with decline in cognitive abilities, particularly in the domains of psychomotor speed and executive functioning. However, “aging,” per se, is not a cause of cognitive decline but rather a variable that likely captures multiple accumulating biological changes over time that collectively affect mental abilities. Recent work has focused on the role of cerebrovascular disease as one of the biological changes. In the current study, we examined whether lobar microbleeds, magnetic resonance imaging (MRI) signal voids due to hemosiderin deposits secondary to cerebral amyloid angiopathy, are associated with cognitive decline in normal aging. Previous studies that reported a relationship between the presence of lobar microbleeds and decreased cognitive abilities have been primarily cross-sectional. Here, we used a retrospective longitudinal design to examine whether the presence of lobar microbleeds is associated with the rate of cognitive decline among non-demented older adults. Methods Participants came from an ongoing longitudinal community-based aging study, in which subjects are evaluated at 18-24 month intervals and received a full medical, neurological, and neuropsychological examination at each of the follow-up visits. Gradient echo MRI scans were available on 197 non-demented participants (mean age: 84.15+/-5.02 years). Microbleeds were rated visually on horizontal view and divided into subcortical (basal ganglia, cerebellum) and lobar (frontal, temporal, parietal, occipital lobe) regions, and confirmed with coronal and sagittal view to exclude artifacts. Cognition was assessed with a neuropsychological battery, providing summary scores for memory, language, executive, and visuospatial abilities calculated through exploratory and confirmatory factor analyses. Using general estimating equations (GEE), we compared cognition cross-sectionally between individuals with 2 or more (n=11) and fewer than 2 (n=186) lobar microbleeds

  17. Longitudinal Assessment of Amyloid Pathology in Transgenic ArcAβ Mice Using Multi-Parametric Magnetic Resonance Imaging.

    Directory of Open Access Journals (Sweden)

    Jan Klohs

    Full Text Available Magnetic resonance imaging (MRI can be used to monitor pathological changes in Alzheimer's disease (AD. The objective of this longitudinal study was to assess the effects of progressive amyloid-related pathology on multiple MRI parameters in transgenic arcAβ mice, a mouse model of cerebral amyloidosis. Diffusion-weighted imaging (DWI, T1-mapping and quantitative susceptibility mapping (QSM, a novel MRI based technique, were applied to monitor structural alterations and changes in tissue composition imposed by the pathology over time. Vascular function and integrity was studied by assessing blood-brain barrier integrity with dynamic contrast-enhanced MRI and cerebral microbleed (CMB load with susceptibility weighted imaging and QSM. A linear mixed effects model was built for each MRI parameter to incorporate effects within and between groups (i.e. genotype and to account for changes unrelated to the disease pathology. Linear mixed effects modelling revealed a strong association of all investigated MRI parameters with age. DWI and QSM in addition revealed differences between arcAβ and wt mice over time. CMBs became apparent in arcAβ mice with 9 month of age; and the CMB load reflected disease stage. This study demonstrates the benefits of linear mixed effects modelling of longitudinal imaging data. Moreover, the diagnostic utility of QSM and assessment of CMB load should be exploited further in studies of AD.

  18. Cerebral toxoplasmosis in AIDS

    Energy Technology Data Exchange (ETDEWEB)

    Christ, F.; Steudel, H.; Klotz, D.

    1986-02-01

    Since 1982 (Hauser and co-workers), literature has reported focal cerebral tissue charges in AIDS patients whose diagnosis was unclear at first but which could be identified finally as florid toxoplasmosis encephalitis by biopsy and autopsy. It was found that the value of otherwise reliable serological tests (KBR, Sabin-Feldmann tests, etc.) is questionable in patients with severely impaired or incompetent immune systems, and, in particular, that a negative or uncharacteristic test result may not preclude any opportunistic infection process. Furthermore, isolation of Toxoplasma gondii or specific antibodies from the cerebrospinal fluid will be successful in exceptional cases only. In patients with AIDS or lymphadenopathy syndrome, the differential diagnosis will have to include - first and foremost - reactivated toxoplasma infection (not newly acquired, as a rule) if central neurological symptoms occur.

  19. Changes of Cerebral

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective: To explore the strengthening of acupuncture analgesic mechanism on the level of β-endorphin and proopimelanocortin mRNA expression in the arcuate nucleus of hypothalamus in rats following electroacupuncture(EA) combined with melatonin (MEL). Methods: Integrated optical density (IOD) was measured by ABC immuno-histochemical and in situ hybridization technique with computerized image processing. The rat's brain was coronally sectioned after combination of EA and MEL. Results: IOD of β-endorphin-like immunopositive substance in rat's brain was lowered significantly, which was measured after MEL (60 mg/kg) was injected intraperitoneally and followed by EA 30 min later for 30 min, and the IOD of cerebral POMC mRNA positive substance increased significantly 10 hrs later. Conclusion:The mechanism of MEL in enhancing EA analgesic effect might be related with the release and synthesis of β-endorphin

  20. Cerebral Arterial Fenestrations

    Science.gov (United States)

    Cooke, Daniel L; Stout, Charles E; Kim, Warren T; Kansagra, Akash P; Yu, John Paul; Gu, Amy; Jewell, Nicholas P; Hetts, Steven W; Higashida, Randall T; Dowd, Christopher F; Halbach, Van V

    2014-01-01

    Summary Arterial fenestrations are an anatomic variant with indeterminate significance. Given the controversy surrounding fenestrations we sought their prevalence within our practice along with their association with other cerebrovascular anomalies. We retrospectively reviewed 10,927 patients undergoing digital subtraction angiography between 1992 and 2011. Dictated reports were searched for the terms “fenestration” or “fenestrated” with images reviewed for relevance, yielding 228 unique cases. A Medline database search from February 1964 to January 2013 generated 304 citations, 127 cases of which were selected for analysis. Cerebral arterial fenestrations were identified in 228 patients (2.1%). At least one aneurysm was noted in 60.5% of patients, with an aneurysm arising from the fenestration in 19.6% of patients. Aneurysmal subarachnoid hemorrhage or non-aneurysmal subarachnoid hemorrhage were present in 60.1% and 15.8%, respectively. For the subset of patients with an aneurysm arising directly from a fenestration relative to those patients with an aneurysm not immediately associated with a fenestration, the prevalence of aneurysmal subarachnoid hemorrhage was 66.7% vs. 58.6% (p = 0.58). Fenestrations were more often within the posterior circulation (73.2%) than the anterior circulation (24.6%), though there was no difference in the prevalence of aneurysms within these groups (61.1% vs. 60.7%, p = 1.0). Cerebral arterial fenestrations are an anatomic variant more often manifesting at the anterior communicating arterial complex and basilar artery and with no definite pathological relationship with aneurysms. PMID:24976087

  1. The formation of bioactive amyloid species by prion proteins in vitro and in cells.

    Science.gov (United States)

    Liu, Yuanbin; Ritter, Christiane; Riek, Roland; Schubert, David

    2006-10-09

    Amyloid proteins are a group of proteins that can polymerize into cross beta-sheeted amyloid species. We have found that enhancing cellular 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) formazan exocytosis is a common property of bioactive amyloid species formed from all of the amyloid proteins tested to date. In this report, we show that the infectious amyloid species of the prion protein HET-s of the filamentous fungus Podospora anserina, like other amyloidogenic proteins, also enhances MTT formazan exocytosis. More strikingly, cellular MTT formazan exocytosis revealed the formation of bioactive amyloid species in prion-infected mouse N2a neuroblastoma cells. These findings suggest that cellular MTT formazan exocytosis can be useful for studying the roles of bioactive amyloid species in prion infectivity and prion-induced neurodegeneration.

  2. Anestesia e paralisia cerebral Anestesia y parálisis cerebral Anesthesia and cerebral palsy

    OpenAIRE

    Március Vinícius M Maranhão

    2005-01-01

    JUSTIFICATIVA E OBJETIVOS: A paralisia cerebral (PC) é uma doença não progressiva decorrente de lesão no sistema nervoso central, levando a um comprometimento motor do paciente. O portador de PC freqüentemente é submetido a procedimentos cirúrgicos devido a doenças usuais e situações particulares decorrentes da paralisia cerebral. Foi objetivo deste artigo revisar aspectos da paralisia cerebral de interesse para o anestesiologista, permitindo um adequado manuseio pré, intra e pós-operatório n...

  3. Neuromodulation of cerebral blood flow

    NARCIS (Netherlands)

    ter Laan, Mark

    2014-01-01

    Dit proefschrift behandelt de modulatie van de cerebrale doorbloeding (cerebral blood flow, CBF) door cervicale elektrische stimulatie en de aanname dat het sympathisch zenuwstelsel hierin een specifieke rol speelt. Enkele resultaten met cervicale ruggenmergsstimulatie (spinal cord stimulation, SCS)

  4. Learn More About Cerebral Palsy

    Centers for Disease Control (CDC) Podcasts

    2008-03-30

    This podcast describes the causes, preventions, types, and signs and symptoms of cerebral palsy.  Created: 3/30/2008 by National Center on Birth Defects and Developmental Disabilities.   Date Released: 3/21/2008.

  5. Cerebral Laterality and Verbal Processes

    Science.gov (United States)

    Sherman, Jay L.; And Others

    1976-01-01

    Research suggests that we process information by way of two distinct and functionally separate coding systems. Their location, somewhat dependent on cerebral laterality, varies in right- and left-handed persons. Tests this dual coding model. (Editor/RK)

  6. Cerebral candidiasis. Computed tomography appearance

    Energy Technology Data Exchange (ETDEWEB)

    Chaabane, M.; Ladeb, M.F.; Bouhaouala, M.H.; Ben Hammouda, M.; Ataalah, R.; Gannouni, A.; Krifa, H.

    1989-07-01

    A three year old child who had been suffering from oral candidiasis since the age of 1 year presented with osteitis of the clavicle, 2 cerebral frontal abscesses and an occipital abscess which extended across the calvaria and was associated with osteolysis. Histological and microbiological studies following surgery confirmed the diagnosis of candidiasis in this girl who was found to have IgA immunodefinciency. The authors report the computed tomographic appearance of the cerebral lesions and review the literature. (orig.).

  7. Parálisis cerebral :

    OpenAIRE

    Giral Lamenca, Mónica

    2015-01-01

    Se aborda el tema de la parálisis cerebral definiendo qué es, clasificando los tipos de parálisis dependiendo de la afectación y las características principales. Se explican algunos de sus tratamientos, se dan sistemas alternativos y/o aumentativos de comunicación para un alumno con PC (parálisis cerebral).

  8. Multiple isoforms of the human pentraxin serum amyloid P component

    DEFF Research Database (Denmark)

    Sørensen, Inge Juul; Andersen, Ove; Nielsen, EH;

    1995-01-01

    Human serum amyloid P component (SAP) isolated from 20 healthy individuals was analyzed by anion exchange chromatography and isoelectric focusing (IEF) in order to investigate the existence of multiple forms of SAP and interindividual structural differences. Anion exchange chromatography showed one...

  9. Peptide concentration alters intermediate species in amyloid β fibrillation kinetics

    Energy Technology Data Exchange (ETDEWEB)

    Garvey, M., E-mail: megan.garvey@molbiotech.rwth-aachen.de [Max-Planck Research Unit for Enzymology of Protein Folding, Weinbergweg 22, 06120 Halle (Saale) (Germany); Morgado, I., E-mail: immorgado@ualg.pt [Max-Planck Research Unit for Enzymology of Protein Folding, Weinbergweg 22, 06120 Halle (Saale) (Germany)

    2013-04-12

    Highlights: ► Aβ(1–40) aggregation in vitro has been monitored at different concentrations. ► Aβ(1–40) fibrillation does not always follow conventional kinetic mechanisms. ► We demonstrate non-linear features in the kinetics of Aβ(1–40) fibril formation. ► At high Aβ(1–40) concentrations secondary processes dictate fibrillation speed. ► Intermediate species may play significant roles on final amyloid fibril development. -- Abstract: The kinetic mechanism of amyloid aggregation remains to be fully understood. Investigations into the species present in the different kinetic phases can assist our comprehension of amyloid diseases and further our understanding of the mechanism behind amyloid β (Aβ) (1–40) peptide aggregation. Thioflavin T (ThT) fluorescence and transmission electron microscopy (TEM) have been used in combination to monitor Aβ(1–40) aggregation in vitro at both normal and higher than standard concentrations. The observed fibrillation behaviour deviates, in several respects, from standard concepts of the nucleation–polymerisation models and shows such features as concentration-dependent non-linear effects in the assembly mechanism. Aβ(1–40) fibrillation kinetics do not always follow conventional kinetic mechanisms and, specifically at high concentrations, intermediate structures become populated and secondary processes may further modify the fibrillation mechanism.

  10. 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

  11. Functional amyloids as inhibitors of plasmid DNA replication

    Science.gov (United States)

    Molina-García, Laura; Gasset-Rosa, Fátima; Moreno-del Álamo, María; Fernández-Tresguerres, M. Elena; Moreno-Díaz de la Espina, Susana; Lurz, Rudi; Giraldo, Rafael

    2016-01-01

    DNA replication is tightly regulated to constrain the genetic material within strict spatiotemporal boundaries and copy numbers. Bacterial plasmids are autonomously replicating DNA molecules of much clinical, environmental and biotechnological interest. A mechanism used by plasmids to prevent over-replication is ‘handcuffing’, i.e. inactivating the replication origins in two DNA molecules by holding them together through a bridge built by a plasmid-encoded initiator protein (Rep). Besides being involved in handcuffing, the WH1 domain in the RepA protein assembles as amyloid fibres upon binding to DNA in vitro. The amyloid state in proteins is linked to specific human diseases, but determines selectable and epigenetically transmissible phenotypes in microorganisms. Here we have explored the connection between handcuffing and amyloidogenesis of full-length RepA. Using a monoclonal antibody specific for an amyloidogenic conformation of RepA-WH1, we have found that the handcuffed RepA assemblies, either reconstructed in vitro or in plasmids clustering at the bacterial nucleoid, are amyloidogenic. The replication-inhibitory RepA handcuff assembly is, to our knowledge, the first protein amyloid directly dealing with DNA. Built on an amyloid scaffold, bacterial plasmid handcuffs can bring a novel molecular solution to the universal problem of keeping control on DNA replication initiation. PMID:27147472

  12. BSE-associated prion-amyloid cardiomyopathy in primates.

    Science.gov (United States)

    Krasemann, Susanne; Mearini, Giulia; Krämer, Elisabeth; Wagenführ, Katja; Schulz-Schaeffer, Walter; Neumann, Melanie; Bodemer, Walter; Kaup, Franz-Josef; Beekes, Michael; Carrier, Lucie; Aguzzi, Adriano; Glatzel, Markus

    2013-06-01

    Prion amyloidosis occurred in the heart of 1 of 3 macaques intraperitoneally inoculated with bovine spongiform encephalopathy prions. This macaque had a remarkably long duration of disease and signs of cardiac distress. Variant Creutzfeldt-Jakob disease, caused by transmission of bovine spongiform encephalopathy to humans, may manifest with cardiac symptoms from prion-amyloid cardiomyopathy.

  13. Renal amyloid A amyloidosis as a complication of hidradenitis suppurativa

    DEFF Research Database (Denmark)

    Schandorff, Kristine D; Miller, Iben M; Krustrup, Dorrit;

    2016-01-01

    Rheumatic disease is the dominant cause of amyloid A (AA) amyloidosis, but other chronic inflammatory diseases may have similar consequences. Hidradenitis suppurativa (HS) is a relatively common, but little known skin disease characterized by chronic inflammation. Here we present a case of chroni...... HS leading to biopsy-verified severe renal AA amyloidosis and dialysis dependency....

  14. Two-Step Amyloid Aggregation: Sequential Lag Phase Intermediates

    Science.gov (United States)

    Castello, Fabio; Paredes, Jose M.; Ruedas-Rama, Maria J.; Martin, Miguel; Roldan, Mar; Casares, Salvador; Orte, Angel

    2017-01-01

    The self-assembly of proteins into fibrillar structures called amyloid fibrils underlies the onset and symptoms of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. However, the molecular basis and mechanism of amyloid aggregation are not completely understood. For many amyloidogenic proteins, certain oligomeric intermediates that form in the early aggregation phase appear to be the principal cause of cellular toxicity. Recent computational studies have suggested the importance of nonspecific interactions for the initiation of the oligomerization process prior to the structural conversion steps and template seeding, particularly at low protein concentrations. Here, using advanced single-molecule fluorescence spectroscopy and imaging of a model SH3 domain, we obtained direct evidence that nonspecific aggregates are required in a two-step nucleation mechanism of amyloid aggregation. We identified three different oligomeric types according to their sizes and compactness and performed a full mechanistic study that revealed a mandatory rate-limiting conformational conversion step. We also identified the most cytotoxic species, which may be possible targets for inhibiting and preventing amyloid aggregation.

  15. Stop-and-go kinetics in amyloid fibrillation

    DEFF Research Database (Denmark)

    Ferkinghoff-Borg, Jesper; Fonslet, Jesper; Andersen, Christian Beyschau;

    2010-01-01

    Many human diseases are associated with protein aggregation and fibrillation. We present experiments on in vitro glucagon fibrillation using total internal reflection fluorescence microscopy, providing real-time measurements of single-fibril growth. We find that amyloid fibrils grow in an intermi...

  16. Amyloid goiter in a child - US, CT and MR evaluation

    Energy Technology Data Exchange (ETDEWEB)

    Perez Fontan, F.J.; Mosquera Oses, J.; Pombo Felipe, F. (Hospital Juan Canalejo, La Coruna (Spain). Dept. of Radiology); Rodriguez Sanchez, I.; Arnaiz Pena, S. (Hospital Juan Canalejo, La Coruna (Spain). Dept. of Pediatric Oncology)

    1992-09-01

    There are few radiological descriptions of amyloid goiter, basically in adult patients or oriental origin. We present a ten-year-old boy with Still's disease and secondary thyroid amyloidosis, describing the US, CT and MR findings. (orig.).

  17. Polymorphic structures of Alzheimer's β-amyloid globulomers.

    Directory of Open Access Journals (Sweden)

    Xiang Yu

    Full Text Available BACKGROUND: Misfolding and self-assembly of Amyloid-β (Aβ peptides into amyloid fibrils is pathologically linked to the development of Alzheimer's disease. Polymorphic Aβ structures derived from monomers to intermediate oligomers, protofilaments, and mature fibrils have been often observed in solution. Some aggregates are on-pathway species to amyloid fibrils, while the others are off-pathway species that do not evolve into amyloid fibrils. Both on-pathway and off-pathway species could be biologically relevant species. But, the lack of atomic-level structural information for these Aβ species leads to the difficulty in the understanding of their biological roles in amyloid toxicity and amyloid formation. METHODS AND FINDINGS: Here, we model a series of molecular structures of Aβ globulomers assembled by monomer and dimer building blocks using our peptide-packing program and explicit-solvent molecular dynamics (MD simulations. Structural and energetic analysis shows that although Aβ globulomers could adopt different energetically favorable but structurally heterogeneous conformations in a rugged energy landscape, they are still preferentially organized by dynamic dimeric subunits with a hydrophobic core formed by the C-terminal residues independence of initial peptide packing and organization. Such structural organizations offer high structural stability by maximizing peptide-peptide association and optimizing peptide-water solvation. Moreover, curved surface, compact size, and less populated β-structure in Aβ globulomers make them difficult to convert into other high-order Aβ aggregates and fibrils with dominant β-structure, suggesting that they are likely to be off-pathway species to amyloid fibrils. These Aβ globulomers are compatible with experimental data in overall size, subunit organization, and molecular weight from AFM images and H/D amide exchange NMR. CONCLUSIONS: Our computationally modeled Aβ globulomers provide useful

  18. Therapeutic implications of melatonin in cerebral edema.

    Science.gov (United States)

    Rathnasamy, Gurugirijha; Ling, Eng-Ang; Kaur, Charanjit

    2014-12-01

    Cerebral edema/brain edema refers to the accumulation of fluid in the brain and is one of the fatal conditions that require immediate medical attention. Cerebral edema develops as a consequence of cerebral trauma, cerebral infarction, hemorrhages, abscess, tumor, hypoxia, and other toxic or metabolic factors. Based on the causative factors cerebral edema is differentiated into cytotoxic cerebral edema, vasogenic cerebral edema, osmotic and interstitial cerebral edema. Treatment of cerebral edema depends on timely diagnosis and medical assistance. Pragmatic treatment strategies such as antihypertensive medications, nonsteroidal anti-inflammatory drugs, barbiturates, steroids, glutamate and N-methyl-D-aspartate receptor antagonists and trometamol are used in clinical practice. Although the above mentioned treatment approaches are being used, owing to the complexity of the mechanisms involved in cerebral edema, a single therapeutic strategy which could ameliorate cerebral edema is yet to be identified. However, recent experimental studies have suggested that melatonin, a neurohormone produced by the pineal gland, could be an effective alternative for treating cerebral edema. In animal models of stroke, melatonin was not only shown to reduce cerebral edema but also preserved the blood brain barrier. Melatonin's beneficial effects were attributed to its properties, such as being a potent anti-oxidant, and its ability to cross the blood brain barrier within minutes after its administration. This review summarizes the beneficial effects of melatonin when used for treating cerebral edema.

  19. Amyloid Precursor Protein Processing in Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Adwait BHADBHADE

    2012-03-01

    Full Text Available How to Cite this Article: Bhadbhade A, Cheng DW. Amyloid Precursor Protein Processing in Alzheimer’s Disease. Iranian Journal of Child Neurology2012;6(1:1-5.Alzheimer’s disease (AD is a progressive neurodegenerative disorder and a leading cause of dementia. The AD is characterized by presence of intraneuronal tangles and extracellular plaques in the brain. The plaques are composed of dense and mostly insoluble deposits of amyloid beta peptide (Aβ, formed by sequential cleavage of the Amyloid Precursor Protein (APP, by two pathways amyloidogenic and non-amyloidogenic. Tangles are composed of paired helical fragments, which aggregate to form, microtubular protein tau. Although Aβ plaques are established to be the cause of the disease, there exist genetic factors and other pathological identifications in addition to these which are an integral part of the disease. This article gives an overview into the mechanism of APP action, genetic factors and other pathological identifications contributing to Alzheimer’s disease formation.References Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer’s disease in the United States and the public health impact of delaying disease onset. American Journal of Public Health 1998;88(9:1337. Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer disease in the US population. Arch Neurol 2003;60(8:1119-22. Möller HJ, Graeber M. The case described by Alois Alzheimer in 1911. European Archives of Psychiatry and Clinical Neuroscience 1998:248(3:111-122. Selkoe D J. (2002. Deciphering the genesis and fate of amyloid beta-protein yields novel therapies for Alzheimer disease. J Clinic Investigat 2002;110(10: 1375-82. Wolfe MS. Tau mutations in neurodegenerative diseases. J Biolog Chem 2009;284(10:6021. Selkoe DJ. Alzheimer’s disease: genes, proteins, and therapy. Physiological reviews 2001;81(2:741. Selkoe DJ. The cell biology of [beta]-amyloid precursor protein and presenilin in Alzheimer

  20. 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.

  1. Amyloid and tau cerebrospinal fluid biomarkers in HIV infection

    Directory of Open Access Journals (Sweden)

    Rosengren Lars

    2009-12-01

    Full Text Available Abstract Background Because of the emerging intersections of HIV infection and Alzheimer's disease, we examined cerebrospinal fluid (CSF biomarkers related of amyloid and tau metabolism in HIV-infected patients. Methods In this cross-sectional study we measured soluble amyloid precursor proteins alpha and beta (sAPPα and sAPPβ, amyloid beta fragment 1-42 (Aβ1-42, and total and hyperphosphorylated tau (t-tau and p-tau in CSF of 86 HIV-infected (HIV+ subjects, including 21 with AIDS dementia complex (ADC, 25 with central nervous system (CNS opportunistic infections and 40 without neurological symptoms and signs. We also measured these CSF biomarkers in 64 uninfected (HIV- subjects, including 21 with Alzheimer's disease, and both younger and older controls without neurological disease. Results CSF sAPPα and sAPPβ concentrations were highly correlated and reduced in patients with ADC and opportunistic infections compared to the other groups. The opportunistic infection group but not the ADC patients had lower CSF Aβ1-42 in comparison to the other HIV+ subjects. CSF t-tau levels were high in some ADC patients, but did not differ significantly from the HIV+ neuroasymptomatic group, while CSF p-tau was not increased in any of the HIV+ groups. Together, CSF amyloid and tau markers segregated the ADC patients from both HIV+ and HIV- neuroasymptomatics and from Alzheimer's disease patients, but not from those with opportunistic infections. Conclusions Parallel reductions of CSF sAPPα and sAPPβ in ADC and CNS opportunistic infections suggest an effect of CNS immune activation or inflammation on neuronal amyloid synthesis or processing. Elevation of CSF t-tau in some ADC and CNS infection patients without concomitant increase in p-tau indicates neural injury without preferential accumulation of hyperphosphorylated tau as found in Alzheimer's disease. These biomarker changes define pathogenetic pathways to brain injury in ADC that differ from those

  2. Endocytosed 2-Microglobulin Amyloid Fibrils Induce Necrosis and Apoptosis of Rabbit Synovial Fibroblasts by Disrupting Endosomal/Lysosomal Membranes: A Novel Mechanism on the Cytotoxicity of Amyloid Fibrils.

    Directory of Open Access Journals (Sweden)

    Tadakazu Okoshi

    Full Text Available Dialysis-related amyloidosis is a major complication in long-term hemodialysis patients. In dialysis-related amyloidosis, β2-microglobulin (β2-m amyloid fibrils deposit in the osteoarticular tissue, leading to carpal tunnel syndrome and destructive arthropathy with cystic bone lesions, but the mechanism by which these amyloid fibrils destruct bone and joint tissue is not fully understood. In this study, we assessed the cytotoxic effect of β2-m amyloid fibrils on the cultured rabbit synovial fibroblasts. Under light microscopy, the cells treated with amyloid fibrils exhibited both necrotic and apoptotic changes, while the cells treated with β2-m monomers and vehicle buffer exhibited no morphological changes. As compared to β2-m monomers and vehicle buffer, β2-m amyloid fibrils significantly reduced cellular viability as measured by the lactate dehydrogenase release assay and the 3-(4,5-di-methylthiazol-2-yl-2,5-diphenyltetrazolium bromide reduction assay and significantly increased the percentage of apoptotic cells as measured by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling method. β2-m amyloid fibrils added to the medium adhered to cell surfaces, but did not disrupt artificial plasma membranes as measured by the liposome dye release assay. Interestingly, when the cells were incubated with amyloid fibrils for several hours, many endosomes/lysosomes filled with amyloid fibrils were observed under confocal laser microscopy and electron microscopy, Moreover, some endosomal/lysosomal membranes were disrupted by intravesicular fibrils, leading to the leakage of the fibrils into the cytosol and adjacent to mitochondria. Inhibition of actin-dependent endocytosis by cytochalasin D attenuated the toxicity of amyloid fibrils. These results suggest that endocytosed β2-m amyloid fibrils induce necrosis and apoptosis by disrupting endosomal/lysosomal membranes, and this novel mechanism on the cytotoxicity of amyloid

  3. Protective effects of Nitraria retusa extract and its constituent isorhamnetin against amyloid β-induced cytotoxicity and amyloid β aggregation.

    Science.gov (United States)

    Iida, Akihisa; Usui, Takeo; Zar Kalai, Feten; Han, Junkyu; Isoda, Hiroko; Nagumo, Yoko

    2015-01-01

    Nitraria retusa is a halophyte species that is distributed in North Africa and used as a traditional medicinal plant. In this study, N. retusa ethanol extract and its constituent isorhamnetin (IRA) protected against amyloid β (Aβ)-induced cytotoxicity in human neuroblastoma SH-SY5Y cells. An in vitro Aβ aggregation assay suggested that IRA destabilizes Aβ fibrils.

  4. Cerebral edema associated with acute hepatic failure.

    Directory of Open Access Journals (Sweden)

    Fujiwara,Masachika

    1985-02-01

    Full Text Available The clinicopathological findings of cerebral edema were investigated in patients with acute hepatic failure autopsied at Okayama University Hospital between 1970 and 1980 retrospectively. Nine (64% of 14 hepatic failure cases were found to have cerebral edema during a post-mortem examination of the brain. Clinical features of the patients with cerebral edema were not significantly different from those of the patients without cerebral edema. However, general convulsions were observed more frequently in patients later found to have cerebral edema. Moreover, the length of time from deep coma to death was much shorter in the brain edema cases with cerebral herniation than without herniation.

  5. Monitoring Cerebral Oxygenation in Neonates: An Update

    Science.gov (United States)

    Dix, Laura Marie Louise; van Bel, Frank; Lemmers, Petra Maria Anna

    2017-01-01

    Cerebral oxygenation is not always reflected by systemic arterial oxygenation. Therefore, regional cerebral oxygen saturation (rScO2) monitoring with near-infrared spectroscopy (NIRS) is of added value in neonatal intensive care. rScO2 represents oxygen supply to the brain, while cerebral fractional tissue oxygen extraction, which is the ratio between rScO2 and systemic arterial oxygen saturation, reflects cerebral oxygen utilization. The balance between oxygen supply and utilization provides insight in neonatal cerebral (patho-)physiology. This review highlights the potential and limitations of cerebral oxygenation monitoring with NIRS in the neonatal intensive care unit. PMID:28352624

  6. Hereditary and Sporadic Forms of Aβ-Cerebrovascular Amyloidosis and Relevant Transgenic Mouse Models

    Directory of Open Access Journals (Sweden)

    Samir Kumar-Singh

    2009-04-01

    Full Text Available Cerebral amyloid angiopathy (CAA refers to the specific deposition of amyloid fibrils in the leptomeningeal and cerebral blood vessel walls, often causing secondary vascular degenerative changes. Although many kinds of peptides are known to be deposited as vascular amyloid, amyloid-β (Aβ-CAA is the most common type associated with normal aging, sporadic CAA, Alzheimer’s disease (AD and Down’s syndrome. Moreover, Aβ-CAA is also associated with rare hereditary cerebrovascular amyloidosis due to mutations within the Aβ domain of the amyloid precursor protein (APP such as Dutch and Flemish APP mutations. Genetics and clinicopathological studies on these familial diseases as well as sporadic conditions have already shown that CAA not only causes haemorrhagic and ischemic strokes, but also leads to progressive dementia. Transgenic mouse models based on familial AD mutations have also successfully reproduced many of the features found in human disease, providing us with important insights into the pathogenesis of CAA. Importantly, such studies have pointed out that specific vastopic Aβ variants or an unaltered Aβ42/Aβ40 ratio favor vascular Aβ deposition over parenchymal plaques, but higher than critical levels of Aβ40 are also observed to be anti-amyloidogenic. These data would be important in the development of therapies targeting amyloid in vessels.

  7. Cerebral trypanosomiasis and AIDS

    Directory of Open Access Journals (Sweden)

    Antunes Apio Claudio Martins

    2002-01-01

    Full Text Available A 36 year-old black female, complaining of headache of one month's duration presented with nausea, vomiting, somnolence, short memory problems, loss of weight, and no fever history. Smoker, intravenous drugs abuser, promiscuous lifestyle. Physical examination: left homonimous hemianopsia, left hemiparesis, no papilledema, diffuse hyperreflexia, slowness of movements. Brain CT scan: tumor-like lesion in the splenium of the corpus calosum, measuring 3.5 x 1.4 cm, with heterogeneous enhancing pattern, sugesting a primary CNS tumor. Due to the possibility of CNS infection, a lumbar puncture disclosed an opening pressure of 380 mmH(20; 11 white cells (lymphocytes; glucose 18 mg/dl (serum glucose 73 mg/dl; proteins 139 mg/dl; presence of Trypanosoma parasites. Serum Elisa-HIV tests turned out to be positive. Treatment with benznidazole dramatically improved clinical and radiographic picture, but the patient died 6 weeks later because of respiratory failure. T. cruzi infection of the CNS is a rare disease, but we have an increasing number of cases in HIV immunecompromised patients. Diagnosis by direct observation of CSF is uncommon, and most of the cases are diagnosed by pathological examination. It is a highly lethal disease, even when properly diagnosed and treated. This article intends to include cerebral trypanosomiasis in the differential diagnosis of intracranial space-occupying lesions, especially in immunecompromised patients from endemic regions.

  8. Pseudotumoral delayed cerebral radionecrosis

    Energy Technology Data Exchange (ETDEWEB)

    Ciaudo-Lacroix, C.; Lapresle, J. (Centre Hospitalier de Bicetre, 94 - Le Kremlin-Bicetre (France))

    1985-01-01

    A 60 year-old woman with a scalp epithelioma underwent radiotherapy, the dose being 57 Gray. A first epileptic seizure occurred twenty months later. Neurological examination revealed signs of left hemisphere involvement. ..gamma..EG, angiography, CT scans, demonstrated a pseudotumoral avascular process. On account of the localisation, the patient being right-handed, no surgical procedure was performed. In spite of corticotherapy and anticonvulsive treatment, seizures recurred and neurological signs slowly progressed. The patient died, 22 months after the first seizure, of an associated disseminated carcinoma with cachexia. Neuropathological examination showed a massive lesion presenting all the features of delayed radionecrosis in the left hemisphere: situated mainly in the white matter; numerous vascular abnormalities; wide-spread demyelination; disappearance of oligoglial cells. The Authors recall the clinical and anatomical aspects of this condition for which the only successful treatment is surgical removal when location and size of the lesion permit. Finally, the mechanisms which have been proposed to explain this delayed cerebral radionecrosis are discussed.

  9. Protective properties of lysozyme on β-amyloid pathology: implications for Alzheimer disease.

    Science.gov (United States)

    Helmfors, Linda; Boman, Andrea; Civitelli, Livia; Nath, Sangeeta; Sandin, Linnea; Janefjord, Camilla; McCann, Heather; Zetterberg, Henrik; Blennow, Kaj; Halliday, Glenda; Brorsson, Ann-Christin; Kågedal, Katarina

    2015-11-01

    The hallmarks of Alzheimer disease are amyloid-β plaques and neurofibrillary tangles accompanied by signs of neuroinflammation. Lysozyme is a major player in the innate immune system and has recently been shown to prevent the aggregation of amyloid-β1-40 in vitro. In this study we found that patients with Alzheimer disease have increased lysozyme levels in the cerebrospinal fluid and lysozyme co-localized with amyloid-β in plaques. In Drosophila neuronal co-expression of lysozyme and amyloid-β1-42 reduced the formation of soluble and insoluble amyloid-β species, prolonged survival and improved the activity of amyloid-β1-42 transgenic flies. This suggests that lysozyme levels rise in Alzheimer disease as a compensatory response to amyloid-β increases and aggregation. In support of this, in vitro aggregation assays revealed that lysozyme associates with amyloid-β1-42 and alters its aggregation pathway to counteract the formation of toxic amyloid-β species. Overall, these studies establish a protective role for lysozyme against amyloid-β associated toxicities and identify increased lysozyme in patients with Alzheimer disease. Therefore, lysozyme has potential as a new biomarker as well as a therapeutic target for Alzheimer disease.

  10. 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.

  11. Cerebrolysin decreases amyloid-beta production by regulating amyloid protein precursor maturation in a transgenic model of Alzheimer's disease.

    Science.gov (United States)

    Rockenstein, Edward; Torrance, Magdalena; Mante, Michael; Adame, Anthony; Paulino, Amy; Rose, John B; Crews, Leslie; Moessler, Herbert; Masliah, Eliezer

    2006-05-15

    Cerebrolysin is a peptide mixture with neurotrophic effects that might reduce the neurodegenerative pathology in Alzheimer's disease (AD). We have previously shown in an amyloid protein precursor (APP) transgenic (tg) mouse model of AD-like neuropathology that Cerebrolysin ameliorates behavioral deficits, is neuroprotective, and decreases amyloid burden; however, the mechanisms involved are not completely clear. Cerebrolysin might reduce amyloid deposition by regulating amyloid-beta (Abeta) degradation or by modulating APP expression, maturation, or processing. To investigate these possibilities, APP tg mice were treated for 6 months with Cerebrolysin and analyzed in the water maze, followed by RNA, immunoblot, and confocal microscopy analysis of full-length (FL) APP and its fragments, beta-secretase (BACE1), and Abeta-degrading enzymes [neprilysin (Nep) and insulin-degrading enzyme (IDE)]. Consistent with previous studies, Cerebrolysin ameliorated the performance deficits in the spatial learning portion of the water maze and reduced the synaptic pathology and amyloid burden in the brains of APP tg mice. These effects were associated with reduced levels of FL APP and APP C-terminal fragments, but levels of BACE1, Notch1, Nep, and IDE were unchanged. In contrast, levels of active cyclin-dependent kinase-5 (CDK5) and glycogen synthase kinase-3beta [GSK-3beta; but not stress-activated protein kinase-1 (SAPK1)], kinases that phosphorylate APP, were reduced. Furthermore, Cerebrolysin reduced the levels of phosphorylated APP and the accumulation of APP in the neuritic processes. Taken together, these results suggest that Cerebrolysin might reduce AD-like pathology in the APP tg mice by regulating APP maturation and transport to sites where Abeta protein is generated. This study clarifies the mechanisms through which Cerebrolysin might reduce Abeta production and deposition in AD and further supports the importance of this compound in the potential treatment of early AD.

  12. 三种微颗粒水平在糖尿病血管病变中的意义%Significance of three kinds of microparticle levels in diabetic angiopathy

    Institute of Scientific and Technical Information of China (English)

    李会娟; 施毕旻; 赵小娟; 沈文红; 阮长耿

    2010-01-01

    目的 分析糖尿病患者微颗粒(包括血小板微颗粒、内皮细胞微颗粒以及组织因子阳性微颗粒)水平,探讨微颗粒水平与糖尿病并发症的相关性.方法 流式细胞仪检测106例糖尿病患者和50例健康志愿者血浆中血小板微颗粒、内皮细胞微颗粒和组织因子阳性微颗粒水平,并比较糖尿病血管病变各组间微颗粒的变化.结果 糖尿病组血小板微颗粒和组织因子阳性微颗粒水平与对照组比较无明显差异(23.09±15.66对38.55±28.56,83.82±82.61对89.06±82.75,均P>0.05),而内皮细胞微颗粒水平在糖尿病组明显高于对照组(164.20±128.88对63.81±40.84,P<0.05),合并有血管病变者其内皮细胞微颗粒水平又高于单纯糖尿病组(184.12±152.77、188.21±149.55对138.53±99.87,P<0.05).结论 内皮细胞功能异常是糖尿病患者,尤其合并有血管病变患者内皮细胞微颗粒升高的原因;内皮细胞微颗粒水平可以用来评价糖尿病患者血管内皮细胞的功能状态和疾病的进展的指标之一.%Objective To investigate the levels of mieropartieles originated from platelet (PMP),endothelium (EMP),and tissue factor-bearing microparticles (TF+ MP) in diabetes mellitus and to analyze its relationship with diabetic angiopathy.Methods PMP,EMP or TF+ MP were measured in 106 cases of diabetes mellitus and 50 controls by flow eytometry.The differences of EMP between groups of diabetic macrovascular disease and diabetic microvascular disease were determined.Results The levels of EMP in diabetic patients were higher than that in the control(164.20±128.88 vs 63.81±40.84,P<0.05).Diabetic cases with complication showed higher expression level of EMP than those without complications(184.12±152.77,188.21±149.55 vs 138.53±99.87,both P<0.05).However,no distinct increase was observed in PMP and TF+ MP level in diabetes groups compared with control group.Conclusions Endothelial dysfunction,may contribute to the increased

  13. Goodpasture Antigen-binding Protein/Ceramide Transporter Binds to Human Serum Amyloid P-Component and Is Present in Brain Amyloid Plaques

    NARCIS (Netherlands)

    Mencarelli, Chiara; Bode, Gerard H.; Losen, Mario; Kulharia, Mahesh; Molenaar, Peter C.; Veerhuis, Robert; Steinbusch, Harry W. M.; De Baets, Marc H.; Nicolaes, Gerry A. F.; Martinez-Martinez, Pilar

    2012-01-01

    Serum amyloid P component (SAP) is a non-fibrillar glycoprotein belonging to the pentraxin family of the innate immune system. SAP is present in plasma, basement membranes, and amyloid deposits. This study demonstrates, for the first time, that the Goodpasture antigen-binding protein (GPBP) binds to

  14. Effect of serum macrophage migration inhibitory factor on type-2 diabetes-related angiopathy%巨噬细胞移动抑制因子对2型糖尿病患者血管病变的影响

    Institute of Scientific and Technical Information of China (English)

    倪正平; 张建; 巴荣; 雷艳花; 金星进; 王建娟; 陆益龙

    2012-01-01

    Objective To investigate the changes of the serum contents of macrophage migration inhibitory factor(MIF) and its effect on the development of angiopathy in the patients with type-2 diabetes mellitus (T2DM). Methods Serum MIF and high-sensitivity C-reactive protein (hs-CRP) were detected with ELISA in 19 T2DM cases with angiopathy (group A) and 19 T2DM without angiopathy (group B) and 16 healthy persons (group C). The contents of blood glucose (BG) and glycosylated hemoglobin A-lc(HbAlc) were tested as well. Results Serum levels of MIF and hs-CRP were higher in groups of A and B than those in group C. Serum hs-CRP was positively correlated to BG in group A. Serum MIF was positively correlated to hs-CRP and BG, and hs-CRP was positively correlated with BG and HbA1c in group B. Conclusion High expressions of MIF and hs-CRP are the important factors to promote the development of angiopathy in the patients with T2DM.%目的 探讨2型糖尿病(T2DM)患者血清巨噬细胞移动抑制因子(MIF)水平变化及其对糖尿病血管病变的影响.方法 用ELISA法检测T2DM合并血管病变患者(A组,19例)、T2DM无血管病变患者(B组,19例)和健康体检者(C组,16例)血清MIF和超敏C反应蛋白(hs-CRP).同时检测血糖(BG)和糖化血红蛋白(HbAlc).结果 A组和B组MIF、hs-CRP水平均高于C组(P<0.01).A组hs-CRP与血糖呈正相关.B组MIF与hs-CRP、BG水平呈正相关,hs-CRP与BG、HbAlc水平呈正相关.结论 糖尿病血管病变患者MIF与hs-CRP高表达是促进血管病变发生的重要因素.

  15. Middle cerebral artery blood velocity during rowing

    DEFF Research Database (Denmark)

    Secher, Niels Henry; Pott, F; Knudsen, L.;

    1997-01-01

    original,arterial blood pressure,central venous pressure,cerebral blood flow, exercise, transcranial Doppler......original,arterial blood pressure,central venous pressure,cerebral blood flow, exercise, transcranial Doppler...

  16. Effect of amyloid on memory and non-memory decline from preclinical to clinical Alzheimer's disease.

    Science.gov (United States)

    Lim, Yen Ying; Maruff, Paul; Pietrzak, Robert H; Ames, David; Ellis, Kathryn A; Harrington, Karra; Lautenschlager, Nicola T; Szoeke, Cassandra; Martins, Ralph N; Masters, Colin L; Villemagne, Victor L; Rowe, Christopher C

    2014-01-01

    High amyloid has been associated with substantial episodic memory decline over 18 and 36 months in healthy older adults and individuals with mild cognitive impairment. However, the nature and magnitude of amyloid-related memory and non-memory change from the preclinical to the clinical stages of Alzheimer's disease has not been evaluated over the same time interval. Healthy older adults (n = 320), individuals with mild cognitive impairment (n = 57) and individuals with Alzheimer's disease (n = 36) enrolled in the Australian Imaging, Biomarkers and Lifestyle study underwent at least one positron emission tomography neuroimaging scan for amyloid. Cognitive assessments were conducted at baseline, and 18- and 36-month follow-up assessments. Compared with amyloid-negative healthy older adults, amyloid-positive healthy older adults, and amyloid-positive individuals with mild cognitive impairment and Alzheimer's disease showed moderate and equivalent decline in verbal and visual episodic memory over 36 months (d's = 0.47-0.51). Relative to amyloid-negative healthy older adults, amyloid-positive healthy older adults showed no decline in non-memory functions, but amyloid-positive individuals with mild cognitive impairment showed additional moderate decline in language, attention and visuospatial function (d's = 0.47-1.12), and amyloid-positive individuals with Alzheimer's disease showed large decline in all aspects of memory and non-memory function (d's = 0.73-2.28). Amyloid negative individuals with mild cognitive impairment did not show any cognitive decline over 36 months. When non-demented individuals (i.e. healthy older adults and adults with mild cognitive impairment) were further dichotomized, high amyloid-positive non-demented individuals showed a greater rate of decline in episodic memory and language when compared with low amyloid positive non-demented individuals. Memory decline does not plateau with increasing disease severity, and decline in non

  17. Effects of grape seed-derived polyphenols on amyloid beta-protein self-assembly and cytotoxicity.

    Science.gov (United States)

    Ono, Kenjiro; Condron, Margaret M; Ho, Lap; Wang, Jun; Zhao, Wei; Pasinetti, Giulio M; Teplow, David B

    2008-11-21

    Epidemiological evidence suggests that moderate consumption of red wine reduces the incidence of Alzheimer disease (AD). To study the protective effects of red wine, experiments recently were executed in the Tg2576 mouse model of AD. These studies showed that a commercially available grape seed polyphenolic extract, MegaNatural-AZ (MN), significantly attenuated AD-type cognitive deterioration and reduced cerebral amyloid deposition (Wang, J., Ho, L., Zhao, W., Ono, K., Rosensweig, C., Chen, L., Humala, N., Teplow, D. B., and Pasinetti, G. M. (2008) J. Neurosci. 28, 6388-6392). To elucidate the mechanistic bases for these observations, here we used CD spectroscopy, photo-induced cross-linking of unmodified proteins, thioflavin T fluorescence, size exclusion chromatography, and electron microscopy to examine the effects of MN on the assembly of the two predominant disease-related amyloid beta-protein alloforms, Abeta40 and Abeta42. We also examined the effects of MN on Abeta-induced cytotoxicity by assaying 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide metabolism and lactate dehydrogenase activity in Abeta-treated, differentiated pheochromocytoma (PC12) cells. Initial studies revealed that MN blocked Abeta fibril formation. Subsequent evaluation of the assembly stage specificity of the effect showed that MN was able to inhibit protofibril formation, pre-protofibrillar oligomerization, and initial coil --> alpha-helix/beta-sheet secondary structure transitions. Importantly, MN had protective effects in assays of cytotoxicity in which MN was mixed with Abeta prior to peptide assembly or following assembly and just prior to peptide addition to cells. These data suggest that MN is worthy of consideration as a therapeutic agent for AD.

  18. Cerebral Salt Wasting Syndrome

    Directory of Open Access Journals (Sweden)

    Mehmet Salih Sevdi

    2016-12-01

    Full Text Available A serum sodium (Na value below 135 mEq/L is evaluated as hyponatremia. Hyponatremia is the most common electrolyte abnormality observed in hospitalized patients in particular. Hypovolemic hypoosmolar hyponatremia is the most frequent clinical table. One of the reasons of this is cerebral salt-wasting syndrome (CSWS. CSWS is a rare condition progressing with low plasma osmolality, urine osmolality above 100-150 mOsm/kg and urine- Na concentration above 20 mEq/L. In the blood and urine sample analysis performed upon sudden loss of consciousness on the 15th day of the intensive care unit follow-up of 79-year-old female patients due to falling from stairs, blood biochemistry Na value was 120 mEq/L, plasma osmolality was 250 mOsm/kg, urine Na value was 180 mEq/L, urine osmolality was 1200 mOsm/kg, urine diuresis was >3 mL/kg/hour. The central venous pressure was 2 mmHg. The patient, considered to be diagnosed with CSWS, was treated with 9% NaCl and 3% hypertonic saline solution. Her clinical course was improved on the 18th day. She died on the 81st day secondary to septicemia in the subsequent follow-up. In this article, it was aimed to report a patient with CSWS which progresses with low percentage in intensive care unit patients with head trauma, is frequently confused with inappropriate antidiuretic hormone syndrome and progresses mortally when not diagnosed distinctively well.

  19. Chronic Cerebral Ischemia and Alzheime Disease%慢性脑缺血与阿尔茨海默病

    Institute of Scientific and Technical Information of China (English)

    徐钧

    2012-01-01

    Currently Alzheimer disease( AD )is the main type of dementia, and is the fourth cause of death in the elders. There are quite a few theories about AD pathogenesis, it's now considered that chronic cerebral ischemia may be the cause of AD. For chronic cerebral ischemia can lead to different degrees of brain pathological damage, the β-amyloid peptide deposition , neurons apoptosis , energy metabolic disorders, and immune oxidative damage caused by chronic cerebral ischemia may be the AD pathogenesis. Here is to make a review' on the role of chronic cerebral ischemia in AD pathogenesis and the ultimate cause of AD.%当前阿尔茨海默病(AD)是痴呆的主要类型,并且是导致老年人死亡的第四大原因.关于AD的病因很多,现在认为慢性脑缺血可能为AD的病因.因为慢性脑缺血能够导致脑组织不同程度的病理损伤,其引起的β淀粉样肽的沉积、神经元的凋亡、能量代谢障碍、免疫氧化损伤可能是AD的发病机制.现对慢性脑缺血在AD发病的作用和其最终导致AD的原因进行综述.

  20. Kinetic studies with iodine-123-labeled serum amyloid P component in patients with systemic AA and AL amyloidosis and assessment of clinical value

    NARCIS (Netherlands)

    Jager, PL; Hazenberg, BPC; Franssen, EJF; Limburg, PC; van Rijswijk, MH; Piers, DA

    1998-01-01

    In systemic amyloidosis, widespread amyloid deposition interferes with organ function, frequently with fatal consequences. Diagnosis rests on demonstrating amyloid deposits in the tissues, traditionally with histology although scintigraphic imaging with radiolabeled serum amyloid P component (SAP) h

  1. Cerebral venous thrombosis in childhood

    Energy Technology Data Exchange (ETDEWEB)

    Huisman, T.A.G.M.; Martin, E.; Willi, U.V. [Dept. of Diagnostic Imaging and Radiology, University Children' s Hospital Zurich (Switzerland); Holzmann, D. [Dept. of Otorhinolaryngology, University Children' s Hospital Zurich, Zurich (Switzerland)

    2001-09-01

    This was a retrospective study to determine different etiologies of cerebral venous thrombosis (CVT) in childhood and to correlate extent and location of thrombosis with the etiology and the age of the child as well as the final outcome. In addition, the radiologic approach is discussed. This was a retrospective analysis of 19 children with CVT. The children were examined by contrast-enhanced dynamic CT. Radiologic findings were correlated with the etiology of CVT. Cerebral venous thrombosis is not as infrequent in children as has been thought. Cerebral venous thrombosis in children can occur due to trauma (n=9), infections (n=7), or coagulation disorders (n=3). Extent and location of thrombosis, as well as complications, final outcome, and therapy, depend on the etiology. Computed tomography remains a valuable primary imaging modality in the diagnosis of CVT in the acutely injured or diseased child. (orig.)

  2. Neuronal autophagy in cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Feng Xu; Jin-Hua Gu; Zheng-Hong Qin

    2012-01-01

    Autophagy has evolved as a conserved process for the bulk degradation and recycling of cytosolic components,such as long-lived proteins and organelles.In neurons,autophagy is important for homeostasis and protein quality control and is maintained at relatively low levels under normal conditions,while it is upregulated in response to pathophysiological conditions,such as cerebral ischemic injury.However,the role of autophagy is more complex.It depends on age or brain maturity,region,severity of insult,and the stage of ischemia.Whether autophagy plays a beneficial or a detrimental role in cerebral ischemia depends on various pathological conditions.In this review,we elucidate the role of neuronal autophagy in cerebral ischemia.

  3. Effect of Metals on Kinetic Pathways of Amyloid-β Aggregation

    Directory of Open Access Journals (Sweden)

    Francis Hane

    2014-01-01

    Full Text Available Metal ions, including copper and zinc, have been implicated in the pathogenesis of Alzheimer’s disease through a variety of mechanisms including increased amyloid-β affinity and redox effects. Recent reports have demonstrated that the amyloid-β monomer does not necessarily travel through a definitive intermediary en-route to a stable amyloid fibril structure. Rather, amyloid-β misfolding may follow a variety of pathways resulting in a fibrillar end-product or a variety of oligomeric end-products with a diversity of structures and sizes. The presence of metal ions has been demonstrated to alter the kinetic pathway of the amyloid-β peptide which may lead to more toxic oligomeric end-products. In this work, we review the contemporary literature supporting the hypothesis that metal ions alter the reaction pathway of amyloid-β misfolding leading to more neurotoxic species.

  4. 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.

  5. Distinguishing the cross-beta spine arrangements in amyloid fibrils using FRET analysis.

    Science.gov (United States)

    Deng, Wei; Cao, Aoneng; Lai, Luhua

    2008-06-01

    The recently published microcrystal structures of amyloid fibrils from small peptides greatly enhanced our understanding of the atomic-level structure of the amyloid fibril. However, only a few amyloid fibrils can form microcrystals. The dansyl-tryptophan fluorescence resonance energy transfer (FRET) pair was shown to be able to detect the inter-peptide arrangement of the Transthyretin (105-115) amyloid fibril. In this study, we combined the known microcrystal structures with the corresponding FRET efficiencies to build a model for amyloid fibril structure classification. We found that fibrils with an antiparallel structural arrangement gave the largest FRET signal, those with a parallel arrangement gave the lowest FRET signal, and those with a mixed arrangement gave a moderate FRET signal. This confirms that the amyloid fibril structure patterns can be classified based on the FRET efficiency.

  6. In vivo amyloid aggregation kinetics tracked by time-lapse confocal microscopy in real-time.

    Science.gov (United States)

    Villar-Piqué, Anna; Espargaró, Alba; Ventura, Salvador; Sabate, Raimon

    2016-01-01

    Amyloid polymerization underlies an increasing number of human diseases. Despite this process having been studied extensively in vitro, aggregation is a difficult process to track in vivo due to methodological limitations and the slow kinetics of aggregation reactions in cells and tissues. Herein we exploit the amyloid properties of the inclusions bodies (IBs) formed by amyloidogenic proteins in bacteria to address the kinetics of in vivo amyloid aggregation. To this aim we used time-lapse confocal microscopy and a fusion of the amyloid-beta peptide (A β42) with a fluorescent reporter. This strategy allowed us to follow the intracellular kinetics of amyloid-like aggregation in real-time and to discriminate between variants exhibiting different in vivo aggregation propensity. Overall, the approach opens the possibility to assess the impact of point mutations as well as potential anti-aggregation drugs in the process of amyloid formation in living cells.

  7. Neurotrophic and Neurotoxic Effects of Amyloid |beta Protein: Reversal by Tachykinin Neuropeptides

    Science.gov (United States)

    Yankner, Bruce A.; Duffy, Lawrence K.; Kirschner, Daniel A.

    1990-10-01

    The amyloid β protein is deposited in the brains of patients with Alzheimer's disease but its pathogenic role is unknown. In culture, the amyloid β protein was neurotrophic to undifferentiated hippocampal neurons at low concentrations and neurotoxic to mature neurons at higher concentrations. In differentiated neurons, amyloid β protein caused dendritic and axonal retraction followed by neuronal death. A portion of the amyloid β protein (amino acids 25 to 35) mediated both the trophic and toxic effects and was homologous to the tachykinin neuropeptide family. The effects of the amyloid β protein were mimicked by tachykinin antagonists and completely reversed by specific tachykinin agonists. Thus, the amyloid β protein could function as a neurotrophic factor for differentiating neurons, but at high concentrations in mature neurons, as in Alzheimer's disease, could cause neuronal degeneration.

  8. Neuroevolutional Approach to Cerebral Palsy and Speech.

    Science.gov (United States)

    Mysak, Edward D.

    Intended for cerebral palsy specialists, the book emphasizes the contribution that a neuroevolutional approach to therapy can make to habilitation goals of the child with cerebral palsy and applies the basic principles of the Bobath approach to therapy. The first section discusses cerebral palsy as a reflection of disturbed neuro-ontogenisis and…

  9. Fenestration of the anterior cerebral artery

    Energy Technology Data Exchange (ETDEWEB)

    Ito, J.; Washiyama, K.; Hong, K.C.; Ibuchi, Y.

    1981-08-01

    Three cases of angiographically demonstrated fenestration of the anterior cerebral artery are reported. Fenestration occurred at the medial half of the horizontal segment of the anterior cerebral artery in all cases. Its embryology and clinical significance are briefly discussed, and the anatomical and radiological literature on fenestration of the anterior cerebral artery is reviewed.

  10. Cerebral toksoplasmose primaert diagnosticeret som tumor

    DEFF Research Database (Denmark)

    Cortsen, M E; Skøt, J; Skriver, E B

    1992-01-01

    Three cases of cerebral toxoplasmosis as the presenting manifestation of AIDS are reported. The initial diagnoses were brain tumors because of the cerebral mass lesions which resembled glioblastoma. In the light of the increasing occurrence of AIDS, attention is drawn to cerebral toxoplasmosis...

  11. Thermodynamics of amyloid formation and the role of intersheet interactions.

    Science.gov (United States)

    Irbäck, Anders; Wessén, Jonas

    2015-09-14

    The self-assembly of proteins into β-sheet-rich amyloid fibrils has been observed to occur with sigmoidal kinetics, indicating that the system initially is trapped in a metastable state. Here, we use a minimal lattice-based model to explore the thermodynamic forces driving amyloid formation in a finite canonical (NVT) system. By means of generalized-ensemble Monte Carlo techniques and a semi-analytical method, the thermodynamic properties of this model are investigated for different sets of intersheet interaction parameters. When the interactions support lateral growth into multi-layered fibrillar structures, an evaporation/condensation transition is observed, between a supersaturated solution state and a thermodynamically distinct state where small and large fibril-like species exist in equilibrium. Intermediate-size aggregates are statistically suppressed. These properties do not hold if aggregate growth is one-dimensional.

  12. Thermodynamics of amyloid formation and the role of intersheet interactions

    CERN Document Server

    Irbäck, Anders

    2016-01-01

    The self-assembly of proteins into $\\beta$-sheet-rich amyloid fibrils has been observed to occur with sigmoidal kinetics, indicating that the system initially is trapped in a metastable state. Here, we use a minimal lattice-based model to explore the thermodynamic forces driving amyloid formation in a finite canonical ($NVT$) system. By means of generalized-ensemble Monte Carlo techniques and a semi-analytical method, the thermodynamic properties of this model are investigated for different sets of intersheet interaction parameters. When the interactions support lateral growth into multi-layered fibrillar structures, an evaporation/condensation transition is observed, between a supersaturated solution state and a thermodynamically distinct state where small and large fibril-like species exist in equilibrium. Intermediate-size aggregates are statistically suppressed. These properties do not hold if aggregate growth is one-dimensional.

  13. Amyloid-like fibril elongation follows michaelis-menten kinetics.

    Science.gov (United States)

    Milto, Katazyna; Botyriute, Akvile; Smirnovas, Vytautas

    2013-01-01

    A number of proteins can aggregate into amyloid-like fibrils. It was noted that fibril elongation has similarities to an enzymatic reaction, where monomers or oligomers would play a role of substrate and nuclei/fibrils would play a role of enzyme. The question is how similar these processes really are. We obtained experimental data on insulin amyloid-like fibril elongation at the conditions where other processes which may impact kinetics of fibril formation are minor and fitted it using Michaelis-Menten equation. The correlation of the fit is very good and repeatable. It speaks in favour of enzyme-like model of fibril elongation. In addition, obtained [Formula: see text] and [Formula: see text] values at different conditions may help in better understanding influence of environmental factors on the process of fibril elongation.

  14. Gold Nanoparticles and Microwave Irradiation Inhibit Beta-Amyloid Amyloidogenesis

    Directory of Open Access Journals (Sweden)

    Bastus Neus

    2008-01-01

    Full Text Available Abstract Peptide-Gold nanoparticles selectively attached to β-amyloid protein (Aβ amyloidogenic aggregates were irradiated with microwave. This treatment produces dramatic effects on the Aβ aggregates, inhibiting both the amyloidogenesis and the restoration of the amyloidogenic potential. This novel approach offers a new strategy to inhibit, locally and remotely, the amyloidogenic process, which could have application in Alzheimer’s disease therapy. We have studied the irradiation effect on the amyloidogenic process in the presence of conjugates peptide-nanoparticle by transmission electronic microscopy observations and by Thioflavine T assays to quantify the amount of fibrils in suspension. The amyloidogenic aggregates rather than the amyloid fibrils seem to be better targets for the treatment of the disease. Our results could contribute to the development of a new therapeutic strategy to inhibit the amyloidogenic process in Alzheimer’s disease.

  15. Management of asymptomatic gene carriers of transthyretin familial amyloid polyneuropathy.

    Science.gov (United States)

    Schmidt, Hartmut H-J; Barroso, Fabio; González-Duarte, Alejandra; Conceição, Isabel; Obici, Laura; Keohane, Denis; Amass, Leslie

    2016-09-01

    Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a rare, severe, and irreversible, adult-onset, hereditary disorder caused by autosomal-dominant mutations in the TTR gene that increase the intrinsic propensity of transthyretin protein to misfold and deposit systemically as insoluble amyloid fibrils in nerve tissues, the heart, and other organs. TTR-FAP is characterized by relentless, progressively debilitating polyneuropathy, and leads to death, on average, within 10 years of symptom onset without treatment. With increased availability of disease-modifying treatment options for a wider spectrum of patients with TTR-FAP, timely detection of the disease may offer substantial clinical benefits. This review discusses mutation-specific predictive genetic testing in first-degree relatives of index patients diagnosed with TTR-FAP and the structured clinical follow-up of asymptomatic gene carriers for prompt diagnosis and early therapeutic intervention before accumulation of substantial damage. Muscle Nerve 54: 353-360, 2016.

  16. Betaine suppressed Aβ generation by altering amyloid precursor protein processing.

    Science.gov (United States)

    Liu, Xiu-Ping; Qian, Xiang; Xie, Yue; Qi, Yan; Peng, Min-Feng; Zhan, Bi-Cui; Lou, Zheng-Qing

    2014-07-01

    Betaine was an endogenous catabolite of choline, which could be isolated from vegetables and marine products. Betaine could promote the metabolism of homocysteine in healthy subjects and was used for hyperlipidemia, coronary atherosclerosis, and fatty liver in clinic. Recent findings shown that Betaine rescued neuronal damage due to homocysteine induced Alzheimer's disease (AD) like pathological cascade, including tau hyperphosphorylation and amyloid-β (Aβ) deposition. Aβ was derived from amyloid precursor protein (APP) processing, and was a triggering factor for AD pathological onset. Here, we demonstrated that Betaine reduced Aβ levels by altering APP processing in N2a cells stably expressing Swedish mutant of APP. Betaine increased α-secretase activity, but decreased β-secretase activity. Our data indicate that Betaine might play a protective role in Aβ production.

  17. New Cyclolignans from Origanumglandulosum Active Against b -amyloid Aggregation

    Directory of Open Access Journals (Sweden)

    Abdelkader Basli

    2014-05-01

    Full Text Available Origanum glandulosum Desf is an endemic flavoring herb widely distributed in North Africa that is commonly used in traditional medicine. This oregano species is rich in essential oils but little is known about its phenolic composition. In the present study, a crude extract of O. glandulosum was prepared in order to isolate and investigate its neuroprotective potential to inhibit β-amyloid peptide (Aβ aggregation. The three major compounds of the extract were isolated: rosmarinic acid and two cyclolignans in Origanum genus, globoidnan A and a new derivative named globoidnan B. Rosmarinic acid and globoidnan A showed significant anti-aggregative activity against β amyloid aggregation (IC50 7.0 and 12.0 µM, respectively. In contrast, globoidnan B was found to be less active.

  18. 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...... on neurological or psychiatric diseases other than dementia were excluded. Corresponding authors of eligible cohorts were invited to provide individual participant data. DATA EXTRACTION AND SYNTHESIS: Data were provided for 1359 participants with clinically diagnosed AD and 538 participants with non-AD dementia...... years; n = 377) and to a lesser degree in APOE ε4 carriers (97% [95% CI, 92%-99%] at 50 years to 90% [95% CI, 83%-94%] at 90 years; n = 593; P non-AD dementias...

  19. How curcumin affords effective protection against amyloid fibrillation in insulin?

    DEFF Research Database (Denmark)

    Rabiee, Atefeh; Ebrahim Habibi, Azadeh; Ghasemi, Atiyeh Ghasemi;

    2013-01-01

    seems to be one of these compounds, possessing key structural components effective toward fibrillation prevention, and its anti-amyloidogenic property has been reported for a number of model and disease-related proteins such as lysozyme and alphasynuclein. In this study, insulin amyloid formation has......Since the formation of amyloid structures from proteins was recognized in numerous diseases, many efforts have been devoted to the task of finding effective anti-amyloidogenic compounds. In a number of these investigations, the existence of “generic” compounds is implicitly acknowledged. Curcumin...... been shown effectively influenced by micro molar concentrations of curcumin. Under amyloidogenic conditions (pH 2.5 and 37°C), the compound was observed to inhibit fibril formation of insulin in a dose-dependent manner. Moreover, addition of curcumin to the protein incubated in such conditions...

  20. 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.)

  1. Melatonin attenuates β-amyloid-induced inhibition of neurofilament expression

    Institute of Scientific and Technical Information of China (English)

    Ying-chun ZHANG; Ze-fen WANG; Qun WANG; Yi-peng WANG; Jian-zhi WANG

    2004-01-01

    AIM: To explore the effect of β-amyloid (Aβ) on metabolism of cytoskeletal protein neurofilament, and search for effective cure to the lesion. METHODS: Wild type murine neuroblastoma N2a (N2awt) and N2a stably transfected with wild type amyloid precursor protein (N2aAPP) were cultured. Sandwich ELISA, immunocytochemistry, and Western blot were used respectively to measure the level of Aβ, the expression and phosphorylation of neurofilament proteins. RESULTS: The immunoreactivity of neurofilament protein was almost abolished in N2aAPP, which beard a significantly higher level of Aβ. Melatonin effectively decreased the level of Aβ, and restored partially the level of phosphorylated and non-phosphorylated neurofilament in N2aAPP. CONCLUSION: Overproduction of Aβ inhibits neurofilament expression, and melatonin attenuates the Aβ-induced lesion in cytoskeletal protein.

  2. Dimensionality of carbon nanomaterial impacting on the modulation of amyloid peptide assembly

    Science.gov (United States)

    Wang, J.; Zhu, Z.; Bortolini, C.; Hoffmann, S. V.; Amari, A.; Zhang, H. X.; Liu, L.; Dong, M. D.

    2016-07-01

    A wide variety of inorganic nanomaterials have been exploited so far for their great potential for biological applications. Some of these materials could be valid candidates to modulate the assembly of amyloid peptides, which is relevant to amyloid-related diseases. In this work, we reveal that a carbon nanomaterial can indeed modulate the assembly of amyloid peptides and, additionally, we show that this modulating effect is closely related to the dimensionality of the nanomaterials.

  3. Dimensionality of carbon nanomaterial impacting on the modulation of amyloid peptide assembly

    DEFF Research Database (Denmark)

    Wang, J.; Zhu, Z.; Bortolini, C.;

    2016-01-01

    A wide variety of inorganic nanomaterials have been exploited so far for their great potential for biological applications. Some of these materials could be valid candidates to modulate the assembly of amyloid peptides, which is relevant to amyloid-related diseases. In this work, we reveal...... that a carbon nanomaterial can indeed modulate the assembly of amyloid peptides and, additionally, we show that this modulating effect is closely related to the dimensionality of the nanomaterials....

  4. Rapid α-oligomer formation mediated by the Aβ C terminus initiates an amyloid assembly pathway

    OpenAIRE

    Misra, Pinaki; Kodali, Ravindra; Chemuru, Saketh; Kar, Karunakar; Wetzel, Ronald

    2016-01-01

    Since early oligomeric intermediates in amyloid assembly are often transient and difficult to distinguish, characterize and quantify, the mechanistic basis of the initiation of spontaneous amyloid growth is often opaque. We describe here an approach to the analysis of the Aβ aggregation mechanism that uses Aβ-polyglutamine hybrid peptides designed to retard amyloid maturation and an adjusted thioflavin intensity scale that reveals structural features of aggregation intermediates. The results ...

  5. Functionalization of multiwalled carbon nanotubes and their pH-responsive hydrogels with amyloid fibrils.

    Science.gov (United States)

    Li, Chaoxu; Mezzenga, Raffaele

    2012-07-10

    New biocompatible, pH-responsive, and fully fibrous hydrogels have been prepared based on amyloid fibrils hybridized and gelled by functionalized multiwalled carbon nanotubes (MWNTs) far below the gelling concentration of amyloid fibrils. Sulfonic functional groups were introduced on the surfaces of MWNTs either by a covalent diazonium reaction or by physical π-π interactions. The presence of the isoelectric point of amyloid fibrils allows a reversible gelling behavior through ionic interactions with functionalized MWNTs.

  6. Immunohistochemical identification and crossreactions of amyloid-A fibril protein in man and eleven other species

    OpenAIRE

    Gruys, E.; Linke, R.P.; Hol, P.R.; Geisel, O.; Nathrath, W.B.J.; Trautwein, G

    1984-01-01

    Antisera were prepared in rabbits, sheep or chicken against purified amyloid fibril protein AA from man, mouse, stone marten, dog, cow and hamster. These antisera were tested by immunodiffusion against all purified antigens and applied to tissue sections containing amyloid from man, mouse, hamster, guinea pig, rabbit, cat, dog, mink, stone marten, pine marten, cow and horse. The binding of the antibodies to amyloid in tissue sections was assessed by the indirect immunoperoxidase method. The s...

  7. Aβ42 Is Essential for Parenchymal and Vascular Amyloid Deposition in Mice

    OpenAIRE

    McGowan, Eileen; Pickford, Fiona; Kim, Jungsu; Onstead, Luisa; Eriksen, Jason; Yu, Cindy; Skipper, Lisa; Murphy, M. Paul; Beard, Jenny; Das, Pritam; Jansen,Karen; DeLucia, Michael; Lin, Wen-Lang; Dolios, Georgia; Wang, Rong

    2005-01-01

    Considerable circumstantial evidence suggests that Aβ42 is the initiating molecule in Alzheimer's disease (AD) pathogenesis. However, the absolute requirement for Aβ42 for amyloid deposition has never been demonstrated in vivo. We have addressed this by developing transgenic models that express Aβ1-40 or Aβ1-42 in the absence of human amyloid β protein precursor (APP) overexpression. Mice expressing high levels of Aβ1-40 do not develop overt amyloid pathology. In contrast, mice expressing low...

  8. Lifetime costs of cerebral palsy

    DEFF Research Database (Denmark)

    Kruse, Marie; Michelsen, Susan Ishøy; Flachs, Esben Meulengracht;

    2009-01-01

    This study quantified the lifetime costs of cerebral palsy (CP) in a register-based setting. It was the first study outside the US to assess the lifetime costs of CP. The lifetime costs attributable to CP were divided into three categories: health care costs, productivity costs, and social costs....... The population analyzed was retrieved from the Danish Cerebral Palsy Register, which covers the eastern part of the country and has registered about half of the Danish population of individuals with CP since 1950. For this study we analyzed 2367 individuals with CP, who were born in 1930 to 2000 and were alive...

  9. Features to validate cerebral toxoplasmosis

    Directory of Open Access Journals (Sweden)

    Carolina da Cunha Correia

    2013-06-01

    Full Text Available Introduction Neurotoxoplasmosis (NT sometimes manifests unusual characteristics. Methods We analyzed 85 patients with NT and AIDS according to clinical, cerebrospinal fluid, cranial magnetic resonance, and polymerase chain reaction (PCR characteristics. Results In 8.5%, focal neurological deficits were absent and 16.4% had single cerebral lesions. Increased sensitivity of PCR for Toxoplasma gondii DNA in the central nervous system was associated with pleocytosis and presence of >4 encephalic lesions. Conclusions Patients with NT may present without focal neurological deficit and NT may occur with presence of a single cerebral lesion. Greater numbers of lesions and greater cellularity in cerebrospinal fluid improve the sensitivity of PCR to T gondii.

  10. β-hairpin-mediated nucleation of polyglutamine amyloid formation

    Science.gov (United States)

    Kar, Karunakar; Hoop, Cody L.; Drombosky, Kenneth W.; Baker, Matthew A.; Kodali, Ravindra; Arduini, Irene; van der Wel, Patrick C. A.; Horne, W. Seth; Wetzel, Ronald

    2013-01-01

    The conformational preferences of polyglutamine (polyQ) sequences are of major interest because of their central importance in the expanded CAG repeat diseases that include Huntington’s disease (HD). Here we explore the response of various biophysical parameters to the introduction of β-hairpin motifs within polyQ sequences. These motifs (trpzip, disulfide, D-Pro-Gly, Coulombic attraction, L-Pro-Gly) enhance formation rates and stabilities of amyloid fibrils with degrees of effectiveness well-correlated with their known abilities to enhance β-hairpin formation in other peptides. These changes led to decreases in the critical nucleus for amyloid formation from a value of n* = 4 for a simple, unbroken Q23 sequence to approximate unitary n* values for similar length polyQs containing β-hairpin motifs. At the same time, the morphologies, secondary structures, and bioactivities of the resulting fibrils were essentially unchanged from simple polyQ aggregates. In particular, the signature pattern of SSNMR 13C Gln resonances that appears to be unique to polyQ amyloid is replicated exactly in fibrils from a β-hairpin polyQ. Importantly, while β-hairpin motifs do produce enhancements in the equilibrium constant for nucleation in aggregation reactions, these Kn* values remain quite low (~ 10−10) and there is no evidence for significant embellishment of β-structure within the monomer ensemble. The results indicate an important role for β-turns in the nucleation mechanism and structure of polyQ amyloid and have implications for the nature of the toxic species in expanded CAG repeat diseases. PMID:23353826

  11. β-hairpin-mediated nucleation of polyglutamine amyloid formation

    OpenAIRE

    Kar, Karunakar; Hoop, Cody L.; Drombosky, Kenneth W.; Baker, Matthew A.; Kodali, Ravindra; Arduini, Irene; van der Wel, Patrick C.A.; Horne, W. Seth; Wetzel, Ronald

    2013-01-01

    The conformational preferences of polyglutamine (polyQ) sequences are of major interest because of their central importance in the expanded CAG repeat diseases that include Huntington’s disease (HD). Here we explore the response of various biophysical parameters to the introduction of β-hairpin motifs within polyQ sequences. These motifs (trpzip, disulfide, D-Pro-Gly, Coulombic attraction, L-Pro-Gly) enhance formation rates and stabilities of amyloid fibrils with degrees of effectiveness well...

  12. 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

  13. Thermodynamics and dynamics of amyloid peptide oligomerization are sequence dependent.

    Science.gov (United States)

    Lu, Yan; Derreumaux, Philippe; Guo, Zhi; Mousseau, Normand; Wei, Guanghong

    2009-06-01

    Aggregation of the full-length amyloid-beta (Abeta) and beta2-microglobulin (beta2m) proteins is associated with Alzheimer's disease and dialysis-related amyloidosis, respectively. This assembly process is not restricted to full-length proteins, however, many short peptides also assemble into amyloid fibrils in vitro. Remarkably, the kinetics of amyloid-fibril formation of all these molecules is generally described by a nucleation-polymerization process characterized by a lag phase associated with the formation of a nucleus, after which fibril elongation occurs rapidly. In this study, we report using long molecular dynamics simulations with the OPEP coarse-grained force field, the thermodynamics and dynamics of the octamerization for two amyloid 7-residue peptides: the beta2m83-89 NHVTLSQ and Abeta16-22 KLVFFAE fragments. Based on multiple trajectories run at 310 K, totaling 2.2 mus (beta2m83-89) and 4.8 mus (Abeta16-22) and starting from random configurations and orientations of the chains, we find that the two peptides not only share common but also very different aggregation properties. Notably, an increase in the hydrophobic character of the peptide, as observed in Abeta16-22 with respect to beta2m83-89 impacts the thermodynamics by reducing the population of bilayer beta-sheet assemblies. Higher hydrophobicity is also found to slow down the dynamics of beta-sheet formation by enhancing the averaged lifetime of all configuration types (CT) and by reducing the complexity of the CT transition probability matrix. Proteins 2009. (c) 2008 Wiley-Liss, Inc.

  14. Crowding alone cannot account for cosolute effect on amyloid aggregation.

    Directory of Open Access Journals (Sweden)

    Shahar Sukenik

    Full Text Available Amyloid fiber formation is a specific form of protein aggregation, often resulting from the misfolding of native proteins. Aimed at modeling the crowded environment of the cell, recent experiments showed a reduction in fibrillation halftimes for amyloid-forming peptides in the presence of cosolutes that are preferentially excluded from proteins and peptides. The effect of excluded cosolutes has previously been attributed to the large volume excluded by such inert cellular solutes, sometimes termed "macromolecular crowding". Here, we studied a model peptide that can fold to a stable monomeric β-hairpin conformation, but under certain solution conditions aggregates in the form of amyloid fibrils. Using Circular Dichroism spectroscopy (CD, we found that, in the presence of polyols and polyethylene glycols acting as excluded cosolutes, the monomeric β-hairpin conformation was stabilized with respect to the unfolded state. Stabilization free energy was linear with cosolute concentration, and grew with molecular volume, as would also be predicted by crowding models. After initiating the aggregation process with a pH jump, fibrillation in the presence and absence of cosolutes was followed by ThT fluorescence, transmission electron microscopy, and CD spectroscopy. Polyols (glycerol and sorbitol increased the lag time for fibril formation and elevated the amount of aggregated peptide at equilibrium, in a cosolute size and concentration dependent manner. However, fibrillation rates remained almost unaffected by a wide range of molecular weights of soluble polyethylene glycols. Our results highlight the importance of other forces beyond the excluded volume interactions responsible for crowding that may contribute to the cosolute effects acting on amyloid formation.

  15. Study of neurotoxic intracellular calcium signalling triggered by amyloids.

    Science.gov (United States)

    Villalobos, Carlos; Caballero, Erica; Sanz-Blasco, Sara; Núñez, Lucía

    2012-01-01

    Neurotoxicity in Alzheimer's disease (AD) is associated to dishomeostasis of intracellular Ca(2+) induced by amyloid β peptide (Aβ) species. Understanding of the effects of Aβ on intracellular Ca(2+) homeostasis requires preparation of the different Aβ assemblies including oligomers and fibrils and the testing of their effects on cytosolic and mitochondrial Ca(2+) in neurons. Procedures for cerebellar granule cell culture, preparation of Aβ species as well as fluorescence and bioluminescence imaging of cytosolic and mitochondrial Ca(2+) in neurons are described.

  16. An interaction of beta-amyloid with aluminium in vitro.

    Science.gov (United States)

    Exley, C; Price, N C; Kelly, S M; Birchall, J D

    1993-06-21

    We have used circular dichroism spectroscopy to confirm that, in a membrane-mimicking solvent, A beta P(1-40) adopts a partially helical conformation and we have demonstrated the loss of this structure in the presence of physiologically relevant concentrations of aluminium. This is the first evidence of a direct biochemical interaction between aluminium and beta-amyloid and may have important implications for the pathogenesis of Alzheimer's disease.

  17. Elongation of the C-terminal domain of an anti-amyloid β single-chain variable fragment increases its thermodynamic stability and decreases its aggregation tendency.

    Science.gov (United States)

    Rivera-Hernández, Geovanny; Marin-Argany, Marta; Blasco-Moreno, Bernat; Bonet, Jaume; Oliva, Baldo; Villegas, Sandra

    2013-01-01

    Amyloid β (Aβ) immunotherapy is considered a promising approach to Alzheimer disease treatment. In contrast to the use of complete antibodies, administration of single-chain variable fragments (scFv) has not been associated with either meningoencephalitis or cerebral hemorrhage. ScFv-h3D6 is known to preclude cytotoxicity of the Aβ 1-42 peptide by removing its oligomers from the amyloid pathway. As is the case for other scFv molecules, the recombinant production of scFv-h3D6 is limited by its folding and stability properties. Here, we show that its urea-induced unfolding pathway is characterized by the presence of an intermediate state composed of the unfolded VL domain and the folded VH domain, which suggests the VL domain as a target for thermodynamic stability redesign. The modeling of the 3D structure revealed that the VL domain, located at the C-terminal of the molecule, was ending before its latest β-strand was completed. Three elongation mutants, beyond VL-K107, showed increased thermodynamic stability and lower aggregation tendency, as determined from urea denaturation experiments and Fourier-transform infrared spectroscopy, respectively. Because the mutants maintained the capability of removing Aβ-oligomers from the amyloid pathway, we expect these traits to increase the half-life of scFv-h3D6 in vivo and, consequently, to decrease the effective doses. Our results led to the improvement of a potential Alzheimer disease treatment and may be extrapolated to other class-I scFv molecules of therapeutic interest.

  18. Brain Amyloid Deposition and Longitudinal Cognitive Decline in Nondemented Older Subjects: Results from a Multi-Ethnic Population.

    Directory of Open Access Journals (Sweden)

    Yian Gu

    Full Text Available We aimed to whether the abnormally high amyloid-β (Aβ level in the brain among apparently healthy elders is related with subtle cognitive deficits and/or accelerated cognitive decline.A total of 116 dementia-free participants (mean age 84.5 years of the Washington Heights Inwood Columbia Aging Project completed 18F-Florbetaben PET imaging. Positive or negative cerebral Aβ deposition was assessed visually. Quantitative cerebral Aβ burden was calculated as the standardized uptake value ratio in pre-established regions of interest using cerebellar cortex as the reference region. Cognition was determined using a neuropsychological battery and selected tests scores were combined into four composite scores (memory, language, executive/speed, and visuospatial using exploratory factor analysis. We examined the relationship between cerebral Aβ level and longitudinal cognition change up to 20 years before the PET scan using latent growth curve models, controlling for age, education, ethnicity, and Apolipoprotein E (APOE genotype.Positive reading of Aβ was found in 41 of 116 (35% individuals. Cognitive scores at scan time was not related with Aβ. All cognitive scores declined over time. Aβ positive reading (B = -0.034, p = 0.02 and higher Aβ burden in temporal region (B = -0.080, p = 0.02 were associated with faster decline in executive/speed. Stratified analyses showed that higher Aβ deposition was associated with faster longitudinal declines in mean cognition, language, and executive/speed in African-Americans or in APOE ε4 carriers, and with faster memory decline in APOE ε4 carriers. The associations remained significant after excluding mild cognitive impairment participants.High Aβ deposition in healthy elders was associated with decline in executive/speed in the decade before neuroimaging, and the association was observed primarily in African-Americans and APOE ε4 carriers. Our results suggest that measuring cerebral Aβ may give us

  19. Co-deposition of basement membrane components during the induction of murine splenic AA amyloid

    DEFF Research Database (Denmark)

    Lyon, A W; Narindrasorasak, S; Young, I D

    1991-01-01

    Past studies have demonstrated that during murine AA amyloid induction there is co-deposition of the AA amyloid peptide and the basement membrane form of heparan sulfate proteoglycan. The synthesis and accumulation of heparan sulfate proteoglycan does not usually occur in the absence of other bas...... enhancing factor induction of amyloid, the period when amyloid is first detected. These observations raise the possibility that an abnormality in basement membrane metabolism is a very early event, and potentially plays an integral part in the process of AA amyloidogenesis....

  20. Effect of Fe{sub 3}O{sub 4} magnetic nanoparticles on lysozyme amyloid aggregation

    Energy Technology Data Exchange (ETDEWEB)

    Bellova, Andrea; Koneracka, Martina; Kopcansky, Peter; Tomasovicova, Natalia; Timko, Milan; Bagelova, Jaroslava; Gazova, Zuzana [Department of Biophysics, Department of Magnetism, Institute of Experimental Physics, Slovak Academy of Science, Watsonova 47, 04001 Kosice (Slovakia); Bystrenova, Eva; Valle, Francesco; Biscarini, Fabio, E-mail: gazova@saske.sk [CNR-Instituto per lo Studio dei Materiali Nanostrutturati, via Gobetti 101, I-40129 Bologna (Italy)

    2010-02-10

    Peptide amyloid aggregation is a hallmark of several human pathologies termed amyloid diseases. We have investigated the effect of electrostatically stabilized magnetic nanoparticles of Fe{sub 3}O{sub 4} on the amyloid aggregation of lysozyme, as a prototypical amyloidogenic protein. Thioflavin T fluorescence assay and atomic force microscopy were used for monitoring the inhibiting and disassembly activity of magnetic nanoparticles of Fe{sub 3}O{sub 4}. We have found that magnetic Fe{sub 3}O{sub 4} nanoparticles are able to interact with lysozyme amyloids in vitro leading to a reduction of the amyloid aggregates, thus promoting depolymerization; the studied nanoparticles also inhibit lysozyme amyloid aggregation. The ability to inhibit lysozyme amyloid formation and promote lysozyme amyloid disassembly exhibit concentration-dependent characteristics with IC50 = 0.65 mg ml{sup -1} and DC50 = 0.16 mg ml{sup -1} indicating that nanoparticles interfere with lysozyme aggregation already at stoichiometric concentrations. These features make Fe{sub 3}O{sub 4} nanoparticles of potential interest as therapeutic agents against amyloid diseases and their non-risk exploitation in nanomedicine and nanodiagnostics.

  1. Copper(II) ions and the Alzheimer's amyloid-β peptide: Affinity and stoichiometry of binding

    Science.gov (United States)

    Tõugu, Vello; Friedemann, Merlin; Tiiman, Ann; Palumaa, Peep

    2014-10-01

    Deposition of amyloid beta (Aβ) peptides into amyloid plaques is the hallmark of Alzheimer's disease. According to the amyloid cascade hypothesis this deposition is an early event and primary cause of the disease, however, the mechanisms that cause this deposition remain elusive. An increasing amount of evidence shows that the interactions of biometals can contribute to the fibrillization and amyloid formation by amyloidogenic peptides. From different anions the copper ions deserve the most attention since it can contribute not only toamyloid formation but also to its toxicity due to the generation of ROS. In this thesis we focus on the affinity and stoichiometry of copper(II) binding to the Aβ molecule.

  2. Non-targeted identification of prions and amyloid-forming proteins from yeast and mammalian cells.

    Science.gov (United States)

    Kryndushkin, Dmitry; Pripuzova, Natalia; Burnett, Barrington G; Shewmaker, Frank

    2013-09-20

    The formation of amyloid aggregates is implicated both as a primary cause of cellular degeneration in multiple human diseases and as a functional mechanism for providing extraordinary strength to large protein assemblies. The recent identification and characterization of several amyloid proteins from diverse organisms argues that the amyloid phenomenon is widespread in nature. Yet identifying new amyloid-forming proteins usually requires a priori knowledge of specific candidates. Amyloid fibers can resist heat, pressure, proteolysis, and denaturation by reagents such as urea or sodium dodecyl sulfate. Here we show that these properties can be exploited to identify naturally occurring amyloid-forming proteins directly from cell lysates. This proteomic-based approach utilizes a novel purification of amyloid aggregates followed by identification by mass spectrometry without the requirement for special genetic tools. We have validated this technique by blind identification of three amyloid-based yeast prions from laboratory and wild strains and disease-related polyglutamine proteins expressed in both yeast and mammalian cells. Furthermore, we found that polyglutamine aggregates specifically recruit some stress granule components, revealing a possible mechanism of toxicity. Therefore, core amyloid-forming proteins as well as strongly associated proteins can be identified directly from cells of diverse origin.

  3. 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.

  4. Apolipoprotein E: Essential Catalyst of the Alzheimer Amyloid Cascade

    Directory of Open Access Journals (Sweden)

    Huntington Potter

    2012-01-01

    Full Text Available The amyloid cascade hypothesis remains a robust model of AD neurodegeneration. However, amyloid deposits contain proteins besides Aβ, such as apolipoprotein E (apoE. Inheritance of the apoE4 allele is the strongest genetic risk factor for late-onset AD. However, there is no consensus on how different apoE isotypes contribute to AD pathogenesis. It has been hypothesized that apoE and apoE4 in particular is an amyloid catalyst or “pathological chaperone”. Alternatively it has been posited that apoE regulates Aβ clearance, with apoE4 been worse at this function compared to apoE3. These views seem fundamentally opposed. The former would indicate that removing apoE will reduce AD pathology, while the latter suggests increasing brain ApoE levels may be beneficial. Here we consider the scientific basis of these different models of apoE function and suggest that these seemingly opposing views can be reconciled. The optimal therapeutic target may be to inhibit the interaction of apoE with Aβ rather than altering apoE levels. Such an approach will not have detrimental effects on the many beneficial roles apoE plays in neurobiology. Furthermore, other Aβ binding proteins, including ACT and apo J can inhibit or promote Aβ oligomerization/polymerization depending on conditions and might be manipulated to effect AD treatment.

  5. 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.

  6. Amyloid fibrils nucleated and organized by DNA origami constructions

    Science.gov (United States)

    Udomprasert, Anuttara; Bongiovanni, Marie N.; Sha, Ruojie; Sherman, William B.; Wang, Tong; Arora, Paramjit S.; Canary, James W.; Gras, Sally L.; Seeman, Nadrian C.

    2014-07-01

    Amyloid fibrils are ordered, insoluble protein aggregates that are associated with neurodegenerative conditions such as Alzheimer's disease. The fibrils have a common rod-like core structure, formed from an elongated stack of β-strands, and have a rigidity similar to that of silk (Young's modulus of 0.2-14 GPa). They also exhibit high thermal and chemical stability and can be assembled in vitro from short synthetic non-disease-related peptides. As a result, they are of significant interest in the development of self-assembled materials for bionanotechnology applications. Synthetic DNA molecules have previously been used to form intricate structures and organize other materials such as metal nanoparticles and could in principle be used to nucleate and organize amyloid fibrils. Here, we show that DNA origami nanotubes can sheathe amyloid fibrils formed within them. The fibrils are built by modifying the synthetic peptide fragment corresponding to residues 105-115 of the amyloidogenic protein transthyretin and a DNA origami construct is used to form 20-helix DNA nanotubes with sufficient space for the fibrils inside. Once formed, the fibril-filled nanotubes can be organized onto predefined two-dimensional platforms via DNA-DNA hybridization interactions.

  7. Curcumin Binding to Beta Amyloid: A Computational Study.

    Science.gov (United States)

    Rao, Praveen P N; Mohamed, Tarek; Teckwani, Karan; Tin, Gary

    2015-10-01

    Curcumin, a chemical constituent present in the spice turmeric, is known to prevent the aggregation of amyloid peptide implicated in the pathophysiology of Alzheimer's disease. While curcumin is known to bind directly to various amyloid aggregates, no systematic investigations have been carried out to understand its ability to bind to the amyloid aggregates including oligomers and fibrils. In this study, we constructed computational models of (i) Aβ hexapeptide (16) KLVFFA(21) octamer steric-zipper β-sheet assembly and (ii) full-length Aβ fibril β-sheet assembly. Curcumin binding in these models was evaluated by molecular docking and molecular dynamics (MD) simulation studies. In both the models, curcumin was oriented in a linear extended conformation parallel to fiber axis and exhibited better stability in the Aβ hexapeptide (16) KLVFFA(21) octamer steric-zipper model (Ebinding  = -10.05 kcal/mol) compared to full-length Aβ fibril model (Ebinding  = -3.47 kcal/mol). Analysis of MD trajectories of curcumin bound to full-length Aβ fibril shows good stability with minimum Cα-atom RMSD shifts. Interestingly, curcumin binding led to marked fluctuations in the (14) HQKLVFFA(21) region that constitute the fibril spine with RMSF values ranging from 1.4 to 3.6 Å. These results show that curcumin binding to Aβ shifts the equilibrium in the aggregation pathway by promoting the formation of non-toxic aggregates.

  8. AMYPdb: A database dedicated to amyloid precursor proteins

    Directory of Open Access Journals (Sweden)

    Delamarche Christian

    2008-06-01

    Full Text Available Abstract Background Misfolding and aggregation of proteins into ordered fibrillar structures is associated with a number of severe pathologies, including Alzheimer's disease, prion diseases, and type II diabetes. The rapid accumulation of knowledge about the sequences and structures of these proteins allows using of in silico methods to investigate the molecular mechanisms of their abnormal conformational changes and assembly. However, such an approach requires the collection of accurate data, which are inconveniently dispersed among several generalist databases. Results We therefore created a free online knowledge database (AMYPdb dedicated to amyloid precursor proteins and we have performed large scale sequence analysis of the included data. Currently, AMYPdb integrates data on 31 families, including 1,705 proteins from nearly 600 organisms. It displays links to more than 2,300 bibliographic references and 1,200 3D-structures. A Wiki system is available to insert data into the database, providing a sharing and collaboration environment. We generated and analyzed 3,621 amino acid sequence patterns, reporting highly specific patterns for each amyloid family, along with patterns likely to be involved in protein misfolding and aggregation. Conclusion AMYPdb is a comprehensive online database aiming at the centralization of bioinformatic data regarding all amyloid proteins and their precursors. Our sequence pattern discovery and analysis approach unveiled protein regions of significant interest. AMYPdb is freely accessible 1.

  9. Mechanism of neuronal versus endothelial cell uptake of Alzheimer's disease amyloid beta protein.

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    Karunya K Kandimalla

    Full Text Available Alzheimer's disease (AD is characterized by significant neurodegeneration in the cortex and hippocampus; intraneuronal tangles of hyperphosphorylated tau protein; and accumulation of beta-amyloid (Abeta proteins 40 and 42 in the brain parenchyma as well as in the cerebral vasculature. The current understanding that AD is initiated by the neuronal accumulation of Abeta proteins due to their inefficient clearance at the blood-brain-barrier (BBB, places the neurovascular unit at the epicenter of AD pathophysiology. The objective of this study is to investigate cellular mechanisms mediating the internalization of Abeta proteins in the principle constituents of the neurovascular unit, neurons and BBB endothelial cells. Laser confocal micrographs of wild type (WT mouse brain slices treated with fluorescein labeled Abeta40 (F-Abeta40 demonstrated selective accumulation of the protein in a subpopulation of cortical and hippocampal neurons via nonsaturable, energy independent, and nonendocytotic pathways. This groundbreaking finding, which challenges the conventional belief that Abeta proteins are internalized by neurons via receptor mediated endocytosis, was verified in differentiated PC12 cells and rat primary hippocampal (RPH neurons through laser confocal microscopy and flow cytometry studies. Microscopy studies have demonstrated that a significant proportion of F-Abeta40 or F-Abeta42 internalized by differentiated PC12 cells or RPH neurons is located outside of the endosomal or lysosomal compartments, which may accumulate without degradation. In contrast, BBME cells exhibit energy dependent uptake of F-Abeta40, and accumulate the protein in acidic cell organelle, indicative of endocytotic uptake. Such a phenomenal difference in the internalization of Abeta40 between neurons and BBB endothelial cells may provide essential clues to understanding how various cells can differentially regulate Abeta proteins and help explain the vulnerability of cortical

  10. Pioglitazone improves reversal learning and exerts mixed cerebrovascular effects in a mouse model of Alzheimer's disease with combined amyloid-β and cerebrovascular pathology.

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    Panayiota Papadopoulos

    Full Text Available Animal models of Alzheimer's disease (AD are invaluable in dissecting the pathogenic mechanisms and assessing the efficacy of potential new therapies. Here, we used the peroxisome proliferator-activated receptor gamma agonist pioglitazone in an attempt to rescue the pathogenic phenotype in adult (12 months and aged (>18 months bitransgenic A/T mice that overexpress a mutated human amyloid precursor protein (APPSwe,Ind and a constitutively active form of transforming growth factor-β1 (TGF-β1. A/T mice recapitulate the AD-related cognitive deficits, amyloid beta (Aβ and cerebrovascular pathologies, as well as the altered metabolic and vascular coupling responses to increased neuronal activity. Pioglitazone normalized neurometabolic and neurovascular coupling responses to sensory stimulation, and reduced cortical astroglial and hippocampal microglial activation in both age groups. Spatial learning and memory deficits in the Morris water maze were not rescued by pioglitazone, but reversal learning was improved in the adult cohort notwithstanding a progressing Aβ pathology. While pioglitazone preserved the constitutive nitric oxide synthesis in the vessel wall, it unexpectedly failed to restore cerebrovascular reactivity in A/T mice and even exacerbated the dilatory deficits. These data demonstrate pioglitazone's efficacy on selective AD hallmarks in a complex AD mouse model of comorbid amyloidosis and cerebrovascular pathology. They further suggest a potential benefit of pioglitazone in managing neuroinflammation, cerebral perfusion and glucose metabolism in AD patients devoid of cerebrovascular pathology.

  11. Effects of Yizhi Capsule (益智胶囊) on Learning and Memory Disorder and β-amyloid Peptide Induced Neurotoxicity in Rats

    Institute of Scientific and Technical Information of China (English)

    WU Hang-yu; XU Jiang-ping; LI Lin; ZHU Bai-hua

    2006-01-01

    Objective: To explore the effects of Yizhi Capsule (益智胶囊, YZC) on learning and memory disorder and β-amyloid peptide induced neurotoxicity in rats. Methods: Various doses of YZC were administered to Sprague-Dawley (SD) rats for 8 consecutive days, twice a day. On the 8th day of the experiment,scopolamine hydrobromide was intraperitoneally injected to every rat and Morris water maze test and shuttle dark avoidance test were carried out respectively to explore the changes of learning and memory capacities in the rats. Besides, after the cerebral cortical neurons of newborn SD rats aged within 3 days were cultured in vitro for 7 days, drug serum containing YZC was added to the cultured neurons before or after β amyloid peptide25-35 (Aβ25-35) intoxication to observe the protective effect of YZC on neurotoxicity by MTT assay and to determine the LDH content in the supernatant. Results: Compared with those untreated with YZC, the rats having received YZC treatment got superiority in shorter time of platform seeking in Morris water maze test,as well as elongated latent period and less times of error in shuttle dark avoidance test. On the cultured neurons, YZC drug serum could effectively increase the survival rate of Aβ25-35 intoxicated neurons and reduce the LDH contents in cultured supernatant. Conclusion: YZC has an action of improving learning and memory disorder, and good protective effect on Aβ25-35 induced neurotoxicity in SD rats.

  12. Contraceptives and cerebral thrombosis: a five-year national case-control study

    DEFF Research Database (Denmark)

    Lidegaard, Øjvind; Kreiner, Svend

    2002-01-01

    Oral contraceptives; Cerebral thrombosis; Thrombotic stroke; Transitory cerebral ischemic attack; Thrombosis......Oral contraceptives; Cerebral thrombosis; Thrombotic stroke; Transitory cerebral ischemic attack; Thrombosis...

  13. Regional amyloid deposition in amnestic mild cognitive impairment and Alzheimer's disease evaluated by [18F]AV-45 positron emission tomography in Chinese population.

    Directory of Open Access Journals (Sweden)

    Kuo-Lun Huang

    Full Text Available BACKGROUND: To compare the neocortical amyloid loads among cognitively normal (CN, amnestic mild cognitive impairment (aMCI, and Alzheimer's disease (AD subjects with [(18F]AV-45 positron emission tomography (PET. MATERIALS AND METHODS: [(18F]AV-45 PET was performed in 11 CN, 13 aMCI, and 12 AD subjects to compare the cerebral cortex-to-whole cerebellum standard uptake value ratios (SUVRs of global and individual volumes of interest (VOIs cerebral cortex. The correlation between global cortical [(18F]AV-45 SUVRs and Mini-Mental State Examination (MMSE scores was analyzed. RESULTS: The global cortical [(18F]AV-45 SUVRs were significantly different among the CN (1.08±0.08, aMCI (1.27±0.06, and AD groups (1.34±0.13 (p = 0.0003 with amyloidosis positivity rates of 9%, 62%, and 92% in the three groups respectively. Compared to CN subjects, AD subjects had higher SUVRs in the global cortical, precuneus, frontal, parietal, occipital, temporal, and posterior cingulate areas; while aMCI subjects had higher values in the global cortical, precuneus, frontal, occipital and posterior cingulate areas. There were negative correlations of MMSE scores with SUVRs in the global cortical, precuneus, frontal, parietal, occipital, temporal, posterior cingulate and anterior cingulate areas on a combined subject pool of the three groups after age and education attainment adjustment. CONCLUSIONS: Amyloid deposition occurs relatively early in precuneus, frontal and posterior cingulate in aMCI subjects. Higher [(18F]AV-45 accumulation is present in parietal, occipital and temporal gyri in AD subjects compared to the aMCI group. Significant correlation between MMSE scores and [(18F]AV-45 SUVRs can be observed among CN, aMCI and AD subjects.

  14. The coarse-grained OPEP force field for non-amyloid and amyloid proteins.

    Science.gov (United States)

    Chebaro, Yassmine; Pasquali, Samuela; Derreumaux, Philippe

    2012-08-02

    Coarse-grained protein models with various levels of granularity and degrees of freedom offer the possibility to explore many phenomena including folding, assembly, and recognition in terms of dynamics and thermodynamics that are inaccessible to all-atom representations in explicit aqueous solution. Here, we present a refined version of the coarse-grained optimized potential for efficient protein structure prediction (OPEP) based on a six-bead representation. The OPEP version 4.0 parameter set, which uses a new analytical formulation for the nonbonded interactions and adds specific side-chain-side-chain interactions for α-helix, is subjected to three tests. First, we show that molecular dynamics simulations at 300 K preserve the experimental rigid conformations of 17 proteins with 37-152 amino acids within a root-mean-square deviation (RMSD) of 3.1 Å after 30 ns. Extending the simulation time to 100 ns for five proteins does not change the RMSDs. Second, replica exchange molecular dynamics (REMD) simulations recover the NMR structures of three prototypical β-hairpin and α-helix peptides and the NMR three-stranded β-sheet topology of a 37-residue WW domain, starting from randomly chosen states. Third, REMD simulations on the ccβ peptide show a temperature transition from a three-stranded coiled coil to amyloid-like aggregates consistent with experiments, while simulations on low molecular weight aggregates of the prion protein helix 1 do not. Overall, these studies indicate the effectiveness of our OPEP4 coarse-grained model for protein folding and aggregation, and report two future directions for improvement.

  15. T cell mediated cerebral hemorrhages and microhemorrhages during passive Aβ immunization in APPPS1 transgenic mice

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    de Calignon Alix

    2011-03-01

    Full Text Available Abstract Background Immunization against amyloid-β (Aβ, the peptide that accumulates in the form of senile plaques and in the cerebrovasculature in Alzheimer's disease (AD, causes a dramatic immune response that prevents plaque formation and clears accumulated Aβ in transgenic mice. In a clinical trial of Aβ immunization, some patients developed meningoencephalitis and hemorrhages. Neuropathological investigations of patients who died after the trial showed clearance of amyloid pathology, but also a powerful immune response involving activated T cells probably underlying the negative effects of the immunization. Results To define the impact of T cells on this inflammatory response we used passive immunization and adoptive transfer to separate the effect of IgG and T cell mediated effects on microhemorrhage in APPPS1 transgenic mice. Neither anti Aβ IgG nor adoptively transferred T cells, alone, led to increased cerebrovascular damage. However, the combination of adoptively transferred T cells and passive immunization led to massive cerebrovascular bleeding that ranged from multiple microhemorrhages in the parenchyma to large hematomas. Conclusions Our results indicate that vaccination can lead to Aβ and T cell induced cerebral micro-hemorrhages and acute hematomas, which are greatly exacerbated by T cell mediated activity.

  16. Aetiology of intracerebral haemorrage

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    Stefano Spolveri

    2011-08-01

    Full Text Available Spontaneous non traumatic intracerebral haemorrhage (ICH is usually caused by many different interacting factors, such as the use of alcohol or fibrinolitic drugs, congenital aneurysm, brain tumors, and blood dyscrasia. Age and hypertension-related small vessel diseases, and cerebral amyloid angiopathy are the most common forms of vascular damage which can lead to ICH. Furthermore, a group of inherited cerebral small vessel diseases linked to ICH have been reported recently and the number of these forms is increasing. The presence of leukoaraiosis, lacunar infarcts and microbleeds has been suggested to indicate a higher risk for cerebral hemorrhage. In recent years, MRI and neuroimaging techniques contributed to the understanding and the diagnosis of this disease.

  17. Susceptibility weighted imaging: a new tool in magnetic resonance imaging of stroke

    Energy Technology Data Exchange (ETDEWEB)

    Santhosh, K. [Department of Imaging Sciences and Interventional Radiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum (India); Kesavadas, C. [Department of Imaging Sciences and Interventional Radiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum (India)], E-mail: chandkesav@yahoo.com; Thomas, B.; Gupta, A.K.; Thamburaj, K.; Kapilamoorthy, T. Raman [Department of Imaging Sciences and Interventional Radiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum (India)

    2009-01-15

    Susceptibility weighted imaging (SWI) is a magnetic resonance (MR) technique that is exquisitely sensitive to paramagnetic substances, such as deoxygenated blood, blood products, iron, and calcium. This sequence allows detection of haemorrhage as early as 6 h and can reliably detect acute intracerebral parenchymal, as well as subarachnoid haemorrhage. It detects early haemorrhagic transformation within an infarct and provides insight into the cerebral haemodynamics following stroke. It helps in the diagnosis of cerebral venous thrombosis. It also has applications in the work-up of stroke patients. The sequence helps in detecting microbleeds in various conditions, such as vasculitis, cerebral autosomal dominant arteriopathy, subacute infarcts and leucoencephalopathy (CADASIL), amyloid angiopathy, and Binswanger's disease. The sequence also aids in the diagnosis of vascular malformations and perinatal cerebrovascular injuries. This review briefly illustrates the utility of this MR technique in various aspects of stroke diagnosis and management.

  18. 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.

  19. Embodying Investigations of Cerebral Palsy

    DEFF Research Database (Denmark)

    Martiny, Kristian Møller Moltke

    The main question of Kristian Martiny’s dissertation is: how do we help persons living with the brain damage, cerebral palsy (CP)? This question is as complex and difficult to answer as any healthcare question. Martiny argues that we need to ‘open up’ how we do ( cognitive ) science in order...

  20. Sirt1 in cerebral ischemia

    Science.gov (United States)

    Koronowski, Kevin B.; Perez-Pinzon, Miguel A.

    2015-01-01

    Cerebral ischemia is among the leading causes of death worldwide. It is characterized by a lack of blood flow to the brain that results in cell death and damage, ultimately causing motor, sensory, and cognitive impairments. Today, clinical treatment of cerebral ischemia, mostly stroke and cardiac arrest, is limited and new neuroprotective therapies are desperately needed. The Sirtuin family of oxidized nicotinamide adenine dinucleotide (NAD+)-dependent deacylases has been shown to govern several processes within the central nervous system as well as to possess neuroprotective properties in a variety of pathological conditions such as Alzheimer’s Disease, Parkinson’s Disease, and Huntington’s Disease, among others. Recently, Sirt1 in particular has been identified as a mediator of cerebral ischemia, with potential as a possible therapeutic target. To gather studies relevant to this topic, we used PubMed and previous reviews to locate, select, and resynthesize the lines of evidence presented here. In this review, we will first describe some functions of Sirt1 in the brain, mainly neurodevelopment, learning and memory, and metabolic regulation. Second, we will discuss the experimental evidence that has implicated Sirt1 as a key protein in the regulation of cerebral ischemia as well as a potential target for the induction of ischemic tolerance. PMID:26819971

  1. Sirt1 in cerebral ischemia

    Directory of Open Access Journals (Sweden)

    Kevin B Koronowski

    2015-01-01

    Full Text Available Cerebral ischemia is among the leading causes of death worldwide. It is characterized by a lack of blood flow to the brain that results in cell death and damage, ultimately causing motor, sensory, and cognitive impairments. Today, clinical treatment of cerebral ischemia, mostly stroke and cardiac arrest, is limited and new neuroprotective therapies are desperately needed. The Sirtuin family of oxidized nicotinamide adenine dinucleotide (NAD +-dependent deacylases has been shown to govern several processes within the central nervous system as well as to possess neuroprotective properties in a variety of pathological conditions such as Alzheimer′s Disease, Parkinson′s Disease, and Huntington′s Disease, among others. Recently, Sirt1 in particular has been identified as a mediator of cerebral ischemia, with potential as a possible therapeutic target. To gather studies relevant to this topic, we used PubMed and previous reviews to locate, select, and resynthesize the lines of evidence presented here. In this review, we will first describe some functions of Sirt1 in the brain, mainly neurodevelopment, learning and memory, and metabolic regulation. Second, we will discuss the experimental evidence that has implicated Sirt1 as a key protein in the regulation of cerebral ischemia as well as a potential target for the induction of ischemic tolerance.

  2. Graft selection in cerebral revascularization.

    Science.gov (United States)

    Baaj, Ali A; Agazzi, Siviero; van Loveren, Harry

    2009-05-01

    Cerebral revascularization constitutes an important treatment modality in the management of complex aneurysms, carotid occlusion, tumor, and moyamoya disease. Graft selection is a critical step in the planning of revascularization surgery, and depends on an understanding of graft and regional hemodynamics, accessibility, and patency rates. The goal of this review is to highlight some of these properties.

  3. MR imaging of cerebral palsy

    Energy Technology Data Exchange (ETDEWEB)

    Saginoya, Toshiyuki [Urasoe General Hospital, Okinawa (Japan); Yamaguchi, Keiichiro; Kuniyoshi, Kazuhide [and others

    1996-06-01

    We evaluated 35 patients with cerebral palsy on the basis of MR imaging findings in the brain. The types of palsy were spastic quadriplegia (n=11), spastic diplegia (n=9), spastic hemiplegia (n=2), double hemiplegia (n=1), athetosis (n=10) and mixed (n=2). Of all patients, 28 (80%) generated abnormal findings. In spastic quadriplegia, although eight cases revealed severe brain damage, two cases showed no abnormal findings in the brain. One of the three had cervical cord compression caused by atlanto-axial subluxation. In spastic diplegia, the findings were divided according to whether the patient was born at term or preterm. If the patient had been born prematurely, the findings showed periventricular leukomalacia and abnormally high intensity in the posterior limbs of the internal capsule on T2-weighted images. MR imaging in spastic hemiplegia revealed cerebral infarction. In the athetoid type, half of all cases showed either no abnormal findings or slight widening of the lateral ventricle. Three cases showed abnormal signals of the basal ganglia. The reason why athetoid-type palsy did not show severe abnormality is unknown. We believe that MR imaging is a useful diagnostic modality to detect damage in the brain in cerebral palsy and plays an important role in the differentiation of cerebral palsy from the spastic palsy disease. (author)

  4. Ocular defects in cerebral palsy

    Directory of Open Access Journals (Sweden)

    Katoch Sabita

    2007-01-01

    Full Text Available There is a high prevalence of ocular defects in children with developmental disabilities. This study evaluated visual disability in a group of 200 cerebral palsy (CP patients and found that 68% of the children had significant visual morbidity. These findings emphasize the need for an early ocular examination in patients with CP.

  5. Doublecortin-expressing cells persist in the associative cerebral cortex and amygdala in aged nonhuman primates

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    Xue-mei Zhang

    2009-10-01

    Full Text Available A novel population of cells that express typical immature neuronal markers including doublecortin (DCX+ has been recently identified throughout the adult cerebral cortex of relatively large mammals (guinea pig, rabbit, cat, monkey and human. These cells are more common in the associative relative to primary cortical areas and appear to develop into interneurons including type II nitrinergic neurons. Here we further describe these cells in the cerebral cortex and amygdala, in comparison with DCX+ cells in the hippocampal dentate gyrus, in 3 age groups of rhesus monkeys: young adult (12.3±0.2 yrs, n=3, mid-age (21.2±1.9 yrs, n=3 and aged (31.3±1.8 yrs, n=4. DCX+ cells with a heterogeneous morphology persisted in layers II/III primarily over the associative cortex and amygdala in all groups (including in two old animals with cerebral amyloid pathology, showing a parallel decline in cell density with age across regions. In contrast to the cortex and amygdala, DCX+ cells in the subgranular zone diminished in the mid-age and aged groups. DCX+ cortical cells might arrange as long tangential migratory chains in the mid-age and aged animals, with apparently distorted cell clusters seen in the aged group. Cortical DCX+ cells colocalized commonly with polysialylated neural cell adhesion molecule (PSA-NCAM and partially with neuron-specific nuclear protein (NeuN and γ-aminobutyric acid (GABA, suggesting a potential differentiation of these cells into interneuron phenotype. These data suggest a life-long role for immature interneuron-like cells in the associative cerebral cortex and amygdala in nonhuman primates.

  6. Association of Cerebral Amyloidosis, Blood Pressure, and Neuronal Injury with Late-life Onset Depression

    Directory of Open Access Journals (Sweden)

    Min Soo Byun

    2016-10-01

    Full Text Available Previous literature suggests that Alzheimer’s disease (AD process may contribute to late-life onset depression (LLOD. Therefore, we investigated the association of LLOD with cerebral amyloidosis and neuronal injury, the two key brain changes in AD, along with vascular risks. Twenty nine non-demented individuals who first experienced major depressive disorder (MDD after age of 60 years were included as LLOD subjects, and 27 non-demented elderly individuals without lifetime experience of MDD were included as normal controls (NC. Comorbid mild cognitive impairment (MCI was diagnosed in 48% of LLOD subjects and in 0% of NC. LLOD, irrespective of comorbid MCI diagnosis, was associated with prominent prefrontal cortical atrophy. Compared to NC, LLOD subjects with comorbid MCI (LLODMCI showed increased cerebral 11C-Pittsburg compound B (PiB retention and plasma beta-amyloid 1-40 and 1-42 peptides, as measures of cerebral amyloidosis; and, such relationship was not observed in overall LLOD or LLOD without MCI (LLODwoMCI. LLOD subjects, particularly the LLODwoMCI, had higher systolic blood pressure (SBP than NC. When analyzed in the same multiple logistic regression model that included prefrontal gray matter (GM density, cerebral amyloidosis and SBP as independent variables, only prefrontal GM density showed a significant independent association with LLOD regardless of MCI comorbidity status. Our findings suggest AD process might be related to LLOD via prefrontal neuronal injury in the MCI stage, whereas vascular processes—SBP elevation, in particular—are associated with LLOD via prefrontal neuronal injury even in cognitively intact or less impaired individuals.

  7. Association of Cerebral Amyloidosis, Blood Pressure, and Neuronal Injury with Late-Life Onset Depression

    Science.gov (United States)

    Byun, Min Soo; Choe, Young Min; Sohn, Bo Kyung; Yi, Dahyun; Han, Ji Young; Park, Jinsick; Choi, Hyo Jung; Baek, Hyewon; Lee, Jun Ho; Kim, Hyun Jung; Kim, Yu Kyeong; Yoon, Eun Jin; Sohn, Chul-Ho; Woo, Jong Inn; Lee, Dong Young

    2016-01-01

    Previous literature suggests that Alzheimer's disease (AD) process may contribute to late-life onset depression (LLOD). Therefore, we investigated the association of LLOD with cerebral amyloidosis and neuronal injury, the two key brain changes in AD, along with vascular risks. Twenty nine non-demented individuals who first experienced major depressive disorder (MDD) after age of 60 years were included as LLOD subjects, and 27 non-demented elderly individuals without lifetime experience of MDD were included as normal controls (NC). Comorbid mild cognitive impairment (MCI) was diagnosed in 48% of LLOD subjects and in 0% of NC. LLOD, irrespective of comorbid MCI diagnosis, was associated with prominent prefrontal cortical atrophy. Compared to NC, LLOD subjects with comorbid MCI (LLODMCI) showed increased cerebral 11C-Pittsburg compound B (PiB) retention and plasma beta-amyloid 1–40 and 1–42 peptides, as measures of cerebral amyloidosis; and, such relationship was not observed in overall LLOD or LLOD without MCI (LLODwoMCI). LLOD subjects, particularly the LLODwoMCI, had higher systolic blood pressure (SBP) than NC. When analyzed in the same multiple logistic regression model that included prefrontal gray matter (GM) density, cerebral amyloidosis, and SBP as independent variables, only prefrontal GM density showed a significant independent association with LLOD regardless of MCI comorbidity status. Our findings suggest AD process might be related to LLOD via prefrontal neuronal injury in the MCI stage, whereas vascular processes—SBP elevation, in particular—are associated with LLOD via prefrontal neuronal injury even in cognitively intact or less impaired individuals. PMID:27790137

  8. Cerebral edema in drug addicts

    Directory of Open Access Journals (Sweden)

    Daruši Dragana J.

    2014-01-01

    Full Text Available Background/Aim. The effect of drugs leaves permanent consequences on the brain, organic in type, followed by numerous manifestations, and it significantly affects the development of mental dysfunctions. The clinicians are often given a task to estimate a patient’s personality during treatment or during experts estimate of a drug addict. The aim of this research was to determine the differences, if any, in characteristics of addicts experience and personality traits in drug addicts with or without cerebral edema. Methods. The research was conducted on a sample of 252 male drug addicts, the average age of 23.3 (SD = 4.3 years. Cerebral edema was confirmed on magnetic resonance (MR images of the brain performed during the treatment of the addicts. The participants were tested by the psychologists using Minnesota Multiphasic Personality Inventory (MMPI-201 test, and the data were processed using canonical discriminate analysis within the SPSS program. The dependent variable in the study was cerebral edema. A block of independent variables, designed for the requirements of this study, consisted of two subgroups. The first one consisted of 12 variables describing the relevant characteristics of drug abuse. The second subgroup consisted of 8 psychopathological tendencies in the personality defined by the mentioned test. Results. Cerebral edema was confirmed in 52 (20.63% of the drug addicts. The differences between the groups of drug addicts with and without cerebral edema were determined in the following: the time span of taking drugs (0.301, use of alcohol parallel with drugs (0.466, and treatment for addiction (0.603. In the drug addicts with a cerebral edema, MMPI-201 confirmed the increase in the scales for hypochondria, psychopathic deviations and psychastenia, and the decrease in the scales for schizophrenia and depression. Conclusion. Our study confirmed a possible connection between cerebral edema and personality traits in a number of the

  9. 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.

  10. Anestesia e paralisia cerebral Anestesia y parálisis cerebral Anesthesia and cerebral palsy

    Directory of Open Access Journals (Sweden)

    Március Vinícius M Maranhão

    2005-12-01

    Full Text Available JUSTIFICATIVA E OBJETIVOS: A paralisia cerebral (PC é uma doença não progressiva decorrente de lesão no sistema nervoso central, levando a um comprometimento motor do paciente. O portador de PC freqüentemente é submetido a procedimentos cirúrgicos devido a doenças usuais e situações particulares decorrentes da paralisia cerebral. Foi objetivo deste artigo revisar aspectos da paralisia cerebral de interesse para o anestesiologista, permitindo um adequado manuseio pré, intra e pós-operatório neste tipo de paciente. CONTEÚDO: O artigo aborda aspectos da paralisia cerebral como etiologia, classificação, fatores de risco, fisiopatologia, quadro clínico, diagnóstico, terapêuticas utilizadas bem como avaliação pré-operatória, medicação pré-anestésica, manuseio intra e pós-operatório, analgesia pós-operatória e dor crônica. CONCLUSÕES: O anestesiologista desempenha um papel importante na diminuição da morbidade e mortalidade anestésico-cirúrgica em pacientes portadores de paralisia cerebral. O conhecimento da fisiopatologia dos diferentes tipos de paralisia cerebral bem como das doenças associadas e suas terapêuticas é imprescindível, pois permite ao anestesiologista antecipar e prevenir complicações intra e pós-operatórias neste tipo de paciente.JUSTIFICATIVA Y OBJETIVOS: La parálisis cerebral (PC es una enfermedad no progresiva consecuente de una lesión en el sistema nervioso central, llevando a un comprometimiento motor del paciente. El portador de PC, frecuentemente es sometido a procedimientos quirúrgicos debido a enfermedades usuales y situaciones particulares consecuentes de la parálisis cerebral. El objetivo de este artículo, fue revisar aspectos de la parálisis cerebral de interés para el anestesista, permitiendo un adecuado manoseo pre, intra y posoperatorio en este tipo de paciente. CONTENIDO: El artículo aborda aspectos de la parálisis cerebral como etiología, clasificación, factores de

  11. Digital subtraction angiography in cerebral infarction

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Sin Young; Kim, Ji Hun; Suh, Hong Kil; Kim, Hyo Heon; Kwack, Eun Young; Lee, Il Seong [College of Medicine Hallym University, Seoul (Korea, Republic of)

    1995-01-15

    The usefulness and radiographic findings of the angiography in cerebral infarction are well known. We attempted to evaluate the angiographic causes, findings, and the usefulness of DSA in cerebral infarction. The authors reviewed retrospectively DSA images of 51 patients who were diagnosed as having cerebral infarction by brain CT and/or MRI and clinical settings. DSA was performed in all 51 patients, and in 3 patients, conventional angiogram was also done. Both carotid DSA images were obtained in AP, lateral, oblique projections, and one or both vertebral DSA images in AP and lateral. The authors reviewed the patient's charts for symptoms, operative findings and final diagnosis, and analysed DSA findings of cerebral atherosclerosis with focus on 6 major cerebral arteries. Among the 51 patients of cerebral infarction 43 patients (84.3%) had cerebral atherosclerosis, 1 dissecting aneurysm, 1 moyamoya disease and 6 negative in angiogram. DSA findings of cerebral atherosclerosis were multiple narrowing in 42 patients (97.7%), tortuosity in 22 (51.2%), dilatation in 14, occlusion in 12, avascular region in 8, collaterals in 7, ulcer in 6, and delayed washout of contrast media in 3. In cerebral atherosclerosis, internal carotid artery was involved in 37 patients (86.0%), middle cerebral artery in 29 (67.4%) posterior cerebral artery in 28, anterior cerebral artery in 26, vertebral artery in 22, and basilar artery in 15. Intracranial involvement of cerebral atherosclerosis (64.9%) was more common than extracranial involvement (16.2%). In cerebral infarction MRA may be the screening test, but for more precise evaluation of vascular abnormality and its extent, DSA should be considered.

  12. The cerebral perivascular cells.

    Science.gov (United States)

    Angelov, D N; Walther, M; Streppel, M; Guntinas-Lichius, O; Neiss, W F

    1998-01-01

    fluorescent mode this DAB reaction product selectively quenches the fluorescence of all immunopositive cells, i.e. only those neuronophages that do not bind to the primary antibody remain fluorescent. Combining FG-labeling of neuronophages with immunoquenching, a population of small round fluorescent cells was discovered, localized in the immediate vicinity of the motoneurons long after the neuronofugal migration of microglia. As the fluorescence of these cells was not quenched after a triple immunostaining with anti-neuronal-specific enolase, anti-GFAP and OX-42 (quenching all fluorescence from neurons, astroglia, and microglia), they seem to represent a new, immunologically unidentified neuronophage. Following this triple immunostaining, a broad panel of antibodies was tested to stain, quench fluorescence, and thus immunotype these enigmatic phagocytes. Only the monoclonal antibody ED2, the classical marker for perivascular cells, specifically stained the small round neuronophages. Although the perivascular cells are in the vicinity of the basal lamina of the cerebral vasculature, they must not be confused with the pericytes, which are not able to perform phagocytosis. In contrast, the perivascular cells are macrophages-ED2 recognizes an established macrophage membrane antigen. In addition, after neuronal injury a subset of the perivascular cells starts to synthesize MHC class II glycoproteins and IL-1 beta. Hence this population of cells seems to possess the complete machinery required for antigen presentation: They are macrophages, upregulate MHC class II molecules and IL-1 beta, and due to their anatomical location, have access to circulating T lymphocytes. What was still lacking, however, was a direct proof of neuronophagia. Our experiments provided this proof. (ABSTRACT TRUNCATED)

  13. Effect of creatine supplementation on cognitive performance and apoptosis in a rat model of amyloid-beta-induced Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Malek Alimohammadi-Kamalabadi

    2016-11-01

    Conclusion: Cr supplementation before and after β-amyloid injection into the CA1 area of hippocampus deteriorates the learning and memory impairment of rats and it does not protect neuronal apoptosis caused by β-amyloid.

  14. Amyloid-beta(29-42) dimer formations studied by a multicanonical-multioverlap molecular dynamics simulation.

    Science.gov (United States)

    Itoh, Satoru G; Okamoto, Yuko

    2008-03-13

    Amyloid-beta peptides are known to form amyloid fibrils and are considered to play an important role in Alzheimer's disease. Amyloid-beta(29-42) is a fragment of the amyloid-beta peptide and also has a tendency to form amyloid fibrils. In order to study the mechanism of amyloidogenesis of this fragment, we applied one of the generalized-ensemble algorithms, the multicanonical-multioverlap algorithm, to amyloid-beta(29-42) dimer in aqueous solution. We obtained a detailed free-energy landscape of the dimer system. From the detailed free-energy landscape, we examined monomer and dimer formations of amyloid-beta(29-42) and deduced dimerization processes, which correspond to seeding processes in the amyloidogenesis of amyloid-beta(29-42).

  15. Na+*K+-ATPase activity of erythrocyte membrane in diabetic type 2 angiopathies%2型糖尿病性血管病和红细胞膜Na+*K+-ATP酶活性

    Institute of Scientific and Technical Information of China (English)

    何浩明; 黄慧建; 徐宁; 李小民; 田小平; 汪洪流

    2001-01-01

    目的:探讨2型糖尿病性血管病患者的红细胞膜Na+*K+-ATP酶活性的变化及其意义。方法:按Reilini制膜法测定55例2型糖尿病性血管病红细胞膜Na+*K+ -ATP酶活性,并与35名健康组作对照,并且将其结果与红细胞内Na+*K+浓度、空腹血糖、糖化血红蛋白等进行相关分析。结果:2型糖尿病血管病患者红细胞膜Na+*K+-ATP酶含量显著低于正常人(P<0.01),且与红细胞内Na+*K+浓度、空腹血糖、糖化血红蛋白等密切相关。结论:红细胞膜Na+*K+-ATP酶活性的下降可能参与糖尿病性血管病变的发生、发展过程。%Objective:To study on the change of Na+*K +-ATPase activity of erythrocyte membrane of patients with diabetic type 2 an giopathies.Methods:According to Reilini method the concentrations of erythrocyt e membrane Na+*K+-ATPase of 55 cases with diabetic type 2 angiopathies and 35 normal controls were measured.With density of Na+ and K+,levels of f asting blood glucose(FBG),glycosylated hemoglobin(GHb) were also detected.Results:Na+*K+-ATPase activity of erythrocyte membrane was sig nificantly decreased in diabetic type 2 patients(P<0.01).Conclusions:Decreased Na+*K+-ATPase activity in erythrocyte me mbrane may be one of factors that contributed to the occurrence and development of diabetic type 2 mellitus.

  16. Nodular goiter with amyloid deposition in an elderly patient: fine-needle cytology diagnosis and review of the literature

    OpenAIRE

    Di Crescenzo, Vincenzo; Garzi, Alfredo; Petruzziello, Fara; Cinelli, Mariapia; Catalano, Lucio; Zeppa, Pio; Vitale, Mario

    2013-01-01

    Background Amyloidosis is a systemic disease characterized by the extracellular deposition of amyloid fibrils in different organs and tissues. The thyroid gland may be affected by diffuse or nodular amyloid deposits, along with multiple myeloma (MM) (Amyloid Light-Chain Amyloidosis, AL amyloidosis) or chronic inflammatory diseases (Amyloid A Amyloidosis, AA amyloidosis), but thyroid gland involvement rarely appears as the first clinical manifestation in both conditions. The present study repo...

  17. Complete Genome Sequence of Pseudomonas sp. UK4, a Model Organism for Studies of Functional Amyloids in Pseudomonas

    DEFF Research Database (Denmark)

    Dueholm, Morten Simonsen; Danielsen, Heidi Nolsøe; Nielsen, Per Halkjær

    2014-01-01

    Here, we present the complete genome of Pseudomonas sp. UK4. This bacterium was the first Pseudomonas strain shown to produce functional amyloids, and it represents a model organism for studies of functional amyloids in Pseudomonas (Fap).......Here, we present the complete genome of Pseudomonas sp. UK4. This bacterium was the first Pseudomonas strain shown to produce functional amyloids, and it represents a model organism for studies of functional amyloids in Pseudomonas (Fap)....

  18. Serum amyloid A: an acute phase apolipoprotein and precursor of AA amyloid.

    Science.gov (United States)

    Marhaug, G; Dowton, S B

    1994-08-01

    Serum amyloid A is an acute phase protein complexed to HDL as an apoprotein. The molecular weight is 11.4-12.5 kDa in different species and the protein has from 104 to 112 amino acids, without or with an insertion of eight amino acids at position 72. The protein is very well conserved throughout evolution, indicating an important biological function. The N-terminal part of the molecule is hydrophobic and probably responsible for the lipid binding properties. The most conserved part is from position 38 to 52 and this part is therefore believed to be responsible for the until now unknown biological function. The protein is coded on chromosome 11p in man, and chromosome 7 in mice, and found in all mammals until now investigated, and also in the Peking duck. In the rat a truncated SAA mRNA has been demonstrated, but no equivalent serum protein has been reported. Acute phase SAA is first of all produced in hepatocytes after induction by cytokines, but extrahepatic expression of both acute phase and constitutive SAA proteins have been demonstrated. Several cytokines, first of all IL-1, IL-6 and TNF are involved in the induction of SAA synthesis, but the mutual importance of these cytokines seems to be cell-type specific and to vary in various experimental settings. The role of corticosteroids in SAA induction is somewhat confusing. In most in vitro studies corticosteroids show an enhancing or synergistic effect with cytokines on SAA production in cultured cell. However, in clinical studies and in vivo studies in animals an inhibitory effect of corticosteroids is evident, probably due to the all over anti-inflammatory effect of the drug. Until now no drug has been found that selectively inhibits SAA production by hepatocytes. Effective anti-inflammatory or antibacterial treatment is the only tool for reducing SAA concentration in serum and reducing the risk of developing secondary amyloidosis. The function of SAA is still unclear. Interesting theories, based on current

  19. Cerebral aterial spasm. I. Adrenergic mechanism in experimental cerebral vasospasm.

    Directory of Open Access Journals (Sweden)

    Morooka,Hiroshi

    1978-04-01

    Full Text Available This study demonstrates that an adrenergic mechanism plays an important role in producing the delayed cerebral vasospasm which follows subarachnoid hemorrhage. Results were as follows: 1. Experimental subarachnoid hemorrhage (SAH was produced by injection of fresh arterial blood into the cisterna magna in cats. The cerebral vasospasm was shown angiographically to be biphasic in nature: immediate constriction lasting 1 h and marked prolonged spasm occurring between the 3rd and 5th day after SAH. The amount of noradrenaline (NA and dopamine-beta-hydroxylase (DBH activity decreased over a period of 24 h both within the wall of the basilar artery and in the locus ceruleus and then gradually increased, reaching a maximum on the 3rd day after SAH. 2. Topical application of spasmogenic substances (NA and blood produced a marked constriction of the hypersensitive basilar artery on the 3rd day after SAH. 3. 6-Hydroxydopamine (6-OHDA injection into the cisterna magna produced prolonged vasocilatation. The dilated vessel responded with mild transient constriction after the topical application of NA or fresh blood. DBH activity and NA concentration in the vessels, locus ceruleus and medial hypothalamus decreased markedly on the 3rd day after the cisternal injection of 6-OHDA. 4. Various spasmogenic substances (i.e. serotonin, NA, prostaglandins and methemoglobin were measured in a mixture of equal volume of CSF and blood in cats. ONly the serotonin in the mixed fluid produced vasoconstriction. Spasmogenic substances decreased markedly in the mixed fluid incubated for 3 days at 37 degrees C, and none of these substances apart from methemoglobin was present in a concentration sufficient to produce constriction of vessels. 5. These results suggest that early spasm is induced by serotonin around the arteries of the cranial base, and delayed spasm might be caused by hyperreaction of cerebral vessels to spasmogenic substances such as methemoglobin, during the

  20. Deposition of mouse amyloid beta in human APP/PS1 double and single AD model transgenic mice.

    NARCIS (Netherlands)

    Groen, T. van; Kiliaan, A.J.; Kadish, I.

    2006-01-01

    The deposition of amyloid beta (Abeta) peptides and neurofibrillary tangles are the two characteristic pathological features of Alzheimer's disease (AD). To investigate the relation between amyloid precursor protein (APP) production, amyloid beta deposition and the type of Abeta in deposits, i.e., h