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  1. Optogenetics for neurodegenerative diseases

    Vann, Kiara T; Xiong, Zhi-Gang

    2016-01-01

    Neurodegenerative diseases are devastating conditions that lead to progressive degeneration of neurons. Neurodegeneration may result in ataxia, dementia, and muscle atrophies, etc. Despite enormous research efforts that have been made, there is lack of effective therapeutic interventions for most of these diseases. Optogenetics is a recently developed novel technique that combines optics and genetics to modulate the activity of specific neurons. Optogenetics has been implemented in various studies including neuropsychiatric disorders and neurodegenerative diseases. This review focuses on the recent advance in using this technique for the studies of common neurodegenerative diseases. PMID:27186317

  2. Driving and Neurodegenerative Diseases

    Uc, Ergun Y.; Rizzo, Matthew

    2008-01-01

    The proportion of elderly in the general population is rising, resulting in greater numbers of drivers with neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). These neurodegenerative disorders impair cognition, visual perception, and motor function, leading to reduced driver fitness and greater crash risk. Yet medical diagnosis or age alone is not reliable enough to predict driver safety or crashes, or revoke the driving privileges of these drivers. Dri...

  3. Sleep in Neurodegenerative Diseases.

    Iranzo, Alex

    2016-03-01

    Disorders of sleep are an integral part of neurodegenerative diseases and include insomnia, sleep-wake cycle disruption, excessive daytime sleepiness that may be manifested as persistent somnolence or sudden onset of sleep episodes, obstructive and central sleep apnea, rapid eye movement sleep behavior disorder, and restless legs syndrome. The origin of these sleep disorders is multifactorial including degeneration of the brain areas that modulate sleep, the symptoms of the disease, and the effect of medications. Treatment of sleep disorders in patients with neurodegenerative diseases should be individualized and includes behavioral therapy, sleep hygiene, bright light therapy, melatonin, hypnotics, waking-promoting agents, and continuous positive airway pressure. PMID:26972029

  4. Glutamate and Neurodegenerative Disease

    Schaeffer, Eric; Duplantier, Allen

    As the main excitatory neurotransmitter in the mammalian central nervous system, glutamate is critically involved in most aspects of CNS function. Given this critical role, it is not surprising that glutamatergic dysfunction is associated with many CNS disorders. In this chapter, we review the literature that links aberrant glutamate neurotransmission with CNS pathology, with a focus on neurodegenerative diseases. The biology and pharmacology of the various glutamate receptor families are discussed, along with data which links these receptors with neurodegenerative conditions. In addition, we review progress that has been made in developing small molecule modulators of glutamate receptors and transporters, and describe how these compounds have helped us understand the complex pharmacology of glutamate in normal CNS function, as well as their potential for the treatment of neurodegenerative diseases.

  5. Stem cells and neurodegenerative diseases

    2008-01-01

    Neurodegenerative diseases are characterized by the neurodegenerative changes or apoptosis of neurons involved in networks, which are important to specific physiological functions. With the de-velopment of old-aging society, the incidence of neurodegenerative diseases is on the increase. How-ever, it is difficult to diagnose for most of neurodegenerative diseases. At present, there are too few effective therapies. Advances in stem cell biology have raised the hope and possibility for the therapy of neurodegenerative diseases. Recently, stem cells have been widely attempted to treat neurodegen-erative diseases of animal model. Here we review the progress and prospects of various stem cells, including embryonic stem cells, mesenchymal stem cell and neural stem cells and so on, for the treatments of neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease, Hunt-ington’s disease and Amyotrophic lateral sclerosis/Lou Gehrig’s disease.

  6. Stem cells and neurodegenerative diseases

    HOU LingLing; HONG Tao

    2008-01-01

    Neurodegenerative diseases are characterized by the neurodegenerative changes or apoptosis of neurons involved in networks, which are important to specific physiological functions. With the development of old-aging society, the incidence of neurodegenerative diseases is on the increase. However, it is difficult to diagnose for most of neurodegenerative diseases. At present, there are too few effective therapies. Advances in stem cell biology have raised the hope and possibility for the therapy of neurodegenerative diseases. Recently, stem cells have been widely attempted to treat neurodegenerative diseases of animal model. Here we review the progress and prospects of various stem cells,including embryonic stem cells, mesenchymal stem cell and neural stem cells and so on, for the treatments of neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, Huntington's disease and Amyotrophic lateral sclerosis/Lou Gehrig's disease.

  7. Molecular chaperones and neurodegenerative diseases

    2006-01-01

    Neurodegenerative diseases are characterized by the accumulation of intracellular or extracellular protein aggregates that result from conformational changes in proteins. These diseases may result from an imbalance between the production of misfolded proteins and normal chaperone capacity. Molecular chaperones provide a first line of defence against misfolded, aggregation-prone proteins and are, therefore, promising therapeutic targets for neurodegenerative diseases.

  8. The lysosome and neurodegenerative diseases

    Lisha Zhang; Rui Sheng; Zhenghong Qin

    2009-01-01

    It has long been believed that the lysosome is an important digestive organelle. There is increasing evidence that the lysosome is also involved in pathogenesis of a variety of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Abnormal protein degradation and deposition induced by lysosoreal dysfunction may be the primary contributor to age-related neurodegeneration. In this review, the possible relationship between lysosome and various neurodegenerative diseases is described.

  9. Mitochondrial Dysfunction in Neurodegenerative Diseases

    Johri, Ashu; Beal, M. Flint

    2012-01-01

    Neurodegenerative diseases are a large group of disabling disorders of the nervous system, characterized by the relative selective death of neuronal subtypes. In most cases, there is overwhelming evidence of impaired mitochondrial function as a causative factor in these diseases. More recently, evidence has emerged for impaired mitochondrial dynamics (shape, size, fission-fusion, distribution, movement etc.) in neurodegenerative diseases such as Parkinson's disease, Huntington's disease, amyo...

  10. The cytoskeleton in neurodegenerative diseases

    Cairns, Nigel J.; Lee, Virginia M-Y.; Trojanowski, John Q.

    2004-01-01

    Abundant abnormal aggregates of cytoskeletal proteins are neuropathological signatures of many neurodegenerative diseases that are broadly classified by filamentous aggregates of neuronal intermediate filament (IF) proteins, or by inclusions containing the microtubule-associated protein (MAP) tau. The discovery of mutations in neuronal IF and tau genes firmly establishes the importance of neuronal IF proteins and tau in the pathogenesis of neurodegenerative diseases. Multiple IF gene mutation...

  11. DNA damage in neurodegenerative diseases

    Coppedè, Fabio, E-mail: fabio.coppede@med.unipi.it; Migliore, Lucia, E-mail: lucia.migliore@med.unipi.it

    2015-06-15

    Highlights: • Oxidative DNA damage is one of the earliest detectable events in the neurodegenerative process. • The mitochondrial DNA is more vulnerable to oxidative attack than the nuclear DNA. • Cytogenetic damage has been largely documented in Alzheimer's disease patients. • The question of whether DNA damage is cause or consequence of neurodegeneration is still open. • Increasing evidence links DNA damage and repair with epigenetic phenomena. - Abstract: Following the observation of increased oxidative DNA damage in nuclear and mitochondrial DNA extracted from post-mortem brain regions of patients affected by neurodegenerative diseases, the last years of the previous century and the first decade of the present one have been largely dedicated to the search of markers of DNA damage in neuronal samples and peripheral tissues of patients in early, intermediate or late stages of neurodegeneration. Those studies allowed to demonstrate that oxidative DNA damage is one of the earliest detectable events in neurodegeneration, but also revealed cytogenetic damage in neurodegenerative conditions, such as for example a tendency towards chromosome 21 malsegregation in Alzheimer's disease. As it happens for many neurodegenerative risk factors the question of whether DNA damage is cause or consequence of the neurodegenerative process is still open, and probably both is true. The research interest in markers of oxidative stress was shifted, in recent years, towards the search of epigenetic biomarkers of neurodegenerative disorders, following the accumulating evidence of a substantial contribution of epigenetic mechanisms to learning, memory processes, behavioural disorders and neurodegeneration. Increasing evidence is however linking DNA damage and repair with epigenetic phenomena, thereby opening the way to a very attractive and timely research topic in neurodegenerative diseases. We will address those issues in the context of Alzheimer's disease

  12. DNA damage in neurodegenerative diseases

    Highlights: • Oxidative DNA damage is one of the earliest detectable events in the neurodegenerative process. • The mitochondrial DNA is more vulnerable to oxidative attack than the nuclear DNA. • Cytogenetic damage has been largely documented in Alzheimer's disease patients. • The question of whether DNA damage is cause or consequence of neurodegeneration is still open. • Increasing evidence links DNA damage and repair with epigenetic phenomena. - Abstract: Following the observation of increased oxidative DNA damage in nuclear and mitochondrial DNA extracted from post-mortem brain regions of patients affected by neurodegenerative diseases, the last years of the previous century and the first decade of the present one have been largely dedicated to the search of markers of DNA damage in neuronal samples and peripheral tissues of patients in early, intermediate or late stages of neurodegeneration. Those studies allowed to demonstrate that oxidative DNA damage is one of the earliest detectable events in neurodegeneration, but also revealed cytogenetic damage in neurodegenerative conditions, such as for example a tendency towards chromosome 21 malsegregation in Alzheimer's disease. As it happens for many neurodegenerative risk factors the question of whether DNA damage is cause or consequence of the neurodegenerative process is still open, and probably both is true. The research interest in markers of oxidative stress was shifted, in recent years, towards the search of epigenetic biomarkers of neurodegenerative disorders, following the accumulating evidence of a substantial contribution of epigenetic mechanisms to learning, memory processes, behavioural disorders and neurodegeneration. Increasing evidence is however linking DNA damage and repair with epigenetic phenomena, thereby opening the way to a very attractive and timely research topic in neurodegenerative diseases. We will address those issues in the context of Alzheimer's disease

  13. Hyperhomocysteinemia: Impact on Neurodegenerative Diseases.

    Sharma, Meenakshi; Tiwari, Manisha; Tiwari, Rakesh Kumar

    2015-11-01

    Neurodegenerative diseases are the diseases of the central nervous system with various aetiology and symptoms. Dementia, Alzheimer's disease (AD), Parkinson's disease (PD) and autism are some examples of neurodegenerative diseases. Hyperhomocysteinemia (Hhcy) is considered to be an independent risk factor for numerous pathological conditions under neurodegenerative diseases. Along with genetic factors that are the prime cause of homocysteine (Hcy) imbalance, the nutritional and hormonal factors are also contributing to high Hcy levels in the body. Numerous clinical and epidemiological data confirm the direct correlation of Hcy levels in the body and generation of different types of central nervous system disorders, cardiovascular diseases, cancer and others. Till now, it is difficult to say whether homocysteine is the cause of the disease or whether it is one of the impacts of the diseases. However, Hhcy is a surrogate marker of vitamin B deficiency and is a neurotoxic agent. This Mini Review will give an overview of how far research has gone into understanding the homocysteine imbalance with prognostic, causative and preventive measures in treating neurodegenerative diseases. PMID:26036286

  14. Depressive symptoms in neurodegenerative diseases.

    Baquero, Miquel; Martín, Nuria

    2015-08-16

    Depressive symptoms are very common in chronic conditions. This is true so for neurodegenerative diseases. A number of patients with cognitive decline and dementia due to Alzheimer's disease and related conditions like Parkinson's disease, Lewy body disease, vascular dementia, frontotemporal degeneration amongst other entities, experience depressive symptoms in greater or lesser grade at some point during the course of the illness. Depressive symptoms have a particular significance in neurological disorders, specially in neurodegenerative diseases, because brain, mind, behavior and mood relationship. A number of patients may develop depressive symptoms in early stages of the neurologic disease, occurring without clear presence of cognitive decline with only mild cognitive deterioration. Classically, depression constitutes a reliable diagnostic challenge in this setting. However, actually we can recognize and evaluate depressive, cognitive or motor symptoms of neurodegenerative disease in order to establish their clinical significance and to plan some therapeutic strategies. Depressive symptoms can appear also lately, when the neurodegenerative disease is fully developed. The presence of depression and other neuropsychiatric symptoms have a negative impact on the quality-of-life of patients and caregivers. Besides, patients with depressive symptoms also tend to further decrease function and reduce cognitive abilities and also uses to present more affected clinical status, compared with patients without depression. Depressive symptoms are treatable. Early detection of depressive symptoms is very important in patients with neurodegenerative disorders, in order to initiate the most adequate treatment. We review in this paper the main neurodegenerative diseases, focusing in depressive symptoms of each other entities and current recommendations of management and treatment. PMID:26301229

  15. Tau imaging in neurodegenerative diseases.

    Dani, M; Brooks, D J; Edison, P

    2016-06-01

    Aggregated tau protein is a major neuropathological substrate central to the pathophysiology of neurodegenerative diseases such as Alzheimer's disease (AD), frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration and chronic traumatic encephalopathy. In AD, it has been shown that the density of hyperphosphorylated tau tangles correlates closely with neuronal dysfunction and cell death, unlike β-amyloid. Until now, diagnostic and pathologic information about tau deposition has only been available from invasive techniques such as brain biopsy or autopsy. The recent development of selective in-vivo tau PET imaging ligands including [(18)F]THK523, [(18)F]THK5117, [(18)F]THK5105 and [(18)F]THK5351, [(18)F]AV1451(T807) and [(11)C]PBB3 has provided information about the role of tau in the early phases of neurodegenerative diseases, and provided support for diagnosis, prognosis, and imaging biomarkers to track disease progression. Moreover, the spatial and longitudinal relationship of tau distribution compared with β - amyloid and other pathologies in these diseases can be mapped. In this review, we discuss the role of aggregated tau in tauopathies, the challenges posed in developing selective tau ligands as biomarkers, the state of development in tau tracers, and the new clinical information that has been uncovered, as well as the opportunities for improving diagnosis and designing clinical trials in the future. PMID:26572762

  16. Tau imaging in neurodegenerative diseases

    Dani, M.; Edison, P. [Imperial College London, Neurology Imaging Unit, Division of Neuroscience, London (United Kingdom); Brooks, D.J. [Imperial College London, Neurology Imaging Unit, Division of Neuroscience, London (United Kingdom); Aarhus University, Institute of Clinical Medicine, Aarhus (Denmark)

    2016-06-15

    Aggregated tau protein is a major neuropathological substrate central to the pathophysiology of neurodegenerative diseases such as Alzheimer's disease (AD), frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration and chronic traumatic encephalopathy. In AD, it has been shown that the density of hyperphosphorylated tau tangles correlates closely with neuronal dysfunction and cell death, unlike β-amyloid. Until now, diagnostic and pathologic information about tau deposition has only been available from invasive techniques such as brain biopsy or autopsy. The recent development of selective in-vivo tau PET imaging ligands including [{sup 18}F]THK523, [{sup 18}F]THK5117, [{sup 18}F]THK5105 and [{sup 18}F]THK5351, [{sup 18}F]AV1451(T807) and [{sup 11}C]PBB3 has provided information about the role of tau in the early phases of neurodegenerative diseases, and provided support for diagnosis, prognosis, and imaging biomarkers to track disease progression. Moreover, the spatial and longitudinal relationship of tau distribution compared with β - amyloid and other pathologies in these diseases can be mapped. In this review, we discuss the role of aggregated tau in tauopathies, the challenges posed in developing selective tau ligands as biomarkers, the state of development in tau tracers, and the new clinical information that has been uncovered, as well as the opportunities for improving diagnosis and designing clinical trials in the future. (orig.)

  17. Oxidative stress in neurodegenerative diseases

    Xueping Chen; Chunyan Guo; Jiming Kong

    2012-01-01

    Reactive oxygen species are constantly produced in aerobic organisms as by-products of normal oxygen metabolism and include free radicals such as superoxide anion (O2-) and hydroxyl radical (OH-), and non-radical hydrogen peroxide (H2O2). The mitochondrial respiratory chain and enzymatic reactions by various enzymes are endogenous sources of reactive oxygen species. Exogenous reactive oxygen species -inducing stressors include ionizing radiation, ultraviolet light, and divergent oxidizing chemicals. At low concentrations, reactive oxygen species serve as an important second messenger in cell signaling; however, at higher concentrations and long-term exposure, reactive oxygen species can damage cellular macromolecules such as DNA, proteins, and lipids, which leads to necrotic and apoptotic cell death. Oxidative stress is a condition of imbalance between reactive oxygen species formation and cellular antioxidant capacity due to enhanced ROS generation and/or dysfunction of the antioxidant system. Biochemical alterations in these macromolecular components can lead to various pathological conditions and human diseases, especially neurodegenerative diseases. Neurodegenerative diseases are morphologically featured by progressive cell loss in specific vulnerable neuronal cells, often associated with cytoskeletal protein aggregates forming inclusions in neurons and/or glial cells. Deposition of abnormal aggregated proteins and disruption of metal ions homeostasis are highly associated with oxidative stress. The main aim of this review is to present as much detailed information as possible that is available on various neurodegenerative disorders and their connection with oxidative stress. A variety of therapeutic strategies designed to address these pathological processes are also described. For the future therapeutic direction, one specific pathway that involves the transcription factor nuclear factor erythroid 2-related factor 2 is receiving considerable attention.

  18. Amyloidosis in Retinal Neurodegenerative Diseases

    Masuzzo, Ambra; Dinet, Virginie; Cavanagh, Chelsea; Mascarelli, Frederic; Krantic, Slavica

    2016-01-01

    As a part of the central nervous system, the retina may reflect both physiological processes and abnormalities related to pathologies that affect the brain. Amyloidosis due to the accumulation of amyloid-beta (Aβ) was initially regarded as a specific and exclusive characteristic of neurodegenerative alterations seen in the brain of Alzheimer’s disease (AD) patients. More recently, it was discovered that amyloidosis-related alterations, similar to those seen in the brain of Alzheimer’s patients, also occur in the retina. Remarkably, these alterations were identified not only in primary retinal pathologies, such as age-related macular degeneration (AMD) and glaucoma, but also in the retinas of Alzheimer’s patients. In this review, we first briefly discuss the biogenesis of Aβ, a peptide involved in amyloidosis. We then discuss some pathological aspects (synaptic dysfunction, mitochondrial failure, glial activation, and vascular abnormalities) related to the neurotoxic effects of Aβ. We finally highlight common features shared by AD, AMD, and glaucoma in the context of Aβ amyloidosis and further discuss why the retina, due to the transparency of the eye, can be considered as a “window” to the brain. PMID:27551275

  19. Sirtuin deacetylases in neurodegenerative diseases of aging

    Adrianna Z Herskovits; Leonard Guarente

    2013-01-01

    Sirtuin enzymes are a family of highly conserved protein deacetylases that depend on nicotinamide adenine dinucleotide (NAD+) for their activity.There are seven sirtuins in mammals and these proteins have been linked with caloric restriction and aging by modulating energy metabolism,genomic stability and stress resistance.Sirtuin enzymes are potential therapeutic targets in a variety of human diseases including cancer,diabetes,inflammatory disorders and neurodegenerative disease.Modulation of sirtuin activity has been shown to impact the course of several aggregate-forming neurodegenerative disorders including Alzheimer's disease,Parkinson's disease,Huntington's disease,amyotrophic lateral sclerosis and spinal and bulbar muscular atrophy.Sirtuins can influence the progression of neurodegenerative disorders by modulating transcription factor activity and directly deacetylating proteotoxic species.Here,we describe sirtuin protein targets in several aggregate-forming neurodegenerative diseases and discuss the therapeutic potential of compounds that modulate sirtuin activity in these disorders.

  20. Coenzyme Q10 effects in neurodegenerative disease

    Meredith Spindler

    2009-11-01

    Full Text Available Meredith Spindler1, M Flint Beal1,2, Claire Henchcliffe1,21Department of Neurology, 2Department of Neuroscience, Weill Medical College of Cornell University, New York, NY, USAAbstract: Coenzyme Q10 (CoQ10 is an essential cofactor in the mitochondrial respiratory chain, and as a dietary supplement it has recently gained attention for its potential role in the treatment of neurodegenerative disease. Evidence for mitochondrial dysfunction in neurodegenerative disorders derives from animal models, studies of mitochondria from patients, identification of genetic defects in patients with neurodegenerative disease, and measurements of markers of oxidative stress. Studies of in vitro models of neuronal toxicity and animal models of neurodegenerative disorders have demonstrated potential neuroprotective effects of CoQ10. With this data in mind, several clinical trials of CoQ10 have been performed in Parkinson’s disease and atypical Parkinson’s syndromes, Huntington’s disease, Alzheimer disease, Friedreich’s ataxia, and amyotrophic lateral sclerosis, with equivocal findings. CoQ10 is widely available in multiple formulations and is very well tolerated with minimal adverse effects, making it an attractive potential therapy. Phase III trials of high-dose CoQ10 in large sample sizes are needed to further ascertain the effects of CoQ10 in neurodegenerative diseases.Keywords: coenzyme Q10, neurodegenerative disease, Parkinson’s disease, Huntington’s disease, mitochondrial dysfunction

  1. Oxidative stress, mitochondrial damage and neurodegenerative diseases****

    Chunyan Guo; Li Sun; Xueping Chen; Danshen Zhang

    2013-01-01

    Oxidative stress and mitochondrial damage have been implicated in the pathogenesis of several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Oxidative stress is characterized by the overproduction of reactive oxygen species, which can induce mitochondrial DNA mutations, damage the mitochondrial respiratory chain, alter membrane permeability, and influence Ca2+ homeostasis and mitochondrial defense systems. Al these changes are implicated in the development of these neurodegenerative diseases, mediating or amplifying neuronal dysfunction and triggering neurodegeneration. This paper summarizes the contribution of oxidative stress and mitochondrial damage to the onset of neurodegenerative eases and discusses strategies to modify mitochondrial dysfunction that may be attractive thera-peutic interventions for the treatment of various neurodegenerative diseases.

  2. Visual Spatial Cognition in Neurodegenerative Disease

    Possin, Katherine L.

    2010-01-01

    Visual spatial impairment is often an early symptom of neurodegenerative disease; however, this multi-faceted domain of cognition is not well-assessed by most typical dementia evaluations. Neurodegenerative diseases cause circumscribed atrophy in distinct neural networks, and accordingly, they impact visual spatial cognition in different and characteristic ways. Anatomically-focused visual spatial assessment can assist the clinician in making an early and accurate diagnosis. This article will...

  3. Coenzyme Q10 effects in neurodegenerative disease

    Henchcliffe, Claire

    2009-01-01

    Meredith Spindler1, M Flint Beal1,2, Claire Henchcliffe1,21Department of Neurology, 2Department of Neuroscience, Weill Medical College of Cornell University, New York, NY, USAAbstract: Coenzyme Q10 (CoQ10) is an essential cofactor in the mitochondrial respiratory chain, and as a dietary supplement it has recently gained attention for its potential role in the treatment of neurodegenerative disease. Evidence for mitochondrial dysfunction in neurodegenerative disorders derives from animal model...

  4. Oligonucleotide-based therapy for neurodegenerative diseases.

    Magen, Iddo; Hornstein, Eran

    2014-10-10

    Molecular genetics insight into the pathogenesis of several neurodegenerative diseases, such as Alzheimer׳s disease, Parkinson׳s disease, Huntington׳s disease and amyotrophic lateral sclerosis, encourages direct interference with the activity of neurotoxic genes or the molecular activation of neuroprotective pathways. Oligonucleotide-based therapies are recently emerging as an efficient strategy for drug development and these can be employed as new treatments of neurodegenerative states. Here we review advances in this field in recent years which suggest an encouraging assessment that oligonucleotide technologies for targeting of RNAs will enable the development of new therapies and will contribute to preservation of brain integrity. PMID:24727531

  5. Walking the tightrope: proteostasis and neurodegenerative disease.

    Yerbury, Justin J; Ooi, Lezanne; Dillin, Andrew; Saunders, Darren N; Hatters, Danny M; Beart, Philip M; Cashman, Neil R; Wilson, Mark R; Ecroyd, Heath

    2016-05-01

    A characteristic of many neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), is the aggregation of specific proteins into protein inclusions and/or plaques in degenerating brains. While much of the aggregated protein consists of disease specific proteins, such as amyloid-β, α-synuclein, or superoxide dismutase1 (SOD1), many other proteins are known to aggregate in these disorders. Although the role of protein aggregates in the pathogenesis of neurodegenerative diseases remains unknown, the ubiquitous association of misfolded and aggregated proteins indicates that significant dysfunction in protein homeostasis (proteostasis) occurs in these diseases. Proteostasis is the concept that the integrity of the proteome is in fine balance and requires proteins in a specific conformation, concentration, and location to be functional. In this review, we discuss the role of specific mechanisms, both inside and outside cells, which maintain proteostasis, including molecular chaperones, protein degradation pathways, and the active formation of inclusions, in neurodegenerative diseases associated with protein aggregation. A characteristic of many neurodegenerative diseases is the aggregation of specific proteins, which alone provides strong evidence that protein homeostasis is disrupted in these disease states. Proteostasis is the maintenance of the proteome in the correct conformation, concentration, and location by functional pathways such as molecular chaperones and protein degradation machinery. Here, we discuss the potential roles of quality control pathways, both inside and outside cells, in the loss of proteostasis during aging and disease. PMID:26872075

  6. Nutritional and biochemical therapies for neurodegenerative diseases

    Barreto, George E.

    2015-01-01

    Neurodegenerative diseases such as Parkinson’s disease, Huntington and Alzheimer’s disease are characterized by neuronal death and loss in different areas of the brain. Downstream signaling mechanisms associated to cellular death/survival are altered, where mitochondrial damage and inflammation, dysfunctional autophagy process, and accumulation of toxins proteins play a central role in the pathogenesis of these diseases. The disabling effects of these diseases on health system are high and gr...

  7. Dendritic Spine Pathology in Neurodegenerative Diseases.

    Herms, Jochen; Dorostkar, Mario M

    2016-05-23

    Substantial progress has been made toward understanding the neuropathology, genetic origins, and epidemiology of neurodegenerative diseases, including Alzheimer's disease; tauopathies, such as frontotemporal dementia; α-synucleinopathies, such as Parkinson's disease or dementia with Lewy bodies; Huntington's disease; and amyotrophic lateral sclerosis with dementia, as well as prion diseases. Recent evidence has implicated dendritic spine dysfunction as an important substrate of the pathogenesis of dementia in these disorders. Dendritic spines are specialized structures, extending from the neuronal processes, on which excitatory synaptic contacts are formed, and the loss of dendritic spines correlates with the loss of synaptic function. We review the literature that has implicated direct or indirect structural alterations at dendritic spines in the pathogenesis of major neurodegenerative diseases, focusing on those that lead to dementias such as Alzheimer's, Parkinson's, and Huntington's diseases, as well as frontotemporal dementia and prion diseases. We stress the importance of in vivo studies in animal models. PMID:26907528

  8. Molecular genetics of neurodegenerative diseases.

    Roses, A D

    1993-02-01

    Recent progress in human neurogenetics has led to the discovery of new modes of inheritance and disease expression, including 1) stably inherited duplications in Charcot-Marie-Tooth disease type 1a, 2) dynamic mutations in fragile X syndrome and myotonic dystrophy, and 3) identical mutations with different phenotypes in fatal familial insomnia and Creutzfeldt-Jakob disease. The mechanisms by which known mutations of the amyloid precursor protein lead to early-onset Alzheimer's disease remain unexplained, despite hundreds of recent studies of beta-amyloid. PMID:8428064

  9. Mitochondrial Medicine for Aging and Neurodegenerative Diseases

    Reddy, P. Hemachandra

    2008-01-01

    Mitochondria are key cytoplasmic organelles, responsible for generating cellular energy, regulating intracellular calcium levels, altering the reduction-oxidation potential of cells, and regulating cell death. Increasing evidence suggests that mitochondria play a central role in aging and in neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and Freidriech ataxia. Further, several lines of evidence suggest that mi...

  10. Studying neurodegenerative diseases in culture models

    Johannes C.M. Schlachetzki

    2013-01-01

    Full Text Available Neurodegenerative diseases are pathological conditions that have an insidious onset and chronic progression. Different models have been established to study these diseases in order to understand their underlying mechanisms and to investigate new therapeutic strategies. Although various in vivo models are currently in use, in vitro models might provide important insights about the pathogenesis of these disorders and represent an interesting approach for the screening of potential pharmacological agents. In the present review, we discuss various in vitro and ex vivo models of neurodegenerative disorders in mammalian cells and tissues.

  11. Neuronal Network Oscillations in Neurodegenerative Diseases.

    Nimmrich, Volker; Draguhn, Andreas; Axmacher, Nikolai

    2015-09-01

    Cognitive and behavioral acts go along with highly coordinated spatiotemporal activity patterns in neuronal networks. Most of these patterns are synchronized by coherent membrane potential oscillations within and between local networks. By entraining multiple neurons into a common time regime, such network oscillations form a critical interface between cellular activity and large-scale systemic functions. Synaptic integrity is altered in neurodegenerative diseases, and it is likely that this goes along with characteristic changes of coordinated network activity. This notion is supported by EEG recordings from human patients and from different animal models of such disorders. However, our knowledge about the pathophysiology of network oscillations in neurodegenerative diseases is surprisingly incomplete, and increased research efforts are urgently needed. One complicating factor is the pronounced diversity of network oscillations between different brain regions and functional states. Pathological changes must, therefore, be analyzed separately in each condition and affected area. However, cumulative evidence from different diseases may result, in the future, in more unifying "oscillopathy" concepts of neurodegenerative diseases. In this review, we report present evidence for pathological changes of network oscillations in Alzheimer's disease (AD), one of the most prominent and challenging neurodegenerative disorders. The heterogeneous findings from AD are contrasted to Parkinson's disease, where motor-related changes in specific frequency bands do already fulfill criteria of a valid biomarker. PMID:25920466

  12. Role of neuroinflammation in neurodegenerative diseases (Review).

    Chen, Wei-Wei; Zhang, Xia; Huang, Wen-Juan

    2016-04-01

    Neurodegeneration is a phenomenon that occurs in the central nervous system through the hallmarks associating the loss of neuronal structure and function. Neurodegeneration is observed after viral insult and mostly in various so-called 'neurodegenerative diseases', generally observed in the elderly, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and amyotrophic lateral sclerosis that negatively affect mental and physical functioning. Causative agents of neurodegeneration have yet to be identified. However, recent data have identified the inflammatory process as being closely linked with multiple neurodegenerative pathways, which are associated with depression, a consequence of neurodegenerative disease. Accordingly, pro‑inflammatory cytokines are important in the pathophysiology of depression and dementia. These data suggest that the role of neuroinflammation in neurodegeneration must be fully elucidated, since pro‑inflammatory agents, which are the causative effects of neuroinflammation, occur widely, particularly in the elderly in whom inflammatory mechanisms are linked to the pathogenesis of functional and mental impairments. In this review, we investigated the role played by the inflammatory process in neurodegenerative diseases. PMID:26935478

  13. Thiol redox homeostasis in neurodegenerative disease

    Gethin J. McBean

    2015-08-01

    Full Text Available This review provides an overview of the biochemistry of thiol redox couples and the significance of thiol redox homeostasis in neurodegenerative disease. The discussion is centred on cysteine/cystine redox balance, the significance of the xc− cystine–glutamate exchanger and the association between protein thiol redox balance and neurodegeneration, with particular reference to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and glaucoma. The role of thiol disulphide oxidoreductases in providing neuroprotection is also discussed.

  14. Neuroimaging diagnosis in neurodegenerative diseases

    Dementia affects about 8% of people age 65 years and older. Identification of dementia is particularly difficult in its early phases when family members and physicians often incorrectly attribute the patients symptoms to normal aging. The most frequently occurring ailments that are connected with neuro degeneration are: Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. A variety of powerful techniques that have allowed visualization of organ structure and function with exact detail have been introduced in the last twenty-five years. One such neuroimaging technique is positron emission tomography (PET), which measures in detail the functioning of distinct areas of the human brain and as a result plays a critical role in clinical and research applications. Radiotracer-based functional imaging provides a sensitive means of recognizing and characterizing the regional changes in brain metabolism and receptor binding associated with cognitive disorders. The next functional imaging technique widely used in the diagnosis of cognitive disorders is single photon emission computed tomography (SPECT). New radiotracers are being developed and promise to expand further the list of indications for PET. Prospects for developing new tracers for imaging other organ diseases also appear to be very promising. In this review, we present current opportunities of neuroimaging techniques in the diagnosis and differentiation of neuro degenerative disorders. (authors)

  15. Autonomic Function in Neurodegenerative Diseases

    Sørensen, Gertrud Laura; Jennum, Poul Jørgen

    2013-01-01

    involving brain stem areas, which is consistent with the Braak hypothesis. In the narcolepsy patients, it was shown that a reduced HRR to arousals was primarily predicted by hypocretin deficiency in both rapid-eye-movement (REM) and non-REM sleep, independent of cataplexy and other factors. The results......, which includes the cardiac centre and controls autonomic functions, and therefore autonomic dysfunction may be experienced early in the disease course. Sleep disturbances are also common non-motor complications of PD, and therefore PD patients undergo polysomnography at the Danish Center for Sleep...... narcolepsy patients on autonomic function and on the sleep transition rate. The results showed an attenuated heart rate response (HRR) in PD patients compared to controls and early PD (iRBD patients). Also iRBD patients had an attenuated HRR compared to control subjects, and the method to measure the HRR may...

  16. [The role of thiamine in neurodegenerative diseases].

    Bubko, Irena; Gruber, Beata M; Anuszewska, Elżbieta L

    2015-01-01

    Vitamin B1 (thiamine) plays an important role in metabolism. It is indispensable for normal growth and development of the organism. Thiamine has a favourable impact on a number of systems, including the digestive, cardiovascular and nervous systems. It also stimulates the brain and improves the psycho-emotional state. Hence it is often called the vitamin of "reassurance of the spirit". Thiamine is a water-soluble vitamin. It can be present in the free form as thiamine or as its phosphate esters: mono-, di- or triphosphate. The main source of thiamine as an exogenous vitamin is certain foodstuffs, but trace amounts can be synthesised by microorganisms of the large intestine. The recommended daily intake of thiamine is about 2.0 mg. Since vitamin B1 has no ability to accumulate in the organism, manifestations of its deficiency begin to appear very quickly. The chronic state of thiamine deficiency, to a large extent, because of its function, contributes to the development of neurodegenerative diseases. It was proved that supporting vitamin B1 therapy not only constitutes neuroprotection but can also have a favourable impact on advanced neurodegenerative diseases. This article presents the current state of knowledge as regards the effects of thiamine exerted through this vitamin in a number of diseases such as Parkinson's disease, Alzheimer's disease, Wernicke's encephalopathy or Wernicke-Korsakoff syndrome and Huntington's disease. PMID:26400895

  17. Transgenic nonhuman primates for neurodegenerative diseases

    Chan Anthony WS

    2004-06-01

    Full Text Available Abstract Animal models that represent human diseases constitute an important tool in understanding the pathogenesis of the diseases, and in developing effective therapies. Neurodegenerative diseases are complex disorders involving neuropathologic and psychiatric alterations. Although transgenic and knock-in mouse models of Alzheimer's disease, (AD, Parkinson's disease (PD and Huntington's disease (HD have been created, limited representation in clinical aspects has been recognized and the rodent models lack true neurodegeneration. Chemical induction of HD and PD in nonhuman primates (NHP has been reported, however, the role of intrinsic genetic factors in the development of the diseases is indeterminable. Nonhuman primates closely parallel humans with regard to genetic, neuroanatomic, and cognitive/behavioral characteristics. Accordingly, the development of NHP models for neurodegenerative diseases holds greater promise for success in the discovery of diagnoses, treatments, and cures than approaches using other animal species. Therefore, a transgenic NHP carrying a mutant gene similar to that of patients will help to clarify our understanding of disease onset and progression. Additionally, monitoring disease onset and development in the transgenic NHP by high resolution brain imaging technology such as MRI, and behavioral and cognitive testing can all be carried out simultaneously in the NHP but not in other animal models. Moreover, because of the similarity in motor repertoire between NHPs and humans, it will also be possible to compare the neurologic syndrome observed in the NHP model to that in patients. Understanding the correlation between genetic defects and physiologic changes (e.g. oxidative damage will lead to a better understanding of disease progression and the development of patient treatments, medications and preventive approaches for high risk individuals. The impact of the transgenic NHP model in understanding the role which

  18. Quantitative interaction proteomics of neurodegenerative disease proteins.

    Hosp, Fabian; Vossfeldt, Hannes; Heinig, Matthias; Vasiljevic, Djordje; Arumughan, Anup; Wyler, Emanuel; Landthaler, Markus; Hubner, Norbert; Wanker, Erich E; Lannfelt, Lars; Ingelsson, Martin; Lalowski, Maciej; Voigt, Aaron; Selbach, Matthias

    2015-05-19

    Several proteins have been linked to neurodegenerative disorders (NDDs), but their molecular function is not completely understood. Here, we used quantitative interaction proteomics to identify binding partners of Amyloid beta precursor protein (APP) and Presenilin-1 (PSEN1) for Alzheimer's disease (AD), Huntingtin (HTT) for Huntington's disease, Parkin (PARK2) for Parkinson's disease, and Ataxin-1 (ATXN1) for spinocerebellar ataxia type 1. Our network reveals common signatures of protein degradation and misfolding and recapitulates known biology. Toxicity modifier screens and comparison to genome-wide association studies show that interaction partners are significantly linked to disease phenotypes in vivo. Direct comparison of wild-type proteins and disease-associated variants identified binders involved in pathogenesis, highlighting the value of differential interactome mapping. Finally, we show that the mitochondrial protein LRPPRC interacts preferentially with an early-onset AD variant of APP. This interaction appears to induce mitochondrial dysfunction, which is an early phenotype of AD. PMID:25959826

  19. Diagnosis of Neurodegenerative Diseases: The Clinical Approach.

    Gómez-Río, Manuel; Caballero, Manuel Moreno; Górriz Sáez, Juan Manuel; Mínguez-Castellanos, Adolfo

    2016-01-01

    There are a number of clinical questions for which there are no easy answers, even for welltrained doctors. The diagnostic tool commonly used to assess cognitive impairment in neurodegenerative diseases is based on established clinical criteria. However, the differential diagnosis between disorders can be difficult, especially in early phases or atypical variants. This takes on particular importance when it is still possible to use an appropriate treatment. To solve this problem, physicians need to have access to an arsenal of diagnostic tests, such as neurofunctional imaging, that allow higher specificity in clinical assessment. However, the reliability of diagnostic tests may vary from one to the next, so the diagnostic validity of a given investigation must be estimated by comparing the results obtained from "true" criteria to the "gold standard" or reference test. While pathological analysis is considered to be the gold standard in a wide spectrum of diseases, it cannot be applied to neurological processes. Other approaches could provide solutions, including clinical patient follow-up, creation of a data bank or use of computer-aided diagnostic algorithms. In this article, we discuss the development of different methodological procedures related to analysis of diagnostic validity and present an example from our own experience based on the use of I-123-ioflupane-SPECT in the study of patients with movement disorders. The aim of this chapter is to approach the problem of diagnosis from the point of view of the clinician, taking into account specific aspects of neurodegenerative disease. PMID:26567736

  20. Heat shock protein 90 in neurodegenerative diseases

    Rodina Anna

    2010-06-01

    Full Text Available Abstract Hsp90 is a molecular chaperone with important roles in regulating pathogenic transformation. In addition to its well-characterized functions in malignancy, recent evidence from several laboratories suggests a role for Hsp90 in maintaining the functional stability of neuronal proteins of aberrant capacity, whether mutated or over-activated, allowing and sustaining the accumulation of toxic aggregates. In addition, Hsp90 regulates the activity of the transcription factor heat shock factor-1 (HSF-1, the master regulator of the heat shock response, mechanism that cells use for protection when exposed to conditions of stress. These biological functions therefore propose Hsp90 inhibition as a dual therapeutic modality in neurodegenerative diseases. First, by suppressing aberrant neuronal activity, Hsp90 inhibitors may ameliorate protein aggregation and its associated toxicity. Second, by activation of HSF-1 and the subsequent induction of heat shock proteins, such as Hsp70, Hsp90 inhibitors may redirect neuronal aggregate formation, and protect against protein toxicity. This mini-review will summarize our current knowledge on Hsp90 in neurodegeneration and will focus on the potential beneficial application of Hsp90 inhibitors in neurodegenerative diseases.

  1. Peripheral arterial endothelial dysfunction of neurodegenerative diseases.

    Fukui, Yusuke; Hishikawa, Nozomi; Shang, Jingwei; Sato, Kota; Nakano, Yumiko; Morihara, Ryuta; Ohta, Yasuyuki; Yamashita, Toru; Abe, Koji

    2016-07-15

    This study evaluates endothelial functions of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and spinocerebellar ataxia (SCA). The reactive hyperemia index (RHI) of peripheral arterial tonometry and serological data were compared between age- and gender-matched normal controls (n=302) and five disease groups (ALS; n=75, PD; n=180, PSP; n=30, MSA; n=35, SCA; n=53). Correlation analyses were performed in ALS with functional rating scale-revised (FRS-R), and in PD with the Hehn-Yahr scale (H-Y) and a heart to mediastinum ratio using (123)I-MIBG scintigraphy (MIBG). The RHI of ALS and PD, but not of PSP, MSA or SCA, were significantly lower than normal controls (p<0.01). ALS showed a negative correlation of RHI with serum triglycerides (TG) and immunoreactive insulin (IRI) levels, but not with disease severity (FRS-R) or rates of disease progression (∆FRS-R). On the other hand, PD showed a negative correlation of RHI with a progressive disease severity (H-Y) and a positive correlation of RHI with early/delayed MIBG scintigraphy, but not with serological data. The present study demonstrated significant declines of peripheral arterial endothelial functions in ALS and PD. The RHI of ALS was more correlated with disease duration and serum parameters while the RHI of PD was more correlated with disease severity and MIBG, suggesting different mechanisms of endothelial dysfunction. PMID:27288784

  2. Neurodegenerative diseases: exercising towards neurogenesis and neuroregeneration

    Eng-Tat Ang

    2010-07-01

    Full Text Available Currently, there is still no effective therapy for neurodegenerative diseases (NDD such as Alzheimer’s disease (AD and Parkinson’s disease (PD despite intensive research and on-going clinical trials. Collectively, these diseases account for the bulk of health care burden associated with age-related neurodegenerative disorders. There is therefore an urgent need to further research into the molecular pathogenesis, histological differentiation, and clinical management of NDD. Importantly, there is also an urgency to understand the similarities and differences between these two diseases so as to identify the common or different upstream and downstream signaling pathways. In this review, the role iron play in NDD will be highlighted, as iron is key to a common underlying pathway in the production of oxidative stress. There is increasing evidence to suggest that oxidative stress predisposed cells to undergo damage to DNA, protein and lipid, and as such a common factor involved in the pathogenesis of AD and PD. The challenge then is to minimize elevated and uncontrolled oxidative stress levels while not affecting basal iron metabolism, as iron plays vital roles in sustaining cellular function. However, overload of iron results in increased oxidative stress due to the Fenton reaction. We discuss evidence to suggest that sustained exercise and diet restriction may be ways to slow the rate of neurodegeneration, by perhaps promoting neurogenesis or antioxidant-related pathways. It is also our intention to cover NDD in a broad sense, in the context of basic and clinical sciences to cater for both clinician’s and the scientist’s needs, and to highlight current research investigating exercise as a therapeutic or preventive measure.

  3. Neurodegenerative Diseases: Multifactorial Conformational Diseases and Their Therapeutic Interventions

    Saba Sheikh

    2013-01-01

    Full Text Available Neurodegenerative diseases are multifactorial debilitating disorders of the nervous system that affect approximately 30 millionindividuals worldwide. Neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis diseases are the consequence of misfolding and dysfunctional trafficking of proteins. Beside that, mitochondrial dysfunction, oxidative stress, and/or environmental factors strongly associated with age have also been implicated in causing neurodegeneration. After years of intensive research, considerable evidence has accumulated that demonstrates an important role of these factors in the etiology of common neurodegenerative diseases. Despite the extensive efforts that have attempted to define the molecular mechanisms underlying neurodegeneration, many aspects of these pathologies remain elusive. However, in order to explore the therapeutic interventions directed towards treatment of neurodegenerative diseases, neuroscientists are now fully exploiting the data obtained from studies of these basic mechanisms that have gone awry. The novelty of these mechanisms represents a challenge to the identification of viable drug targets and biomarkers for early diagnosis of the diseases. In this paper, we are reviewing various aspects associated with the disease and the recent trends that may have an application for the treatment of the neurodegenerative disorders.

  4. THE MITOCHONDRIAL DERANGEMENTS IN NEURONAL DEGENER ATION AND NEURODEGENERATIVE DISEASES

    Xue, Qi-ming; Gao, Feng; Chen, Qin-tang

    2000-01-01

    @@There are diverse concepts on the pathogenesis of neuronal degeneration and the neurodegenerative diseases. Among them there are different factors which might influence the initiation of neuronal degeneration as well as the pathogenesis of neurodegenerative diseases, such as Alzheimer′s disease, Parkinson′s disease, motor neuron disease, and so on.

  5. A Potential Alternative against Neurodegenerative Diseases: Phytodrugs

    Pérez-Hernández, Jesús; Zaldívar-Machorro, Víctor Javier; Villanueva-Porras, David; Vega-Ávila, Elisa; Chavarría, Anahí

    2016-01-01

    Neurodegenerative diseases (ND) primarily affect the neurons in the human brain secondary to oxidative stress and neuroinflammation. ND are more common and have a disproportionate impact on countries with longer life expectancies and represent the fourth highest source of overall disease burden in the high-income countries. A large majority of the medicinal plant compounds, such as polyphenols, alkaloids, and terpenes, have therapeutic properties. Polyphenols are the most common active compounds in herbs and vegetables consumed by man. The biological bioactivity of polyphenols against neurodegeneration is mainly due to its antioxidant, anti-inflammatory, and antiamyloidogenic effects. Multiple scientific studies support the use of herbal medicine in the treatment of ND; however, relevant aspects are still pending to explore such as metabolic analysis, pharmacokinetics, and brain bioavailability. PMID:26881043

  6. Computed tomography of neurodegenerative disease in childhood

    Serial computed tomographic scans were performed on seven children with neurodegenerative disorders. In two cases of white-matter diseases (Krabbe's disease and metachromatic leukodystrophy), diffuse, low-density lesions of white matter were visible in the early stage of the diseases. In one case of adrenoleukodystrophy, regional low-density lesions of the white matter around the posterior horns and peculiar high-density strip lesions were visible in the early stage. In two cases of storage-type gray-matter diseases (Tay-Sachs' and infantile Gaucher's disease), there were no abnormalities in the early stage, but diffuse cortical atrophies in the late stage. In one case of Leigh's disease, there were small, low-density lesions of the basal ganglia and multiple low-density lesions of the gray matter in the early stage. In one case of subacute sclerosing panencephalitis, there were no abnormalities in the early stage, but small, low-density lesions of the basal ganglia and diffuse cerebral atrophies in the late stage. Diagnostic values were recognized dominantly in two cases of adrenoleukodystrophy and Leigh's disease. In the other cases, however, serial CT scans were useful in the diagnostic process. (author)

  7. Modelling Neurodegenerative Diseases Using Human Pluripotent Stem Cells

    Hall, Vanessa J.

    2016-01-01

    Neurodegenerative diseases are being modelled in-vitro using human patient-specific, induced pluripotent stem cells and transgenic embryonic stem cells to determine more about disease mechanisms, as well as to discover new treatments for patients. Current research in modelling Alzheimer’s disease......, frontotemporal dementia and Parkinson’s disease using pluripotent stem cells is described, along with the advent of gene-editing, which has been the complimentary tool for the field. Current methods used to model these diseases are predominantly dependent on 2D cell culture methods. Outcomes reveal that only...... includes studying more complex 3D cell cultures, as well as accelerating aging of the neurons, may help to yield stronger phenotypes in the cultured cells. Thus, the use and application of pluripotent stem cells for modelling disease have already shown to be a powerful approach for discovering more about...

  8. Quantitative Interaction Proteomics of Neurodegenerative Disease Proteins

    Fabian Hosp

    2015-05-01

    Full Text Available Several proteins have been linked to neurodegenerative disorders (NDDs, but their molecular function is not completely understood. Here, we used quantitative interaction proteomics to identify binding partners of Amyloid beta precursor protein (APP and Presenilin-1 (PSEN1 for Alzheimer’s disease (AD, Huntingtin (HTT for Huntington’s disease, Parkin (PARK2 for Parkinson’s disease, and Ataxin-1 (ATXN1 for spinocerebellar ataxia type 1. Our network reveals common signatures of protein degradation and misfolding and recapitulates known biology. Toxicity modifier screens and comparison to genome-wide association studies show that interaction partners are significantly linked to disease phenotypes in vivo. Direct comparison of wild-type proteins and disease-associated variants identified binders involved in pathogenesis, highlighting the value of differential interactome mapping. Finally, we show that the mitochondrial protein LRPPRC interacts preferentially with an early-onset AD variant of APP. This interaction appears to induce mitochondrial dysfunction, which is an early phenotype of AD.

  9. The Role of Copper in Neurodegenerative Disease

    Rose, Francis M.

    My research concerns the fundamental atomistic mechanisms of neurodegenerative diseases and the methodologies by which they may be discerned. This thesis consists of three primary parts. The introductory material is the raison d'etre for this work and a critical overview of the specific physics, mathematics and algorithms used in this research. The methods are presented along with specific details in order to facilitate future replication and enhancement. With the groundwork of mechanisms and methods out of the way, we then explore a nouveau atomistic mechanism describing the onset of Parkinson's disease, a disease that has been closely linked to misfolded metalloproteins. Further exploration of neurodegeneration takes place in the following chapter, where a remedial approach to Alzheimer's disease via a simulated chelation of a metalloprotein is undertaken. Altogether, the methods and techniques applied here allow for simulated exploration of both the atomistic mechanisms of neurodegeneration and their potential remediation strategies. The beginning portion of the research efforts explore protein misfolding dynamics in the presence a copper ion. Misfolding of the human alpha-synuclein (aS) protein has been implicated as a central constituent in neurodegenerative disease. In Parkinson's disease (PD) in particular, aS is thought to be the causative participant when found concentrated into neuritic plaques. Here we propose a scenario involving the metal ion Cu2+ as the protein misfolding initiator of fibrillized aS, the chief component of neuritic plaques. From experimental results we know these misfolded proteins have a rich beta--sheet signature, a marker that we reproduce with our simulated model. This model identifies a process of structural modifications to a natively unfolded alpha-synuclein resulting in a partially folded intermediate with a well defined nucleation site. It serves as a precursor to the fully misfolded protein. Understanding the nucleation

  10. Neurodegenerative disease. Genetic discrimination in Huntington disease.

    Pulst, Stefan M

    2009-10-01

    A survey conducted in Canada examined the prevalence of perceived genetic discrimination against patients with Huntington disease. The respondents reported discrimination not only by insurance or mortgage companies, but also in family and social contexts. Discrimination was more frequently attributed to family history than to genetic test results. PMID:19794509

  11. Resurrection of Neurodegenerative diseases via Stem cells

    Siranjeevi Nagaraj

    2016-07-01

    Full Text Available Neurodegenerative diseases (NDDs are complex disorders that degenerates central nervous system. To this end, we have achieved only palliative treatments and their success is limited. Emerging studies suggest stem cells could be an alternative to recover lost neural network. Transplanting stem cells for replacing damaged neurons is a pivotal step in cell replacement therapies. In this article, NDDs and their pathology, current methods of combating NDDs and potentiality of stem cells in treating NDDs have been reviewed briefly. In addition to this , technical issues that hamper clinical applications of stem cells in creating cellular models and grafted cells for neuron resurrection have been discussed. [Biomed Res Ther 2016; 3(7.000: 699-706

  12. Epigenetics and etiology of neurodegenerative diseases

    Beata M. Gruber

    2011-08-01

    Full Text Available Determination of specific gene profile expression is essential for morphological and functional differentiation of cells in the human organism. The human genome consists of 25–30 thousands genes but only some of them are expressed in each cell. Epigenetic modifications such as DNA methylation, histone and chromatin modifications or non-coding RNA functions are also responsible for the unique gene expression patterns. It is suggested that transcriptional gene activation is related to hypomethylation and the transcriptionally non-active sequences are hypermethylated. Covalent histone modifications and DNA methylation are correlated and interacting. Chromatin modeling is regulated not only by specific enzymes but also by protein kinases or phosphatases and coactivators, such as CBP. Such interaction makes the “histone code” which with the chromatin proteins determines gene expression patterns as the response to external agents. Evidence of a major role for epigenetic modifications in neurological disease has come from three converging lines of enquiry: high conservation throughout evolution of the histone residues that are the target for epigenetic modifications; association between mutations in epigenetic components and multisystem disease syndrome in the nervous system; and broad efficacy of small-molecule epigenetic modulators, e.g. histone deacetylase inhibitors, in models of neurological diseases incurable up to now, such as Huntington’s disease, (HD, Parkinson’s disease (PD and Alzheimer’s disease (AD. This article is a survey of the literature concerning the characterization of gene expression patterns correlated with some neurodegenerative diseases. The processes of DNA hypomethylation and histone acetylation are emphasized. The histone deacetylases are indicated as the basis for design of potential drugs.

  13. Mitochondrial Dysfunctions in Neurodegenerative Diseases: Relevance to Alzheimer's Disease

    Jana Hroudová; Namrata Singh; Zdeněk Fišar

    2014-01-01

    Mitochondrial dysfunctions are supposed to be responsible for many neurodegenerative diseases dominating in Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). A growing body of evidence suggests that defects in mitochondrial metabolism and particularly of electron transport chain may play a role in pathogenesis of AD. Structurally and functionally damaged mitochondria do not produce sufficient ATP and are more prominent in producing proapoptotic factors and rea...

  14. Brainstem: neglected locus in neurodegenerative diseases

    LeaTGrinberg

    2011-07-01

    Full Text Available The most frequent neurodegenerative diseases (NDs are Alzheimer’s disease (AD, Parkinson’s disease (PD, and frontotemporal lobar degeneration associated with protein TDP-43 (FTLD-TDP. Neuropathologically, NDs are characterized by abnormal intracellular and extracellular protein deposits and by disease-specific neuronal death. Practically all terminal stages of NDs are clinically associated with dementia. Therefore, major attention was directed to protein deposits and neuron loss in supratentorial (telencephalic brain regions in the course of NDs. This was also true for PD, although the pathological hallmark of PD is degeneration of pigmented neurons of the brainstem’s substantia nigra. However, PD pathophysiology was explained by dopamine depletion in the telencephalic basal ganglia due to insufficiency and degeneration of the projection neurons located in substantia nigra. In a similar line of argumentation AD- and FTLD-related clinical deficits were exclusively explained by supratentorial allo- and neocortical laminar neuronal necrosis. Recent comprehensive studies in AD and PD early stages found considerable and unexpected involvement of brainstem nuclei, which could have the potential to profoundly change our present concepts on origin, spread, and early clinical diagnosis of these diseases. In contrast with PD and AD, few studies addressed brainstem involvement in the course of the different types of FTLD-TDP. Some of the results, including ours, disclosed a higher and more widespread pathology than anticipated. The present review will focus mainly on the impact of brainstem changes during the course of the most frequent NDs including PD, AD, and FTLD-TDP, with special emphasis on the need for more comprehensive research on FTLDs.

  15. Neurodegenerative diseases: From available treatments to prospective herbal therapy.

    Solanki, Isha; Parihar, Priyanka; Parihar, Mordhwaj Singh

    2016-05-01

    Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and many others represent a relevant health problem with age worldwide. Efforts have been made in recent years to discover the mechanism of neurodegenerative diseases and prospective therapy that can help to slow down the effects of the aging and prevent these diseases. Since pathogenesis of these diseases involves multiple factors therefore the important task for neuroscientists is to identify such multiple factors and prevent age-associated neurodegenerative diseases. For these neurodegenerative diseases yet we have only palliative therapies and none of them significantly capable to slow down or halt the underlying pathology. Polyphenolic compounds such as flavonoids present in vegetables and fruits are believed to have anti-aging properties and reduce the risk of neurodegenerative diseases. Despite their abundance, investigations into the benefits of these polyphenolic compounds in human health have only recently begun. Preclinical and clinical studies have demonstrated the potential beneficial effects of flavonoids in neurons. Although clinical trials on the effectiveness of dietary flavonoids to treat human diseases are limited but various animal models and cell culture studies have shown a great promise in developing these compounds as suitable therapeutic targets. In this review, we elaborate the neuroprotective properties of flavonoids especially their applications in prevention and intervention of different neurodegenerative diseases. Their multi-target properties may allow them to be potential dietary supplement in prevention and treatment of the age-associated neurodegenerative diseases. PMID:26550708

  16. Recent advances in using Drosophila to model neurodegenerative diseases

    Lu, Bingwei

    2009-01-01

    Neurodegenerative diseases are progressive disorders of the nervous system that affect the function and maintenance of specific neuronal populations. Most disease cases are sporadic with no known cause. The identification of genes associated with familial cases of these diseases has enabled the development of animal models to study disease mechanisms. The model organism Drosophila has been successfully used to study pathogenic mechanisms of a wide range of neurodegenerative diseases. Recent g...

  17. Mitochondria as a Therapeutic Target for Aging and Neurodegenerative Diseases

    Reddy, P. Hemachandra; Reddy, Tejaswini P.

    2011-01-01

    Mitochondria are cytoplasmic organelles responsible for life and death. Extensive evidence from animal models, postmortem brain studies of and clinical studies of aging and neurodegenerative diseases suggests that mitochondrial function is defective in aging and neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Several lines of research suggest that mitochondrial abnormalities, including defects in oxidative ...

  18. Neuroprotective and Neurotherapeutic Effects of Bee Venom on Neurodegenerative Diseases

    Miran K. Rakha

    2013-01-01

    Acute and chronic neurodegenerative diseases are illnesses associated with high morbidity and mortality, and few or no effective options are available for their treatment. A characteristic of many neurodegenerative diseases — which include stroke, brain trauma, spinal cord injury, amyotrophic lateral sclerosis, Huntington’s disease, Alzheimer’s disease, and Parkinson’s disease — is neuronal cell death. Given that central nervous system tissue has very limited, if any, regenerative capacity, i...

  19. Human DNA methylomes of neurodegenerative diseases show common epigenomic patterns.

    Sanchez-Mut, J V; Heyn, H; Vidal, E; Moran, S; Sayols, S; Delgado-Morales, R; Schultz, M D; Ansoleaga, B; Garcia-Esparcia, P; Pons-Espinal, M; de Lagran, M M; Dopazo, J; Rabano, A; Avila, J; Dierssen, M; Lott, I; Ferrer, I; Ecker, J R; Esteller, M

    2016-01-01

    Different neurodegenerative disorders often show similar lesions, such as the presence of amyloid plaques, TAU-neurotangles and synuclein inclusions. The genetically inherited forms are rare, so we wondered whether shared epigenetic aberrations, such as those affecting DNA methylation, might also exist. The studied samples were gray matter samples from the prefrontal cortex of control and neurodegenerative disease-associated cases. We performed the DNA methylation analyses of Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease and Alzheimer-like neurodegenerative profile associated with Down's syndrome samples. The DNA methylation landscapes obtained show that neurodegenerative diseases share similar aberrant CpG methylation shifts targeting a defined gene set. Our findings suggest that neurodegenerative disorders might have similar pathogenetic mechanisms that subsequently evolve into different clinical entities. The identified aberrant DNA methylation changes can be used as biomarkers of the disorders and as potential new targets for the development of new therapies. PMID:26784972

  20. Roles of peroxiredoxins in cancer, neurodegenerative diseases and inflammatory diseases.

    Park, Mi Hee; Jo, MiRan; Kim, Yu Ri; Lee, Chong-Kil; Hong, Jin Tae

    2016-07-01

    Peroxiredoxins (PRDXs) are antioxidant enzymes, known to catalyze peroxide reduction to balance cellular hydrogen peroxide (H2O2) levels, which are essential for cell signaling and metabolism and act as a regulator of redox signaling. Redox signaling is a critical component of cell signaling pathways that are involved in the regulation of cell growth, metabolism, hormone signaling, immune regulation and variety of other physiological functions. Early studies demonstrated that PRDXs regulates cell growth, metabolism and immune regulation and therefore involved in the pathologic regulator or protectant of several cancers, neurodegenerative diseases and inflammatory diseases. Oxidative stress and antioxidant systems are important regulators of redox signaling regulated diseases. In addition, thiol-based redox systems through peroxiredoxins have been demonstrated to regulate several redox-dependent process related diseases. In this review article, we will discuss recent findings regarding PRDXs in the development of diseases and further discuss therapeutic approaches targeting PRDXs. Moreover, we will suggest that PRDXs could be targets of several diseases and the therapeutic agents for targeting PRDXs may have potential beneficial effects for the treatment of cancers, neurodegenerative diseases and inflammatory diseases. Future research should open new avenues for the design of novel therapeutic approaches targeting PRDXs. PMID:27130805

  1. Transcranial Direct Current Stimulation in Neurodegenerative Disease

    Argye E. Hillis

    2014-04-01

    Full Text Available We review rationale, challenges, study designs, reported results, and future directions in the use of transcranial direct cranial stimulation (tDCS in neurodegenerative disease, focusing on treatment of spelling in primary progressive aphasia (PPA. Rationale Evidence from both animal studies and human studies indicates that anodal and cathodal tDCS over the brain result in a temporary change in membrane potentials, reducing the threshold for long-term potentiation of neurons in the affected area. This may allow unaffected brain regions to assume functions of diseased regions. Challenges Special challenges in treating individuals with progressive conditions include altered goals of treatment and the possibility that participants may accumulate new deficits over the course of the treatment program that interfere with their ability to understand, retain, or cooperate with aspects of the program. The most serious challenge – particularly for single case designs - is that there may be no stable baseline against which to measure change with treatment. Thus, it is essential to demonstrate that treatment results in a statistically significant change in the slope of decline or improvement. Therefore, demonstration of a significant difference between tDCS and control (sham requires either a large number of participants or a large effect size. Designs The choice of a treatment design reflects these limitations. Group studies with a randomized, double-blind, sham control trial design (without cross-over provide the greatest power to detect a difference between intervention and control conditions, with the fewest participants. A cross-over design, in which all participants (from 1 to many receive both active and sham conditions, in randomized order, requires a larger effect size for the active condition relative to the control condition (or little to no maintenance of treatment gains or carry-over effect to show significant differences between treatment

  2. Neuroprotective effects of berry fruits on neurodegenerative diseases

    Selvaraju Subash; Musthafa Mohamed Essa; Samir Al-Adawi; Mushtaq A.Memon; hTamilarasan Manivasagam; Mohammed Akbar

    2014-01-01

    Recent clinical research has demonstrated that berry fruits can prevent age-related neurodegen-erative diseases and improve motor and cognitive functions. The berry fruits are also capable of modulating signaling pathways involved in inflammation, cell survival, neurotransmission and enhancing neuroplasticity. The neuroprotective effects of berry fruits on neurodegenerative diseases are related to phytochemicals such as anthocyanin, caffeic acid, catechin, quercetin, kae-mpferol and tannin. In this review, we made an attempt to clearly describe the beneifcial effects of various types of berries as promising neuroprotective agents.

  3. Reprogramming therapeutics: iPS cell prospects for neurodegenerative disease

    Abeliovich, Asa; Doege, Claudia A.

    2009-01-01

    The recent description of somatic cell reprogramming to an embryonic stem (ES) cell-like phenotype, termed induced pluripotent stem (iPS) cell technology, presents an exciting potential venue towards cell-based therapeutics and disease models for neurodegenerative disorders Two recent studies from Dimos et al. (Dimos et al., 2008) and Ebert et al. (Ebert et al., 2008) describe the initial characterization of neurodegenerative disease patient-derived iPS cell cultures as proof-of-concept for t...

  4. Redox Imbalance and Viral Infections in Neurodegenerative Diseases

    Dolores Limongi

    2016-01-01

    Full Text Available Reactive oxygen species (ROS are essential molecules for many physiological functions and act as second messengers in a large variety of tissues. An imbalance in the production and elimination of ROS is associated with human diseases including neurodegenerative disorders. In the last years the notion that neurodegenerative diseases are accompanied by chronic viral infections, which may result in an increase of neurodegenerative diseases progression, emerged. It is known in literature that enhanced viral infection risk, observed during neurodegeneration, is partly due to the increase of ROS accumulation in brain cells. However, the molecular mechanisms of viral infection, occurring during the progression of neurodegeneration, remain unclear. In this review, we discuss the recent knowledge regarding the role of influenza, herpes simplex virus type-1, and retroviruses infection in ROS/RNS-mediated Parkinson’s disease (PD, Alzheimer’s disease (AD, and amyotrophic lateral sclerosis (ALS.

  5. Oxidative stress treatment for clinical trials in neurodegenerative diseases.

    Ienco, Elena Caldarazzo; LoGerfo, Annalisa; Carlesi, Cecilia; Orsucci, Daniele; Ricci, Giulia; Mancuso, Michelangelo; Siciliano, Gabriele

    2011-01-01

    Oxidative stress is a metabolic condition arising from imbalance between the production of potentially reactive oxygen species and the scavenging activities. Mitochondria are the main providers but also the main scavengers of cell oxidative stress. The role of mitochondrial dysfunction and oxidative stress in the pathogenesis of neurodegenerative diseases is well documented. Therefore, therapeutic approaches targeting mitochondrial dysfunction and oxidative damage hold great promise in neurodegenerative diseases. Despite this evidence, human experience with antioxidant neuroprotectants has generally been negative with regards to the clinical progress of disease, with unclear results in biochemical assays. Here we review the antioxidant approaches performed so far in neurodegenerative diseases and the future challenges in modern medicine. PMID:21422516

  6. Stem Cells for the Treatment of Neurodegenerative Diseases

    Ning Zhang

    2010-09-01

    Full Text Available Neurodegenerative diseases are characterized by neurodegenerative changes or apoptosis of neurons involved in networks, leading to permanent paralysis and loss of sensation below the site of the injury. Cell replacement therapy has provided the basis for the development of potentially powerful new therapeutic strategies for a broad spectrum of human neurological diseases. In recent years, neurons and glial cells have successfully been generated from stem cells, and extensive efforts by investigators to develop stem cell-based brain transplantation therapies have been carried out. We review here notable previously published experimental and preclinical studies involving stem cell-based cell for neurodegenerative diseases and discuss the future prospects for stem cell therapy of neurological disorders in the clinical setting. Steady and solid progress in stem cell research in both basic and preclinical settings should support the hope for development of stem cell-based cell therapies for neurological diseases.

  7. Absence of consensus in diagnostic criteria for familial neurodegenerative diseases.

    Byrne, Susan

    2012-04-01

    A small proportion of cases seen in neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS), Parkinson\\'s disease and Alzheimer disease are familial. These familial cases are usually clinically indistinguishable from sporadic cases. Identifying familial cases is important both in terms of clinical guidance for family members and for gene discovery.

  8. Molecular Chaperone Dysfunction in Neurodegenerative Diseases and Effects of Curcumin

    Panchanan Maiti

    2014-01-01

    Full Text Available The intra- and extracellular accumulation of misfolded and aggregated amyloid proteins is a common feature in several neurodegenerative diseases, which is thought to play a major role in disease severity and progression. The principal machineries maintaining proteostasis are the ubiquitin proteasomal and lysosomal autophagy systems, where heat shock proteins play a crucial role. Many protein aggregates are degraded by the lysosomes, depending on aggregate size, peptide sequence, and degree of misfolding, while others are selectively tagged for removal by heat shock proteins and degraded by either the proteasome or phagosomes. These systems are compromised in different neurodegenerative diseases. Therefore, developing novel targets and classes of therapeutic drugs, which can reduce aggregates and maintain proteostasis in the brains of neurodegenerative models, is vital. Natural products that can modulate heat shock proteins/proteosomal pathway are considered promising for treating neurodegenerative diseases. Here we discuss the current knowledge on the role of HSPs in protein misfolding diseases and knowledge gained from animal models of Alzheimer’s disease, tauopathies, and Huntington’s diseases. Further, we discuss the emerging treatment regimens for these diseases using natural products, like curcumin, which can augment expression or function of heat shock proteins in the cell.

  9. The Use of Proteomics in Biomarker Discovery in Neurodegenerative Diseases

    Pia Davidsson

    2005-01-01

    Full Text Available Biomarkers for neurodegenerative diseases should reflect the central pathogenic processes of the diseases. The field of clinical proteomics is especially well suited for discovery of biomarkers in cerebrospinal fluid (CSF, which reflects the proteins in the brain under healthy conditions as well as in several neurodegenerative diseases. Known proteins involved in the pathology of neurodegenerative diseases are, respectively, normal tau protein, β-amyloid (1-42, synaptic proteins, amyloid precursor protein (APP, apolipoprotein E (apoE, which previously have been studied by protein immunoassays. The objective of this paper was to summarize results from proteomic studies of differential protein patterns in neurodegenerative diseases with focus on Alzheimer's disease (AD. Today, discrimination of AD from controls and from other neurological diseases has been improved by simultaneous analysis of both β-amyloid (1-42, total-tau, and phosphorylated tau, where a combination of low levels of CSF-β-amyloid 1-42 and high levels of CSF-tau and CSF-phospho-tau is associated with an AD diagnosis. Detection of new biomarkers will further strengthen diagnosis and provide useful information in drug trials. The combination of immunoassays and proteomic methods show that the CSF proteins express differential protein patterns in AD, FTD, and PD patients, which reflect divergent underlying pathophysiological mechanisms and neuropathological changes in these diseases.

  10. Melatonin for Sleep Disorders in Patients with Neurodegenerative Diseases.

    Trotti, Lynn Marie; Karroum, Elias G

    2016-07-01

    In patients with neurodegenerative diseases, sleep disorders are common; they impair the quality of life for patients and caregivers and are associated with poorer clinical outcomes. Melatonin has circadian, hypnotic, and free radical-scavenging effects, and preclinical data suggest benefits of melatonin on neurodegeneration. However, randomized, controlled trials of melatonin in patients with neurodegenerative diseases have not shown strong effects. Trials in Alzheimer's patients demonstrate a lack of benefit on sleep quantity. Subjective measures of sleep quality are mixed, with possible symptomatic improvements seen only on some measures or at some time points. Benefits on cognition have not been observed across several studies. In Parkinson's patients, there may be minimal benefit on objective sleep measures, but a suggestion of subjective benefit in few, small studies. Effective treatments for the sleep disorders associated with neurodegenerative diseases are urgently needed, but current data are insufficient to establish melatonin as such a treatment. PMID:27180068

  11. Hemichannels in neurodegenerative diseases: is there a link to pathology?

    Megan Bosch

    2014-08-01

    Full Text Available Although originally considered a structural component of gap junctions, connexin hemichannels (HCs are now recognized as functional entities capable of influencing metabolic gradients within the CNS, allowing direct communication between the intra- and extracellular milieus. Besides connexins, HCs can also be formed by pannexins, which are not capable of gap junction assembly. Both positive and negative effects have been attributed to HC activity in the context of neurodegenerative diseases. For example, HCs can exert neuroprotective effects by promoting the uptake of neurotoxic molecules, whereas chronic HC opening can disrupt molecular gradients leading to cellular dysfunction and death. The latter scenario has been suggested for multiple neurodegenerative disorders, including Alzheimer’s Disease and more recently, lysosomal storage disorders, which are the focus of this review. Currently available evidence suggests a complex role for HCs in neurodegenerative disorders, which sets the stage for future studies to determine whether targeting HC action may improve disease outcomes.

  12. Chronic sleep disturbance and neural injury: links to neurodegenerative disease

    Abbott SM

    2016-01-01

    Full Text Available Sabra M Abbott,1 Aleksandar Videnovic21Department of Neurology, Northwestern Feinberg School of Medicine, Chicago, IL, USA; 2Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Abstract: Sleep–wake disruption is frequently observed and often one of the earliest reported symptoms of many neurodegenerative disorders. This provides insight into the underlying pathophysiology of these disorders, as sleep–wake abnormalities are often accompanied by neurodegenerative or neurotransmitter changes. However, in addition to being a symptom of the underlying neurodegenerative condition, there is also emerging evidence that sleep disturbance itself may contribute to the development and facilitate the progression of several of these disorders. Due to its impact both as an early symptom and as a potential factor contributing to ongoing neurodegeneration, the sleep–wake cycle is an ideal target for further study for potential interventions not only to lessen the burden of these diseases but also to slow their progression. In this review, we will highlight the sleep phenotypes associated with some of the major neurodegenerative disorders, focusing on the circadian disruption associated with Alzheimer’s disease, the rapid eye movement behavior disorder and sleep fragmentation associated with Parkinson’s disease, and the insomnia and circadian dysregulation associated with Huntington’s disease. Keywords: sleep, neurodegeneration, Alzheimer's disease, Parkinson's disease, Huntington's disease

  13. Modelling Neurodegenerative Diseases Using Human Pluripotent Stem Cells

    Hall, Vanessa Jane

    2016-01-01

    Neurodegenerative diseases are being modelled in-vitro using human patient-specific, induced pluripotent stem cells and transgenic embryonic stem cells to determine more about disease mechanisms, as well as to discover new treatments for patients. Current research in modelling Alzheimer’s disease...... these diseases, but will lead to even more findings in the future as gene and cell culture technology continues to develop....

  14. Neurodegenerative diseases studied in human brain and rodent models

    Gellhaar, Sandra

    2015-01-01

    Parkinson’s and Alzheimer’s disease are the two most common neurodegenerative diseases world-wide, but are still little understood. Papers in this thesis examine some of the possible pathogenic mechanisms with the help of mouse models and analysis of human post-mortem tissue. Gene-based animal models have been developed to study pathological pathways during disease progression. Using mouse models with overexpression or ablation of disease-related genes we analyzed effects of pathogenic...

  15. Mitochondrial and Cell Death Mechanisms in Neurodegenerative Diseases

    Martin, Lee J.

    2010-01-01

    Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) are the most common human adult-onset neurodegenerative diseases. They are characterized by prominent age-related neurodegeneration in selectively vulnerable neural systems. Some forms of AD, PD, and ALS are inherited, and genes causing these diseases have been identified. Nevertheless, the mechanisms of the neuronal cell death are unresolved. Morphological, biochemical, genetic, as well as cell and ani...

  16. Role of autophagy in prion protein-induced neurodegenerative diseases

    Hao Yao; Deming Zhao; Sher Hayat Khan; Lifeng Yang

    2013-01-01

    Prion diseases,characterized by spongiform degeneration and the accumulation of misfolded and aggregated PrPSc in the central nervous system,are one of fatal neurodegenerative and infectious disorders of humans and animals.In earlier studies,autophagy vacuoles in neurons were frequently observed in neurodegenerative diseases such as Alzheimer's,Parkinson's,and Huntington's diseases as well as prion diseases.Autophagy is a highly conserved homeostatic process by which several cytoplasmic components (proteins or organelles) are sequestered in a doublemembrane-bound vesicle termed 'autophagosome' and degraded upon their fusion with lysosome.The pathway of intercellular self-digestion at basal physiological levels is indispensable for maintaining the healthy status of tissues and organs.In case of prion infection,increasing evidence indicates that autophagy has a crucial ability of eliminating pathological PrPSc accumulated within neurons.In contrast,autophagy dysfunction in affected neurons may contribute to the formation of spongiform changes.In this review,we summarized recent findings about the effect of mammalian autophagy in neurodegenerative disorders,particularly in prion diseases.We also summarized the therapeutic potential of some small molecules (such as lithium,rapamycin,Sirtuin 1 and resveratrol) targets to mitigate such diseases on brain function.Furthermore,we discussed the controversial role of autophagy,whether it mediates neuronal toxicity or serves a protective function in neurodegenerative disorders.

  17. Targeting New Candidate Genes by Small Molecules Approaching Neurodegenerative Diseases

    Hueng-Chuen Fan; Ching-Shiang Chi; Shin-Nan Cheng; Hsiu-Fen Lee; Jeng-Dau Tsai; Shinn-Zong Lin; Horng-Jyh Harn

    2015-01-01

    Neurodegenerative diseases (NDs) are among the most feared of the disorders that afflict humankind for the lack of specific diagnostic tests and effective treatments. Understanding the molecular, cellular, biochemical changes of NDs may hold therapeutic promise against debilitating central nerve system (CNS) disorders. In the present review, we summarized the clinical presentations and biology backgrounds of NDs, including Parkinson’s disease (PD), Huntington’s disease (HD), and Alzheimer’s d...

  18. Mitochondria, calcium-dependent neuronal death and neurodegenerative disease.

    Duchen, M R

    2012-01-01

    Understanding the mechanisms of neuronal dysfunction and death represents a major frontier in contemporary medicine, involving the acute cell death in stroke, and the attrition of the major neurodegenerative diseases, including Parkinson's, Alzheimer's, Huntington's and Motoneuron diseases. A growing body of evidence implicates mitochondrial dysfunction as a key step in the pathogenesis of all these diseases, with the promise that mitochondrial processes represent valuable potential therapeut...

  19. Sublethal RNA Oxidation as a Mechanism for Neurodegenerative Disease

    Mark A. Smith

    2008-05-01

    Full Text Available Although cellular RNA is subjected to the same oxidative insults as DNA and other cellular macromolecules, oxidative damage to RNA has not been a major focus in investigations of the biological consequences of free radical damage. In fact, because it is largely single-stranded and its bases lack the protection of hydrogen bonding and binding by specific proteins, RNA may be more susceptible to oxidative insults than is DNA. Oxidative damage to protein-coding RNA or non-coding RNA will, in turn, potentially cause errors in proteins and/or dysregulation of gene expression. While less lethal than mutations in the genome, such sublethal insults to cells might be associated with underlying mechanisms of several chronic diseases, including neurodegenerative disease. Recently, oxidative RNA damage has been described in several neurodegenerative diseases including Alzheimer disease, Parkinson disease, dementia with Lewy bodies, and prion diseases. Of particular interest, oxidative RNA damage can be demonstrated in vulnerable neurons early in disease, suggesting that RNA oxidation may actively contribute to the onset of the disease. An increasing body of evidence suggests that, mechanistically speaking, the detrimental effects of oxidative RNA damage to protein synthesis are attenuated, at least in part, by the existence of protective mechanisms that prevent the incorporation of the damaged ribonucleotides into the translational machinery. Further investigations aimed at understanding the processing mechanisms related to oxidative RNA damage and its consequences may provide significant insights into the pathogenesis of neurodegenerative and other degenerative diseases and lead to better therapeutic strategies.

  20. Reverse engineering human neurodegenerative disease using pluripotent stem cell technology.

    Liu, Ying; Deng, Wenbin

    2016-05-01

    With the technology of reprogramming somatic cells by introducing defined transcription factors that enables the generation of "induced pluripotent stem cells (iPSCs)" with pluripotency comparable to that of embryonic stem cells (ESCs), it has become possible to use this technology to produce various cells and tissues that have been difficult to obtain from living bodies. This advancement is bringing forth rapid progress in iPSC-based disease modeling, drug screening, and regenerative medicine. More and more studies have demonstrated that phenotypes of adult-onset neurodegenerative disorders could be rather faithfully recapitulated in iPSC-derived neural cell cultures. Moreover, despite the adult-onset nature of the diseases, pathogenic phenotypes and cellular abnormalities often exist in early developmental stages, providing new "windows of opportunity" for understanding mechanisms underlying neurodegenerative disorders and for discovering new medicines. The cell reprogramming technology enables a reverse engineering approach for modeling the cellular degenerative phenotypes of a wide range of human disorders. An excellent example is the study of the human neurodegenerative disease amyotrophic lateral sclerosis (ALS) using iPSCs. ALS is a progressive neurodegenerative disease characterized by the loss of upper and lower motor neurons (MNs), culminating in muscle wasting and death from respiratory failure. The iPSC approach provides innovative cell culture platforms to serve as ALS patient-derived model systems. Researchers have converted iPSCs derived from ALS patients into MNs and various types of glial cells, all of which are involved in ALS, to study the disease. The iPSC technology could be used to determine the role of specific genetic factors to track down what׳s wrong in the neurodegenerative disease process in the "disease-in-a-dish" model. Meanwhile, parallel experiments of targeting the same specific genes in human ESCs could also be performed to

  1. Epigenetic mechanisms in neurological and neurodegenerative diseases.

    Jorge eLandgrave-Gómez

    2015-02-01

    Full Text Available The role of epigenetic mechanisms in the function and homeostasis of the central nervous system (CNS and its regulation in diseases is one of the most interesting processes of contemporary neuroscience. In the last decade, a growing body of literature suggests that long-term changes in gene transcription associated with CNS´s regulation and neurological disorders are mediated via modulation of chromatin structure.Epigenetics, introduced for the first time by Waddington in the early 1940s, has been traditionally referred to a variety of mechanisms that allow heritable changes in gene expression even in the absence of DNA mutation. However, new definitions acknowledge that many of these mechanisms used to perpetuate epigenetic traits in dividing cells are used by neurons to control a variety of functions dependent on gene expression. Indeed, in the recent years these mechanisms have shown their importance in the maintenance of a healthy CNS. Moreover, environmental inputs that have shown effects in CNS diseases, such as nutrition, that can modulate the concentration of a variety of metabolites such as acetyl-coenzyme A (acetyl-coA, nicotinamide adenine dinucleotide (NAD+ and beta hydroxybutyrate (β-HB, regulates some of these epigenetic modifications, linking in a precise way environment with gene expression.This manuscript will portray what is currently understood about the role of epigenetic mechanisms in the function and homeostasis of the CNS and their participation in a variety of neurological disorders. We will discuss how the machinery that controls these modifications plays an important role in processes involved in neurological disorders such as neurogenesis and cell growth. Moreover, we will discuss how environmental inputs modulate these modifications producing metabolic and physiological alterations that could exert beneficial effects on neurological diseases. Finally, we will highlight possible future directions in the field of

  2. ETHICAL AND GENETIC ASPECTS REGARDING PRESYMPTOMATIC TESTING FOR NEURODEGENERATIVE DISEASES.

    Cozaru, Georgeta Camelial; Aşchie, Mariana; Mitroi, Anca Florentina; Poinăreanu, I; Gorduza, E V

    2016-01-01

    Neurodegenerative diseases, such as Alzheimer's dementia, Huntington's chorea, Parkinson's disease or spinocerebellar ataxia, manifests into adulthood with an insidious onset, slowly of progressive symptoms. All of these diseases are characterized by presimptomatic stages that preceded with many years of clinical debut. In Parkinson's disease, more than half of the dopaminergic neurons of the black substance are lost before the advent of motor characteristic manifestations. In Huntington's chorea, the progressive neurodegenerative disease could be diagnose prenatal and presymptomatic by analyse of the number of CAG repeats in exon 1 of the huntingtin gene. A similar mechanism represented by expansion of trinucleotide repeats during hereditary transmission from parents to children was identified in fragile X syndrome, spinocerebellar ataxia, spinal muscular and bulbar atrophy, or myotonic dystrophy. Presymptomatic diagnosis in all these progressive diseases raise many ethical issues, due to the psychological impact that can cause the prediction of a disease for which there is currently no curative treatment. Therefore, a positive result can produce serious psychological trauma and major changes in the lifestyle of the individual, instead, a negative result can bring joy and tranquillity. But the problem arises if presymptomatic testing in these neurodegenerative diseases brings greater benefits compared to the possible psychological damage, which can add the risk of stigmatization or discrimination. PMID:27125067

  3. Quantitative analysis on electrooculography (EOG) for neurodegenerative disease

    Liu, Chang-Chia; Chaovalitwongse, W. Art; Pardalos, Panos M.; Seref, Onur; Xanthopoulos, Petros; Sackellares, J. C.; Skidmore, Frank M.

    2007-11-01

    Many studies have documented abnormal horizontal and vertical eye movements in human neurodegenerative disease as well as during altered states of consciousness (including drowsiness and intoxication) in healthy adults. Eye movement measurement may play an important role measuring the progress of neurodegenerative diseases and state of alertness in healthy individuals. There are several techniques for measuring eye movement, Infrared detection technique (IR). Video-oculography (VOG), Scleral eye coil and EOG. Among those available recording techniques, EOG is a major source for monitoring the abnormal eye movement. In this real-time quantitative analysis study, the methods which can capture the characteristic of the eye movement were proposed to accurately categorize the state of neurodegenerative subjects. The EOG recordings were taken while 5 tested subjects were watching a short (>120 s) animation clip. In response to the animated clip the participants executed a number of eye movements, including vertical smooth pursued (SVP), horizontal smooth pursued (HVP) and random saccades (RS). Detection of abnormalities in ocular movement may improve our diagnosis and understanding a neurodegenerative disease and altered states of consciousness. A standard real-time quantitative analysis will improve detection and provide a better understanding of pathology in these disorders.

  4. Molecular Chaperone Dysfunction in Neurodegenerative Diseases and Effects of Curcumin

    Panchanan Maiti; Jayeeta Manna; Shobi Veleri; Sally Frautschy

    2014-01-01

    The intra- and extracellular accumulation of misfolded and aggregated amyloid proteins is a common feature in several neurodegenerative diseases, which is thought to play a major role in disease severity and progression. The principal machineries maintaining proteostasis are the ubiquitin proteasomal and lysosomal autophagy systems, where heat shock proteins play a crucial role. Many protein aggregates are degraded by the lysosomes, depending on aggregate size, peptide sequence, and degree of...

  5. Single-Chain Fragment Variable Passive Immunotherapies for Neurodegenerative Diseases

    Liang Huang; Federoff, Howard J.; Xiaomin Su

    2013-01-01

    Accumulation of misfolded proteins has been implicated in a variety of neurodegenerative diseases including prion diseases, Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). In the past decade, single-chain fragment variable (scFv) -based immunotherapies have been developed to target abnormal proteins or various forms of protein aggregates including Aβ, SNCA, Htt, and PrP proteins. The scFvs are produced by fusing the variable regions of the antibody heavy and...

  6. PREFACE: Physics and biology of neurodegenerative diseases Physics and biology of neurodegenerative diseases

    Pastore, Annalisa

    2012-06-01

    , about 15 years after the original reports, it is clear that amyloids are special structures that occur in nature under several different guises, some good, some evil [3]. The number of diseases associated with misfolding and fibrillogenesis has steadily increased. Examples of fairly common pathologies associated with fibre formation include Alzheimer's disease (currently one of the major threats for human health in our increasingly aging world), Parkinson's disease and several rare, but not less severe, pathologies. On the other hand, it is also clear that amyloid formation is a convenient mechanism for storing peptides and/or proteins in a compact and resistant way. The number of organisms/tissues in which amyloid deposits are found is thus increasing. It is also not too far-fetched to expect that the mechanical properties of amyloids could be used in biotechnology to design new materials. Because of the importance of this topic in so many scientific fields, we have dedicated this special issue of Journal of Physics: Condensed Matter to the topic of protein aggregation and disease. In the following pages we have collected two reviews and five articles that explore new and interesting developments in the field. References [1] Olby R 1994 The Path of the Double Helix: The Discovery of DNA (New York: Dover) [2] Dobson C M 2004 Principles of protein folding, misfolding and aggregation Semin. Cell Dev. Biol. 15 3-16 [3] Hammer N D, Wang X, McGuffie B A, Chapman M R 2008 Amyloids: friend or foe? J. Alzheimers Dis. 13 407-19 Physics and biology of neurodegenerative diseases contents Protein aggregation and misfolding: good or evil?Annalisa Pastore and Pierandrea Temussi Alzheimer's disease: biological aspects, therapeutic perspectives and diagnostic toolsM Di Carlo, D Giacomazza and P L San Biagio Entrapment of Aβ1-40 peptide in unstructured aggregatesC Corsale, R Carrotta, M R Mangione, S Vilasi, A Provenzano, G Cavallaro, D Bulone and P L San Biagio Elemental micro

  7. Protein Modification by Dicarbonyl Molecular Species in Neurodegenerative Diseases

    Wesley M. Williams

    2011-01-01

    Full Text Available Neurodegeneration results from abnormalities in cerebral metabolism and energy balance within neurons, astrocytes, microglia, or microvascular endothelial cells of the blood-brain barrier. In Alzheimer's disease, -amyloid is considered the primary contributor to neuropathology and neurodegeneration. It now is believed that certain systemic diseases, such as diabetes mellitus, can contribute to neurodegeneration through the effects of chronic hyperglycemia/insulin resistance resulting in protein glycation, oxidative stress and inflammation within susceptible brain regions. Here, we present an overview of research focusing on the role of protein glycation, oxidative stress, and inflammation in the neurodegenerative process. Of special interest in this paper is the effect of methylglyoxal (MGO, a cytotoxic byproduct of glucose metabolism, elevated in neurodegenerative disease, and diabetes mellitus, on cerebral protein function and oxidative stress. How MGO interacts with amino acid residues within -amyloid, and small peptides within the brain, is also discussed in terms of the affect on protein function.

  8. Neurofilament proteins in axonal regeneration and neurodegenerative diseases

    Haitao Wang; Minfei Wu; Chuanjun Zhan; Enyuan Ma; Maoguang Yang; Xiaoyu Yang; Yingpu Li

    2012-01-01

    Neurofilament protein is a component of the mature neuronal cytoskeleton, and it interacts with the zygosome, which is mediated by neurofilament-related proteins. Neurofilament protein regulates enzyme function and the structure of linker proteins. In addition, neurofilament gene expression plays an important role in nervous system development. Previous studies have shown that neurofilament gene transcriptional regulation is crucial for neurofilament protein expression, especially in axonal regeneration and degenerative diseases. Post-transcriptional regulation increased neurofilament protein gene transcription during axonal regeneration, ultimately resulting in a pattern of neurofilament protein expression. An expression imbalance of post-transcriptional regulatory proteins and other disorders could lead to amyotrophic lateral sclerosis or other neurodegenerative diseases. These findings indicated that after transcription, neurofilament protein regulated expression of related proteins and promoted regeneration of damaged axons, suggesting that regulation disorders could lead to neurodegenerative diseases.

  9. cNEUPRO: Novel Biomarkers for Neurodegenerative Diseases

    Philipp Spitzer

    2010-01-01

    Full Text Available “clinical NEUroPROteomics of neurodegenerative diseases” (cNEUPRO is a Specific Targeted Research Project (STREP within the sixth framework program of the European Commission dedicated to the search for novel biomarker candidates for Alzheimer's disease and other neurodegenerative diseases. The ultimate goal of cNEUPRO is to identify one or more valid biomarker(s in blood and CSF applicable to support the early and differential diagnosis of dementia disorders. The consortium covers all steps required for the discovery of novel biomarker candidates such as acquisition of high quality CSF and blood samples from relevant patient groups and controls, analysis of body fluids by various methods, and finally assay development and assay validation. Here we report the standardized procedures for diagnosis and preanalytical sample-handling within the project, as well as the status of the ongoing research activities and some first results.

  10. Clinical neurogenetics: behavioral management of inherited neurodegenerative disease.

    Wexler, Eric

    2013-11-01

    Psychiatric symptoms often manifest years before overt neurologic signs in patients with inherited neurodegenerative disease. The most frequently cited example of this phenomenon is the early onset of personality changes in "presymptomatic" Huntington patients. In some cases the changes in mood and cognition are even more debilitating than their neurologic symptoms. The goal of this article is to provide the neurologist with a concise primer that can be applied in a busy clinic or private practice. PMID:24176427

  11. Neural Basis of Interpersonal Traits in Neurodegenerative Diseases

    Sollberger, Marc; Stanley, Christine M.; Wilson, Stephen M; Gyurak, Anett; Beckman, Victoria; Growdon, Matthew; Jang, Jung; Weiner, Michael W.; Miller, Bruce L.; Rankin, Katherine P.

    2009-01-01

    Several functional and structural imaging studies have investigated the neural basis of personality in healthy adults, but human lesions studies are scarce. Personality changes are a common symptom in patients with neurodegenerative diseases like frontotemporal dementia (FTD) and semantic dementia (SD), allowing a unique window into the neural basis of personality. In this study, we used the Interpersonal Adjective Scales to investigate the structural basis of eight interpersonal traits (domi...

  12. Neural substrates of spontaneous narrative production in focal neurodegenerative disease.

    Gola, Kelly A; Thorne, Avril; Veldhuisen, Lisa D; Felix, Cordula M; Hankinson, Sarah; Pham, Julie; Shany-Ur, Tal; Schauer, Guido P; Stanley, Christine M; Glenn, Shenly; Miller, Bruce L; Rankin, Katherine P

    2015-12-01

    Conversational storytelling integrates diverse cognitive and socio-emotional abilities that critically differ across neurodegenerative disease groups. Storytelling patterns may have diagnostic relevance and predict anatomic changes. The present study employed mixed methods discourse and quantitative analyses to delineate patterns of storytelling across focal neurodegenerative disease groups, and to clarify the neuroanatomical contributions to common storytelling characteristics. Transcripts of spontaneous social interactions of 46 participants (15 behavioral variant frontotemporal dementia (bvFTD), 7 semantic variant primary progressive aphasia (svPPA), 12 Alzheimer's disease (AD), and 12 healthy older normal controls (NC)) were analyzed for storytelling frequency and characteristics, and videos of the interactions were rated for patients' level of social attentiveness. Compared to controls, svPPAs told more stories and autobiographical stories, and perseverated on aspects of self during the interaction, whereas ADs told fewer autobiographical stories than NCs. svPPAs and bvFTDs were rated as less attentive to social cues. Aspects of storytelling were related to diverse cognitive and socio-emotional functions, and voxel-based anatomic analysis of structural magnetic resonance imaging revealed that temporal organization, narrative evaluations patterns, and social attentiveness correlated with atrophy corresponding to known intrinsic connectivity networks, including the default mode, limbic, salience, and stable task control networks. Differences in spontaneous storytelling among neurodegenerative groups elucidated diverse cognitive, socio-emotional, and neural contributions to narrative production, with implications for diagnostic screening and therapeutic intervention. PMID:26485159

  13. Single-Chain Fragment Variable Passive Immunotherapies for Neurodegenerative Diseases

    Liang Huang

    2013-09-01

    Full Text Available Accumulation of misfolded proteins has been implicated in a variety of neurodegenerative diseases including prion diseases, Alzheimer’s disease (AD, Parkinson’s disease (PD, and Huntington’s disease (HD. In the past decade, single-chain fragment variable (scFv -based immunotherapies have been developed to target abnormal proteins or various forms of protein aggregates including Aβ, SNCA, Htt, and PrP proteins. The scFvs are produced by fusing the variable regions of the antibody heavy and light chains, creating a much smaller protein with unaltered specificity. Because of its small size and relative ease of production, scFvs are promising diagnostic and therapeutic reagents for protein misfolded diseases. Studies have demonstrated the efficacy and safety of scFvs in preventing amyloid protein aggregation in preclinical models. Herein, we discuss recent developments of these immunotherapeutics. We review efforts of our group and others using scFv in neurodegenerative disease models. We illustrate the advantages of scFvs, including engineering to enhance misfolded conformer specificity and subcellular targeting to optimize therapeutic action.

  14. Evidence-based therapy for sleep disorders in neurodegenerative diseases

    LIU Ling

    2013-08-01

    Full Text Available Objective To evaluate the effectiveness of the treatments for sleep disorders in neurodegenerative diseases so as to provide the best therapeutic regimens for the evidence-based treatment. Methods Search PubMed, MEDLINE, Cochrane Library, Wanfang Data and China National Knowledge Infrastructure (CNKI databases with "sleep disorder or sleep disturbance", "neurodegenerative diseases", "Parkinson's disease or PD", "Alzheimer's disease or AD", "multiple system atrophy or MSA" as retrieval words. The quality of the articles were evaluated with Jadad Scale. Results A total of 35 articles, including 2 systematic reviews, 5 randomized controlled trials, 13 clinical controlled trials, 13 case series and 2 epidemiological investigation studies were included for evaluation, 13 of which were high grade and 22 were low grade articles. Clinical evidences showed that: 1 advice on sleep hygiene, careful use of dopaminergic drugs and hypnotic sedative agents should be considered for PD. Bright light therapy (BLT may improve circadian rhythm sleep disorders and clonazepam may be effective for rapid eye movement sleep behavior disorder (RBD. However, to date, very few controlled studies are available to make a recommendation for the management of sleep disorders in PD; 2 treatments for sleep disorders in AD include drug therapy (e.g. melatonin, acetylcholinesterase inhibitors, antipsychotic drugs, antidepressants and non-drug therapy (e.g. BLT, behavior therapy, but very limited evidence shows the effectiveness of these treatments; 3 the first line treatment for sleep-related breathing disorder in MSA is nasal continuous positive airway pressure (nCPAP, and clonazepam is effective for RBD in MSA; 4 there is rare evidence related to the treatment of sleep disorders in dementia with Lewy body (DLB and amyotrophic lateral sclerosis (ALS. Conclusion Evidence-based medicine can provide the best clinical evidence on sleep disorders' treatment in neurodegenerative

  15. Mitochondrial and Cell Death Mechanisms in Neurodegenerative Diseases

    Lee J. Martin

    2010-03-01

    Full Text Available Alzheimer’s disease (AD, Parkinson’s disease (PD and amyotrophic lateral sclerosis (ALS are the most common human adult-onset neurodegenerative diseases. They are characterized by prominent age-related neurodegeneration in selectively vulnerable neural systems. Some forms of AD, PD, and ALS are inherited, and genes causing these diseases have been identified. Nevertheless, the mechanisms of the neuronal cell death are unresolved. Morphological, biochemical, genetic, as well as cell and animal model studies reveal that mitochondria could have roles in this neurodegeneration. The functions and properties of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to cellular aging and stress and overlying genetic variations, triggering neurodegeneration according to a cell death matrix theory. In AD, alterations in enzymes involved in oxidative phosphorylation, oxidative damage, and mitochondrial binding of Aβ and amyloid precursor protein have been reported. In PD, mutations in putative mitochondrial proteins have been identified and mitochondrial DNA mutations have been found in neurons in the substantia nigra. In ALS, changes occur in mitochondrial respiratory chain enzymes and mitochondrial cell death proteins. Transgenic mouse models of human neurodegenerative disease are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria and the mitochondrial permeability transition pore. This review summarizes how mitochondrial pathobiology might contribute to neuronal death in AD, PD, and ALS and could serve as a target for drug therapy.

  16. Targeting New Candidate Genes by Small Molecules Approaching Neurodegenerative Diseases

    Hueng-Chuen Fan

    2015-12-01

    Full Text Available Neurodegenerative diseases (NDs are among the most feared of the disorders that afflict humankind for the lack of specific diagnostic tests and effective treatments. Understanding the molecular, cellular, biochemical changes of NDs may hold therapeutic promise against debilitating central nerve system (CNS disorders. In the present review, we summarized the clinical presentations and biology backgrounds of NDs, including Parkinson’s disease (PD, Huntington’s disease (HD, and Alzheimer’s disease (AD and explored the role of molecular mechanisms, including dys-regulation of epigenetic control mechanisms, Ataxia-telangiectasia-mutated protein kinase (ATM, and neuroinflammation in the pathogenesis of NDs. Targeting these mechanisms may hold therapeutic promise against these devastating diseases.

  17. Corruption and Spread of Pathogenic Proteins in Neurodegenerative Diseases*

    Walker, Lary C.; LeVine, Harry

    2012-01-01

    With advancing age, the brain becomes increasingly susceptible to neurodegenerative diseases, most of which are characterized by the misfolding and errant aggregation of certain proteins. The induction of aggregation involves a crystallization-like seeding mechanism by which a specific protein is structurally corrupted by its misfolded conformer. The latest research indicates that, once formed, proteopathic seeds can spread from one locale to another via cellular uptake, transport, and release. Impeding this process could represent a unified therapeutic strategy for slowing the progression of a wide range of currently intractable disorders. PMID:22879600

  18. Unfolding the promise of translational targeting in neurodegenerative disease.

    Drake, Thomas M

    2015-06-01

    With the rise of aging populations, new challenges for health care systems are emerging. Degenerative conditions of the central nervous system share a strikingly great deal of similarities, particularly the production and buildup of malfolded proteins. As a result, stress pathways within the endoplasmic reticulum become activated, triggering widespread neuronal apoptosis. New pharmacological compounds targeting this response are emerging as promising treatment strategies. This review examines the current evidence for protein aggregation in neurodegenerative disease states and discusses future mechanisms of therapeutically targeting the endoplasmic reticulum. PMID:25697885

  19. Endogenously Nitrated Proteins in Mouse Brain: Links To Neurodegenerative Disease

    Sacksteder, Colette A.; Qian, Weijun; Knyushko, Tanya V.; Wang, Haixing H.; Chin, Mark H.; Lacan, Goran; Melega, William P.; Camp, David G.; Smith, Richard D.; Smith, Desmond J.; Squier, Thomas C.; Bigelow, Diana J.

    2006-07-04

    Increased nitrotyrosine modification of proteins has been documented in multiple pathologies in a variety of tissue types; emerging evidence suggests its additional role in redox regulation of normal metabolism. In order to identify proteins sensitive to nitrating conditions in vivo, a comprehensive proteomic dataset identifying 7,792 proteins from whole mouse brain, generated by LC/LC-MS/MS analyses, was used to identify nitrated proteins. This analysis resulted in identification of 31 unique nitrotyrosine sites within 29 different proteins. Over half of the nitrated proteins identified have been reported to be involved in Parkinson's disease, Alzheimer's disease, or other neurodegenerative disorders. Similarly, nitrotyrosine immunoblots of whole brain homogenates show that treatment of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an experimental model of Parkinson's disease, induces increased nitration of the same protein bands observed to be nitrated in brains of untreated animals. Comparing sequences and available high resolution structures around nitrated tyrosines with those of unmodified sites indicates a preference of nitration in vivo for surface accessible tyrosines in loops, characteristics consistent with peroxynitrite-induced tyrosine modification. More striking is the five-fold greater nitration of tyrosines having nearby basic sidechains, suggesting electrostatic attraction of basic groups with the negative charge of peroxynitrite. Together, these results suggest that elevated peroxynitrite generation plays a role in neurodegenerative changes in the brain and provides a predictive tool of functionally important sites of nitration.

  20. The role of the mitochondrial dysfunction in two neurodegenerative diseases, Huntington's disease and Parkinson's disease

    Damiano, Maria

    2014-01-01

    Mitochondrial dysfunction has been implicated in several neurodegenerative diseases and is correlated with augmented levels of intracellular oxydant stress. The mitochondrial defects observed in tissues from patients, as well as in animal and cellular models of Huntington’s and Parkinson’s diseases, suggest the implication of mitochondria in the pathogenesis of these diseases. The two projects discussed in this manuscript focus on the role of particular aspects of mitochondrial physiology in ...

  1. Autophagy as an essential cellular antioxidant pathway in neurodegenerative disease

    Samantha Giordano

    2014-01-01

    Full Text Available Oxidative stress including DNA damage, increased lipid and protein oxidation, are important features of aging and neurodegeneration suggesting that endogenous antioxidant protective pathways are inadequate or overwhelmed. Importantly, oxidative protein damage contributes to age-dependent accumulation of dysfunctional mitochondria or protein aggregates. In addition, environmental toxins such as rotenone and paraquat, which are risk factors for the pathogenesis of neurodegenerative diseases, also promote protein oxidation. The obvious approach of supplementing the primary antioxidant systems designed to suppress the initiation of oxidative stress has been tested in animal models and positive results were obtained. However, these findings have not been effectively translated to treating human patients, and clinical trials for antioxidant therapies using radical scavenging molecules such as α-tocopherol, ascorbate and coenzyme Q have met with limited success, highlighting several limitations to this approach. These could include: (1 radical scavenging antioxidants cannot reverse established damage to proteins and organelles; (2 radical scavenging antioxidants are oxidant specific, and can only be effective if the specific mechanism for neurodegeneration involves the reactive species to which they are targeted and (3 since reactive species play an important role in physiological signaling, suppression of endogenous oxidants maybe deleterious. Therefore, alternative approaches that can circumvent these limitations are needed. While not previously considered an antioxidant system we propose that the autophagy-lysosomal activities, may serve this essential function in neurodegenerative diseases by removing damaged or dysfunctional proteins and organelles.

  2. Neurodegenerative diseases: quantitative predictions of protein-RNA interactions.

    Cirillo, Davide; Agostini, Federico; Klus, Petr; Marchese, Domenica; Rodriguez, Silvia; Bolognesi, Benedetta; Tartaglia, Gian Gaetano

    2013-02-01

    Increasing evidence indicates that RNA plays an active role in a number of neurodegenerative diseases. We recently introduced a theoretical framework, catRAPID, to predict the binding ability of protein and RNA molecules. Here, we use catRAPID to investigate ribonucleoprotein interactions linked to inherited intellectual disability, amyotrophic lateral sclerosis, Creutzfeuld-Jakob, Alzheimer's, and Parkinson's diseases. We specifically focus on (1) RNA interactions with fragile X mental retardation protein FMRP; (2) protein sequestration caused by CGG repeats; (3) noncoding transcripts regulated by TAR DNA-binding protein 43 TDP-43; (4) autogenous regulation of TDP-43 and FMRP; (5) iron-mediated expression of amyloid precursor protein APP and α-synuclein; (6) interactions between prions and RNA aptamers. Our results are in striking agreement with experimental evidence and provide new insights in processes associated with neuronal function and misfunction. PMID:23264567

  3. Neurodegenerative diseases: Quantitative predictions of protein–RNA interactions

    Cirillo, Davide; Agostini, Federico; Klus, Petr; Marchese, Domenica; Rodriguez, Silvia; Bolognesi, Benedetta; Tartaglia, Gian Gaetano

    2013-01-01

    Increasing evidence indicates that RNA plays an active role in a number of neurodegenerative diseases. We recently introduced a theoretical framework, catRAPID, to predict the binding ability of protein and RNA molecules. Here, we use catRAPID to investigate ribonucleoprotein interactions linked to inherited intellectual disability, amyotrophic lateral sclerosis, Creutzfeuld-Jakob, Alzheimer’s, and Parkinson’s diseases. We specifically focus on (1) RNA interactions with fragile X mental retardation protein FMRP; (2) protein sequestration caused by CGG repeats; (3) noncoding transcripts regulated by TAR DNA-binding protein 43 TDP-43; (4) autogenous regulation of TDP-43 and FMRP; (5) iron-mediated expression of amyloid precursor protein APP and α-synuclein; (6) interactions between prions and RNA aptamers. Our results are in striking agreement with experimental evidence and provide new insights in processes associated with neuronal function and misfunction. PMID:23264567

  4. REM behaviour disorder detection associated with neurodegenerative diseases

    Kempfner, Jacob; Sorensen, Gertrud; Zoetmulder, Marielle;

    2010-01-01

    Abnormal skeleton muscle activity during REM sleep is characterized as REM Behaviour Disorder (RBD), and may be an early marker for different neurodegenerative diseases. Early detection of RBD is therefore highly important, and in this ongoing study a semi-automatic method for RBD detection is...... proposed by analyzing the motor activity during sleep. Method: A total number of twelve patients have been involved in this study, six normal controls and six patients diagnosed with Parkinsons Disease (PD) with RBD. All subjects underwent at least one ambulant polysomnographic (PSG) recording. The sleep...... computerized algorithm has been attempted implemented. By analysing the REM and non-REM EMG activity, using advanced signal processing tools combined with a statistical classifier, it is possible to discriminate normal and abnormal EMG activity. Due to the small number of patients, the overall performance of...

  5. Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders.

    Mahley, Robert W

    2016-07-01

    Apolipoprotein (apo) E was initially described as a lipid transport protein and major ligand for low density lipoprotein (LDL) receptors with a role in cholesterol metabolism and cardiovascular disease. It has since emerged as a major risk factor (causative gene) for Alzheimer's disease and other neurodegenerative disorders. Detailed understanding of the structural features of the three isoforms (apoE2, apoE3, and apoE4), which differ by only a single amino acid interchange, has elucidated their unique functions. ApoE2 and apoE4 increase the risk for heart disease: apoE2 increases atherogenic lipoprotein levels (it binds poorly to LDL receptors), and apoE4 increases LDL levels (it binds preferentially to triglyceride-rich, very low density lipoproteins, leading to downregulation of LDL receptors). ApoE4 also increases the risk for neurodegenerative diseases, decreases their age of onset, or alters their progression. ApoE4 likely causes neurodegeneration secondary to its abnormal structure, caused by an interaction between its carboxyl- and amino-terminal domains, called domain interaction. When neurons are stressed or injured, they synthesize apoE to redistribute cholesterol for neuronal repair or remodeling. However, because of its altered structure, neuronal apoE4 undergoes neuron-specific proteolysis, generating neurotoxic fragments (12-29 kDa) that escape the secretory pathway and cause mitochondrial dysfunction and cytoskeletal alterations, including tau phosphorylation. ApoE4-associated pathology can be prevented by small-molecule structure correctors that block domain interaction by converting apoE4 to a molecule that resembles apoE3 both structurally and functionally. Structure correctors are a potential therapeutic approach to reduce apoE4 pathology in both cardiovascular and neurological disorders. PMID:27277824

  6. Does neuroinflammation fan the flame in neurodegenerative diseases?

    McAlpine Fiona E

    2009-11-01

    Full Text Available Abstract While peripheral immune access to the central nervous system (CNS is restricted and tightly controlled, the CNS is capable of dynamic immune and inflammatory responses to a variety of insults. Infections, trauma, stroke, toxins and other stimuli are capable of producing an immediate and short lived activation of the innate immune system within the CNS. This acute neuroinflammatory response includes activation of the resident immune cells (microglia resulting in a phagocytic phenotype and the release of inflammatory mediators such as cytokines and chemokines. While an acute insult may trigger oxidative and nitrosative stress, it is typically short-lived and unlikely to be detrimental to long-term neuronal survival. In contrast, chronic neuroinflammation is a long-standing and often self-perpetuating neuroinflammatory response that persists long after an initial injury or insult. Chronic neuroinflammation includes not only long-standing activation of microglia and subsequent sustained release of inflammatory mediators, but also the resulting increased oxidative and nitrosative stress. The sustained release of inflammatory mediators works to perpetuate the inflammatory cycle, activating additional microglia, promoting their proliferation, and resulting in further release of inflammatory factors. Neurodegenerative CNS disorders, including multiple sclerosis (MS, Alzheimer's disease (AD, Parkinson's disease (PD, Huntington's disease (HD, amyotrophic lateral sclerosis (ALS, tauopathies, and age-related macular degeneration (ARMD, are associated with chronic neuroinflammation and elevated levels of several cytokines. Here we review the hallmarks of acute and chronic inflammatory responses in the CNS, the reasons why microglial activation represents a convergence point for diverse stimuli that may promote or compromise neuronal survival, and the epidemiologic, pharmacologic and genetic evidence implicating neuroinflammation in the

  7. Vitagenes, dietary antioxidants and neuroprotection in neurodegenerative diseases.

    Calabrese, Vittorio; Cornelius, Carolin; Mancuso, Cesare; Barone, Eugenio; Calafato, Stella; Bates, Timothy; Rizzarelli, Enrico; Kostova, Albena T Dinkova

    2009-01-01

    The ability of a cell to counteract stressful conditions, known as cellular stress response, requires the activation of pro-survival pathways and the production of molecules with anti-oxidant, anti-apoptotic or pro-apoptotic activities. Among the cellular pathways conferring protection against oxidative stress, a key role is played by vitagenes, which include heat shock proteins (Hsps) heme oxygenase-1 and Hsp70, as well as the thioredoxin/thioredoxin reductase system. Heat shock response contributes to establish a cytoprotective state in a wide variety of human diseases, including inflammation, cancer, aging and neurodegenerative disorders. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing stress responses. Dietary antioxidants, such as curcumin, L-carnitine/acetyl-L-carnitine and carnosine have recently been demonstrated in vitro to be neuroprotective through the activation of hormetic pathways, including vitagenes. In the present review we discuss the importance of vitagenes in the cellular stress response and analyse, from a pharmacological point of view, the potential use of dietary antioxidants in the treatment of neurodegenerative disorders in humans. PMID:19273073

  8. Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases.

    Irwin, Michael H; Moos, Walter H; Faller, Douglas V; Steliou, Kosta; Pinkert, Carl A

    2016-05-01

    Preclinical Research In this review, we discuss epigenetic-driven methods for treating neurodegenerative disorders associated with mitochondrial dysfunction, focusing on carnitinoid antioxidant-histone deacetylase inhibitors that show an ability to reinvigorate synaptic plasticity and protect against neuromotor decline in vivo. Aging remains a major risk factor in patients who progress to dementia, a clinical syndrome typified by decreased mental capacity, including impairments in memory, language skills, and executive function. Energy metabolism and mitochondrial dysfunction are viewed as determinants in the aging process that may afford therapeutic targets for a host of disease conditions, the brain being primary in such thinking. Mitochondrial dysfunction is a core feature in the pathophysiology of both Alzheimer and Parkinson diseases and rare mitochondrial diseases. The potential of new therapies in this area extends to glaucoma and other ophthalmic disorders, migraine, Creutzfeldt-Jakob disease, post-traumatic stress disorder, systemic exertion intolerance disease, and chemotherapy-induced cognitive impairment. An emerging and hopefully more promising approach to addressing these hard-to-treat diseases leverages their sensitivity to activation of master regulators of antioxidant and cytoprotective genes, antioxidant response elements, and mitophagy. Drug Dev Res 77 : 109-123, 2016. © 2016 Wiley Periodicals, Inc. PMID:26899010

  9. Differential diagnosis of neurodegenerative diseases using structural MRI data.

    Koikkalainen, Juha; Rhodius-Meester, Hanneke; Tolonen, Antti; Barkhof, Frederik; Tijms, Betty; Lemstra, Afina W; Tong, Tong; Guerrero, Ricardo; Schuh, Andreas; Ledig, Christian; Rueckert, Daniel; Soininen, Hilkka; Remes, Anne M; Waldemar, Gunhild; Hasselbalch, Steen; Mecocci, Patrizia; van der Flier, Wiesje; Lötjönen, Jyrki

    2016-01-01

    Different neurodegenerative diseases can cause memory disorders and other cognitive impairments. The early detection and the stratification of patients according to the underlying disease are essential for an efficient approach to this healthcare challenge. This emphasizes the importance of differential diagnostics. Most studies compare patients and controls, or Alzheimer's disease with one other type of dementia. Such a bilateral comparison does not resemble clinical practice, where a clinician is faced with a number of different possible types of dementia. Here we studied which features in structural magnetic resonance imaging (MRI) scans could best distinguish four types of dementia, Alzheimer's disease, frontotemporal dementia, vascular dementia, and dementia with Lewy bodies, and control subjects. We extracted an extensive set of features quantifying volumetric and morphometric characteristics from T1 images, and vascular characteristics from FLAIR images. Classification was performed using a multi-class classifier based on Disease State Index methodology. The classifier provided continuous probability indices for each disease to support clinical decision making. A dataset of 504 individuals was used for evaluation. The cross-validated classification accuracy was 70.6% and balanced accuracy was 69.1% for the five disease groups using only automatically determined MRI features. Vascular dementia patients could be detected with high sensitivity (96%) using features from FLAIR images. Controls (sensitivity 82%) and Alzheimer's disease patients (sensitivity 74%) could be accurately classified using T1-based features, whereas the most difficult group was the dementia with Lewy bodies (sensitivity 32%). These results were notable better than the classification accuracies obtained with visual MRI ratings (accuracy 44.6%, balanced accuracy 51.6%). Different quantification methods provided complementary information, and consequently, the best results were obtained by

  10. Differential diagnosis of neurodegenerative diseases using structural MRI data

    Koikkalainen, Juha; Rhodius-Meester, Hanneke; Tolonen, Antti; Barkhof, Frederik; Tijms, Betty; Lemstra, Afina W.; Tong, Tong; Guerrero, Ricardo; Schuh, Andreas; Ledig, Christian; Rueckert, Daniel; Soininen, Hilkka; Remes, Anne M.; Waldemar, Gunhild; Hasselbalch, Steen; Mecocci, Patrizia; van der Flier, Wiesje; Lötjönen, Jyrki

    2016-01-01

    Different neurodegenerative diseases can cause memory disorders and other cognitive impairments. The early detection and the stratification of patients according to the underlying disease are essential for an efficient approach to this healthcare challenge. This emphasizes the importance of differential diagnostics. Most studies compare patients and controls, or Alzheimer's disease with one other type of dementia. Such a bilateral comparison does not resemble clinical practice, where a clinician is faced with a number of different possible types of dementia. Here we studied which features in structural magnetic resonance imaging (MRI) scans could best distinguish four types of dementia, Alzheimer's disease, frontotemporal dementia, vascular dementia, and dementia with Lewy bodies, and control subjects. We extracted an extensive set of features quantifying volumetric and morphometric characteristics from T1 images, and vascular characteristics from FLAIR images. Classification was performed using a multi-class classifier based on Disease State Index methodology. The classifier provided continuous probability indices for each disease to support clinical decision making. A dataset of 504 individuals was used for evaluation. The cross-validated classification accuracy was 70.6% and balanced accuracy was 69.1% for the five disease groups using only automatically determined MRI features. Vascular dementia patients could be detected with high sensitivity (96%) using features from FLAIR images. Controls (sensitivity 82%) and Alzheimer's disease patients (sensitivity 74%) could be accurately classified using T1-based features, whereas the most difficult group was the dementia with Lewy bodies (sensitivity 32%). These results were notable better than the classification accuracies obtained with visual MRI ratings (accuracy 44.6%, balanced accuracy 51.6%). Different quantification methods provided complementary information, and consequently, the best results were obtained by

  11. The emerging role of 5-hydroxymethylcytosine in neurodegenerative diseases

    Sahar eAl-Mahdawi

    2014-12-01

    Full Text Available DNA methylation primarily occurs within human cells as a 5-methylcytosine (5mC modification of the cytosine bases in CpG dinucleotides. 5mC has proven to be an important epigenetic mark that is involved in the control of gene transcription for processes such as development and differentiation. However, recent studies have identified an alternative modification, 5-hydroxymethylcytosine (5hmC, which is formed by oxidation of 5mC by ten-eleven translocation (TET enzymes. The overall levels of 5hmC in the mammalian genome are approximately 10% of 5mC levels, although higher levels have been detected in tissues of the central nervous system (CNS. The functions of 5hmC are not yet fully known, but evidence suggests that 5hmC may be both an intermediate product during the removal of 5mC by passive or active demethylation processes and also an epigenetic modification in its own right, regulating chromatin or transcriptional factors involved in processes such as neurodevelopment or environmental stress response. This review highlights our current understanding of the role that 5hmC plays in neurodegenerative diseases, including Alzheimer’s disease (AD, amyotrophic lateral sclerosis (ALS, fragile X-associated tremor/ataxia syndrome (FXTAS, Friedreich ataxia (FRDA, Huntington’s disease (HD, and Parkinson’s disease (PD.

  12. Oxidative Stress and Its Significant Roles in Neurodegenerative Diseases and Cancer

    Raynoo Thanan; Shinji Oikawa; Yusuke Hiraku; Shiho Ohnishi; Ning Ma; Somchai Pinlaor; Puangrat Yongvanit; Shosuke Kawanishi; Mariko Murata

    2014-01-01

    Reactive oxygen and nitrogen species have been implicated in diverse pathophysiological conditions, including inflammation, neurodegenerative diseases and cancer. Accumulating evidence indicates that oxidative damage to biomolecules including lipids, proteins and DNA, contributes to these diseases. Previous studies suggest roles of lipid peroxidation and oxysterols in the development of neurodegenerative diseases and inflammation-related cancer. Our recent studies identifying and characterizi...

  13. Overnutrition Determines LPS Regulation of Mycotoxin Induced Neurotoxicity in Neurodegenerative Diseases

    Ian James Martins

    2015-12-01

    Full Text Available Chronic neurodegenerative diseases are now associated with obesity and diabetes and linked to the developing and developed world. Interests in healthy diets have escalated that may prevent neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. The global metabolic syndrome involves lipoprotein abnormalities and insulin resistance and is the major disorder for induction of neurological disease. The effects of bacterial lipopolysaccharides (LPS on dyslipidemia and NAFLD indicate that the clearance and metabolism of fungal mycotoxins are linked to hypercholesterolemia and amyloid beta oligomers. LPS and mycotoxins are associated with membrane lipid disturbances with effects on cholesterol interacting proteins, lipoprotein metabolism, and membrane apo E/amyloid beta interactions relevant to hypercholesterolemia with close connections to neurological diseases. The influence of diet on mycotoxin metabolism has accelerated with the close association between mycotoxin contamination from agricultural products such as apple juice, grains, alcohol, and coffee. Cholesterol efflux in lipoproteins and membrane cholesterol are determined by LPS with involvement of mycotoxin on amyloid beta metabolism. Nutritional interventions such as diets low in fat/carbohydrate/cholesterol have become of interest with relevance to low absorption of lipophilic LPS and mycotoxin into lipoproteins with rapid metabolism of mycotoxin to the liver with the prevention of neurodegeneration.

  14. Cell ageing: a flourishing field for neurodegenerative diseases

    Dora Brites

    2015-06-01

    Full Text Available Cellular senescence is viewed as an irreversible cell-cycle arrest mechanism involving a complexity of biological progressive processes and the acquisition of diverse cellular phenotypes. Several cell-intrinsic and extrinsic causes (stresses may lead to diverse cellular signaling cascades that include oxidative stress, mitochondrial dysfunction, DNA damage, excessive accumulation of misfolded proteins, impaired microRNA processing and inflammation. Here we review recent advances in the causes and consequences of brain cell ageing, including the senescence of endothelial cells at the central nervous system barriers, as well as of neurons and glial cells. We address what makes ageing an important risk factor for neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and cerebrovascular disease. In particular, we highlight the importance of defects in mitochondrial dynamics, in the cathepsin activity imbalance, in cell-cell communication, in the accumulation of misfolded and unfolded proteins and in the microRNA profiling as having potential impact on cellular ageing processes. Another important aspect is that the absence of specific senescence biomarkers has hampered the characterization of senescent cells in ageing and age-associated diseases. In accordance, the senescence-associated secretory phenotype (SASP or secretome was shown to vary in distinct cell types and upon different stressors, and SASP heterogeneity is believed to create subsets of senenescent cells. In addition to secreted proteins, we then place extracellular vesicles (exosomes and ectosomes as important mediators of intercellular communication with pathophysiological roles in disease spreading, and as emerging targets for therapeutic intervention. We also discuss the application of engineered extracellular vesicles as vehicles for drug delivery. Finally, we summarize current knowledge on methods to rejuvenate senescent cells

  15. Molecular Pathological Classification of Neurodegenerative Diseases: Turning towards Precision Medicine.

    Kovacs, Gabor G

    2016-01-01

    Neurodegenerative diseases (NDDs) are characterized by selective dysfunction and loss of neurons associated with pathologically altered proteins that deposit in the human brain but also in peripheral organs. These proteins and their biochemical modifications can be potentially targeted for therapy or used as biomarkers. Despite a plethora of modifications demonstrated for different neurodegeneration-related proteins, such as amyloid-β, prion protein, tau, α-synuclein, TAR DNA-binding protein 43 (TDP-43), or fused in sarcoma protein (FUS), molecular classification of NDDs relies on detailed morphological evaluation of protein deposits, their distribution in the brain, and their correlation to clinical symptoms together with specific genetic alterations. A further facet of the neuropathology-based classification is the fact that many protein deposits show a hierarchical involvement of brain regions. This has been shown for Alzheimer and Parkinson disease and some forms of tauopathies and TDP-43 proteinopathies. The present paper aims to summarize current molecular classification of NDDs, focusing on the most relevant biochemical and morphological aspects. Since the combination of proteinopathies is frequent, definition of novel clusters of patients with NDDs needs to be considered in the era of precision medicine. Optimally, neuropathological categorizing of NDDs should be translated into in vivo detectable biomarkers to support better prediction of prognosis and stratification of patients for therapy trials. PMID:26848654

  16. The involvement of microRNAs in neurodegenerative diseases

    Simona eMaciotta Rolandin

    2013-12-01

    Full Text Available Neurodegenerative diseases (NDDs originate from loss of neurons in the central nervous system and are severely debilitating. They are worldwide spread and their incidence increases with age so that they are supposed to become more common due to extended life expectancy. Since no cure is available they have become a major challenge to neurobiology. The increasing relevance of microRNAs (miRNAs in biology has prompt the scientific society to investigate on their possible involvement in neurodegeneration with the aim to find new therapeutic targets. Indeed the idea of using miRNAs as therapeutic targets is nowadays not far from realization but important issues need to be addressed before moving towards the clinics. With the present review we aim to resume what have been so far disclose on the involvement of miRNAs in NDDs pathogenesis. Furthermore, their expression levels in peripheral tissues of patients affected by NDDs will be here reported in order to evaluate their application as biomarker of disease. Finally the discrepancy, innovation and effectiveness of data collected will be elucidated and discussed.

  17. Molecular Pathological Classification of Neurodegenerative Diseases: Turning towards Precision Medicine

    Gabor G. Kovacs

    2016-02-01

    Full Text Available Neurodegenerative diseases (NDDs are characterized by selective dysfunction and loss of neurons associated with pathologically altered proteins that deposit in the human brain but also in peripheral organs. These proteins and their biochemical modifications can be potentially targeted for therapy or used as biomarkers. Despite a plethora of modifications demonstrated for different neurodegeneration-related proteins, such as amyloid-β, prion protein, tau, α-synuclein, TAR DNA-binding protein 43 (TDP-43, or fused in sarcoma protein (FUS, molecular classification of NDDs relies on detailed morphological evaluation of protein deposits, their distribution in the brain, and their correlation to clinical symptoms together with specific genetic alterations. A further facet of the neuropathology-based classification is the fact that many protein deposits show a hierarchical involvement of brain regions. This has been shown for Alzheimer and Parkinson disease and some forms of tauopathies and TDP-43 proteinopathies. The present paper aims to summarize current molecular classification of NDDs, focusing on the most relevant biochemical and morphological aspects. Since the combination of proteinopathies is frequent, definition of novel clusters of patients with NDDs needs to be considered in the era of precision medicine. Optimally, neuropathological categorizing of NDDs should be translated into in vivo detectable biomarkers to support better prediction of prognosis and stratification of patients for therapy trials.

  18. The pathogenic role of the inflammasome in neurodegenerative diseases.

    Freeman, Leslie C; Ting, Jenny P-Y

    2016-01-01

    The inflammasome is a large macromolecular complex that contains multiple copies of a receptor or sensor of pathogen-derived or damage-derived molecular patterns, pro-caspase-1, and an adaptor called ASC (apoptotic speck containing protein with a CARD), which results in caspase-1 maturation. Caspase-1 then mediates the release of pro-inflammatory cytokines such as IL-1β and IL-18. These cytokines play critical roles in mediating immune responses during inflammation and innate immunity. Broader studies of the inflammasome over the years have implicated their roles in the pathogenesis of a variety of inflammatory diseases. Recently, studies have shown that the inflammasome modulates neuroinflammatory cells and the initial stages of neuroinflammation. A secondary cascade of events associated with neuroinflammation (such as oxidative stress) has been shown to activate the inflammasome, making the inflammasome a promising therapeutic target in the modulation of neurodegenerative diseases. This review will focus on the pathogenic role that inflammasomes play in neurologic diseases such as Alzheimer's disease, traumatic brain injury, and multiple sclerosis. We here review the role of the inflammasome in the pathogenesis of traumatic brain injury (TBI). TBI is initiated by physical force exerted to head, resulting in neuronal injury and death. Primary insult is followed by a secondary cascade of events following neuroinflammation such as mitochondrial dysfunction, production of reactive oxygen species, potassium effluxes, and release of circulating DNA. These events can potentially trigger the activation of NLRP3, NLRP1, and AIM2 during TBI but have yet to be confirmed (dashed lines). NLRP3, NLRP1, and AIM2 associate with the adaptor protein ASC, which initiates the cleavage of pro-caspase-1 to the mature form of caspase-1 which cleaves pro-IL-1β and pro-IL-18 into their mature forms of IL-1β and IL-18. PMID:26119245

  19. Oxidative Stress in Neurodegenerative Diseases: Mechanisms and Therapeutic Perspectives

    Ailton Melo

    2011-01-01

    Full Text Available The incidence and prevalence of neurodegenerative diseases (ND increase with life expectancy. This paper reviews the role of oxidative stress (OS in ND and pharmacological attempts to fight against reactive oxygen species (ROS-induced neurodegeneration. Several mechanisms involved in ROS generation in neurodegeneration have been proposed. Recent articles about molecular pathways involved in ROS generation were reviewed. The progress in the development of neuroprotective therapies has been hampered because it is difficult to define targets for treatment and determine what should be considered as neuroprotective. Therefore, the attention was focused on researches about pharmacological targets that could protect neurons against OS. Since it is necessary to look for genes as the ultimate controllers of all biological processes, this paper also tried to identify gerontogenes involved in OS and neurodegeneration. Since neurons depend on glial cells to survive, recent articles about the functioning of these cells in aging and ND were also reviewed. Finally, clinical trials testing potential neuroprotective agents were critically reviewed. Although several potential drugs have been screened in in vitro and in vivo models of ND, these results were not translated in benefit of patients, and disappointing results were obtained in the majority of clinical trials.

  20. Association between environmental exposure to pesticides and neurodegenerative diseases

    Parron, Tesifon [University of Almeria, Department of Neurosciences and Health Sciences, Almeria (Spain); Andalusian Council of Health at Almeria province, Almeria (Spain); Requena, Mar [Andalusian Council of Health at Almeria province, Almeria (Spain); Hernandez, Antonio F., E-mail: ajerez@ugr.es [University of Granada School of Medicine, Granada (Spain); Alarcon, Raquel [Andalusian Council of Health at Almeria province, Almeria (Spain)

    2011-11-15

    Preliminary studies have shown associations between chronic pesticide exposure in occupational settings and neurological disorders. However, data on the effects of long-term non-occupational exposures are too sparse to allow any conclusions. This study examines the influence of environmental pesticide exposure on a number of neuropsychiatric conditions and discusses their underlying pathologic mechanisms. An ecological study was conducted using averaged prevalence rates of Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebral degeneration, polyneuropathies, affective psychosis and suicide attempts in selected Andalusian health districts categorized into areas of high and low environmental pesticide exposure based on the number of hectares devoted to intensive agriculture and pesticide sales per capita. A total of 17,429 cases were collected from computerized hospital records (minimum dataset) between 1998 and 2005. Prevalence rates and the risk of having Alzheimer's disease, Parkinson's disease, multiple sclerosis and suicide were significantly higher in districts with greater pesticide use as compared to those with lower pesticide use. The multivariate analyses showed that the population living in areas with high pesticide use had an increased risk for Alzheimer's disease and suicide attempts and that males living in these areas had increased risks for polyneuropathies, affective disorders and suicide attempts. In conclusion, this study supports and extends previous findings and provides an indication that environmental exposure to pesticides may affect the human health by increasing the incidence of certain neurological disorders at the level of the general population. -- Highlights: Black-Right-Pointing-Pointer Environmental exposure to pesticides and neurodegenerative-psychiatric disorders. Black-Right-Pointing-Pointer Increased risk for Alzheimer's disease and suicide attempts in high exposure areas. Black

  1. Flavonoid-Based Therapies in the Early Management of Neurodegenerative Diseases12

    Solanki, Isha; Parihar, Priyanka; Mansuri, Mohammad Lukman; Parihar, Mordhwaj S.

    2015-01-01

    During the past several years, there has been enormous progress in the understanding of the causative factors that initiate neuronal damage in various neurodegenerative diseases, including Alzheimer disease, Parkinson disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington disease. Preventing neuronal damage and neuronal death will have a huge clinical benefit. However, despite major advances in causative factors that trigger these neurodegenerative diseases, to date there ...

  2. Mass Spectrometry of Non-protein Amino Acids : BMAA and Neurodegenerative Diseases

    Jiang, Liying

    2015-01-01

    Neurodegenerative diseases have been shown to correlate positively with an ageing population. The most common neurodegenerative diseases are amyotrophic lateral sclerosis (ALS), Parkinson’s disease and Alzheimer’s disease. The cause of these diseases is believed to be the interaction between genetic and environmental factors, synergistically acting with ageing. BMAA (β-methylamino-L-alanine) is one kind of toxin present in our environment and might play an important role in the development of...

  3. Sleep disturbance in mental health problems and neurodegenerative disease

    Anderson KN

    2013-05-01

    Full Text Available Kirstie N Anderson1 Andrew J Bradley2,3 1Department of Neurology, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne, UK; 2Eli Lilly and Company Limited, Lilly House, Basingstoke, UK; 3Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, UK Abstract: Sleep has been described as being of the brain, by the brain, and for the brain. This fundamental neurobiological behavior is controlled by homeostatic and circadian (24-hour processes and is vital for normal brain function. This review will outline the normal sleep–wake cycle, the changes that occur during aging, and the specific patterns of sleep disturbance that occur in association with both mental health disorders and neurodegenerative disorders. The role of primary sleep disorders such as insomnia, obstructive sleep apnea, and REM sleep behavior disorder as potential causes or risk factors for particular mental health or neurodegenerative problems will also be discussed. Keywords: sleep, mental health, neurodegenerative disorders, cognition

  4. The ubiquitin proteasome system in glia and its role in neurodegenerative disease

    Anne H.P. Jansen

    2014-08-01

    Full Text Available The ubiquitin proteasome system (UPS is crucial for intracellular protein homeostasis and for degradation of aberrant and damaged proteins. The accumulation of ubiquitinated proteins is a hallmark of many neurodegenerative diseases, including Amyotrophic lateral sclerosis, Alzheimer’s, Parkinson’s and Huntington’s disease, leading to the hypothesis that proteasomal impairment is contributing to these diseases. So far, most research related to the UPS in neurodegenerative diseases has been focused on neurons, while glial cells have been largely disregarded in this respect. However, glial cells are essential for proper neuronal functioning and adopt a reactive phenotype in neurodegenerative diseases, thereby contributing to an inflammatory response. This process is called reactive gliosis, which in turn affects UPS functioning in glial cells. In many neurodegenerative diseases, mostly neurons show accumulation and aggregation of ubiquitinated proteins, suggesting that glial cells may be better equipped to maintain proper protein homeostasis. During an inflammatory reaction, the immunoproteasome is induced in glia, which may contribute to a more efficient degradation of disease-related proteins. Here we review the role of the UPS in glial cells in various neurodegenerative diseases, and we discuss how studying glial cell functioning might provide essential information in unraveling mechanisms of neurodegenerative diseases.

  5. Chronic sleep disturbance and neural injury: links to neurodegenerative disease

    Abbott SM; Videnovic A

    2016-01-01

    Sabra M Abbott,1 Aleksandar Videnovic21Department of Neurology, Northwestern Feinberg School of Medicine, Chicago, IL, USA; 2Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Abstract: Sleep–wake disruption is frequently observed and often one of the earliest reported symptoms of many neurodegenerative disorders. This provides insight into the underlying pathophysiology of these disorders, as sleep–wake abnormalities are often accomp...

  6. Chronic sleep disturbance and neural injury: links to neurodegenerative disease

    Videnovic, Aleksandar

    2016-01-01

    Sabra M Abbott,1 Aleksandar Videnovic21Department of Neurology, Northwestern Feinberg School of Medicine, Chicago, IL, USA; 2Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Abstract: Sleep–wake disruption is frequently observed and often one of the earliest reported symptoms of many neurodegenerative disorders. This provides insight into the underlying pathophysiology of these disorders, as sleep–wake abnormalities are ofte...

  7. The role of mitochondria in neurodegenerative diseases: mitochondria as a therapeutic target in Alzheimer’s disease

    Reddy, P. Hemachandra

    2009-01-01

    Mitochondria are cytoplasmic organelles responsible for life and death. Extensive evidence from animal and clinical studies suggests that mitochondria play a critical role in aging, cancer, diabetes and neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. Several lines of research suggest that mitochondrial oxidative damage is an important cellular change in most late-onset neurodegenerative diseases. Further, emerging evidence suggests that ...

  8. Cytoplasmic Inclusions of TDP-43 in Neurodegenerative Diseases: A Potential Role for Caspases

    Rohn, Troy T

    2009-01-01

    TAR DNA-binding protein-43 (TDP-43) proteinopathies are classified based upon the extent of modified TDP-43 inclusions and include a growing number of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with ubiquitin immunoreactive, tau negative inclusions (FTLD-U) and FTLD with motor neuron disease (FTLD-MND). In addition, TDP-43 inclusions have also been identified in a number of other neurodegenerative diso...

  9. A Comparative Survey of the Topographical Distribution of Signature Molecular Lesions in Major Neurodegenerative Diseases

    Arnold, Steven E.; Toledo, Jon B.; Appleby, Dina H; Xie, Sharon X.; Wang, Li-San; Baek, Young; David A Wolk; Lee, Edward B.; Miller, Bruce L.; Lee, Virginia M.-Y.; Trojanowski, John Q.

    2013-01-01

    An understanding of the anatomic distributions of major neurodegenerative disease lesions is important to appreciate the differential clinical profiles of these disorders and to serve as neuropathological standards for emerging molecular neuroimaging methods. To address these issues, here we present a comparative survey of the topographical distribution of the defining molecular neuropathological lesions among ten neurodegenerative diseases from a large and uniformly assessed brain collection...

  10. Genistein Improves Neuropathology and Corrects Behaviour in a Mouse Model of Neurodegenerative Metabolic Disease

    Marcelina Malinowska; Wilkinson, Fiona L.; Langford-Smith, Kia J; Alex Langford-Smith; Brown, Jillian R.; Crawford, Brett E.; Marie T Vanier; Grzegorz Grynkiewicz; Rob F Wynn; J Ed Wraith; Grzegorz Wegrzyn; Bigger, Brian W.

    2010-01-01

    BACKGROUND: Neurodegenerative metabolic disorders such as mucopolysaccharidosis IIIB (MPSIIIB or Sanfilippo disease) accumulate undegraded substrates in the brain and are often unresponsive to enzyme replacement treatments due to the impermeability of the blood brain barrier to enzyme. MPSIIIB is characterised by behavioural difficulties, cognitive and later motor decline, with death in the second decade of life. Most of these neurodegenerative lysosomal storage diseases lack effective treatm...

  11. Is Neurodegenerative Disease a Long-Latency Response to Early-Life Genotoxin Exposure?

    Glen E. Kisby

    2011-09-01

    Full Text Available Western Pacific amyotrophic lateral sclerosis and parkinsonism-dementia complex, a disappearing neurodegenerative disease linked to use of the neurotoxic cycad plant for food and/or medicine, is intensively studied because the neuropathology (tauopathy is similar to that of Alzheimer’s disease. Cycads contain neurotoxic and genotoxic principles, notably cycasin and methylazoxymethanol, the latter sharing chemical relations with nitrosamines, which are derived from nitrates and nitrites in preserved meats and fertilizers, and also used in the rubber and leather industries. This review includes new data that influence understanding of the neurobiological actions of cycad and related genotoxins and the putative mechanisms by which they might trigger neurodegenerative disease.

  12. Dysregulation of cholesterol balance in the brain: contribution to neurodegenerative diseases

    Vance, Jean E.

    2012-01-01

    Dysregulation of cholesterol homeostasis in the brain is increasingly being linked to chronic neurodegenerative disorders, including Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), Niemann-Pick type C (NPC) disease and Smith-Lemli Opitz syndrome (SLOS). However, the molecular mechanisms underlying the correlation between altered cholesterol metabolism and the neurological deficits are, for the most part, not clear. NPC disease and SLOS are caused by mutations in...

  13. Filamentous nerve cell inclusions in neurodegenerative diseases: tauopathies and alpha-synucleinopathies.

    Goedert, M

    1999-01-01

    Alzheimer's disease and Parkinson's disease are the most common neurodegenerative diseases. They are characterized by the degeneration of selected populations of nerve cells that develop filamentous inclusions before degeneration. The neuronal inclusions of Alzheimer's disease are made of the microtubule-associated protein tau, in a hyperphosphorylated state. Recent work has shown that the filamentous inclusions of Parkinson's disease are made of the protein alpha-synuclein and that rare, fam...

  14. Progress of GAITRite testing in different large animal models of neurodegenerative diseases

    Hölzner, E.; Marcegaglia, M.; Skillings, L.; Baxa, Monika; Morton, J.; Reilmann, R.

    Mělník: IAPG, 2013. [Large Animal Models of Neurodegenerative Diseases /2./. 17.11.2013-19.11.2013, Liblice] Institutional support: RVO:67985904 Keywords : GAITRite * phenotyping * Huntington´s disease * minipig Subject RIV: EB - Genetics ; Molecular Biology

  15. Combination Comprising Parthenolide For Use In The Treatment Of Alzheimer's Disease And Other Neurodegenerative Disorders

    Bajic, Vladimir B.

    2015-06-18

    The present invention generally concerns particular methods and compositions for treatment of a neurodegenerative disease, such as Alzheimer\\'s Disease. In particular embodiments, there is a composition comprising Parthenolide and a second agent, including an inhibitor of TLR4/MD-2/CD14, nAChR agonist, Resatorvid, Curcumin, Tilorone or a Tilorone analog, or a combination thereof.

  16. Antibody-based investigational approaches in neuro-proteomics and neurodegenerative diseases

    Gadher, S. J.; Kovářová, Hana

    2015-01-01

    Roč. 78, Suppl 2 (2015), s. 10-10. ISSN 1210-7859. [Conference on Animal Models for neurodegenerative Diseases /3./. 08.11.2015-10.11.2015, Liblice] R&D Projects: GA MŠk ED2.1.00/03.0124 Institutional support: RVO:67985904 Keywords : neurodegeneration * disease models * multiplexing Subject RIV: EB - Genetics ; Molecular Biology

  17. The Role of TNF Related Apoptosis-Inducing Ligand in Neurodegenerative Diseases

    Y.Huang; N.Erdmann; H.Peng; Y.Zhao

    2005-01-01

    A hallmark of all forms of neurodegenerative diseases is impairment of neuronal functions, and in many cases neuronal cell death. Although the etiology of neurodegenerative diseases may be distinct, different diseases display a similar pathogenesis, for example abnormal immunity within the central nervous system (CNS), activation of macrophage/microglia and the involvement of proinflammatory cytokines. Recent studies show that neurons in a neurodegenerative state undergo a highly regulated programmed cell death, also called apoptosis. TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF family, has been shown to be involved in apoptosis during many diseases. As one member of a death ligand family, TRAIL was originally thought to target only tumor cells and was not present in CNS. However, recent data showed that TRAIL was unregulated in HIV-l-infected and immune-activated macrophages, a major disease inducing cell during HIV-l-associated dementia (HAD). TRAIL is also induced on neuron by [$-amyloid protein, an important pathogen for Alzheimer's disease. In this review, we summarize the possible common aspects that TRAIL involved those neurodegenerative diseases, TRAIL induced apoptosis signaling in the CNS cells, and specific role of TRAIL in individual diseases. Cellular & MolecularImmunology. 2005;2(2):113-122.

  18. Isoprostanes and Neuroprostanes as Biomarkers of Oxidative Stress in Neurodegenerative Diseases

    Elżbieta Miller

    2014-01-01

    Full Text Available Accumulating data shows that oxidative stress plays a crucial role in neurodegenerative disorders. The literature data indicate that in vivo or postmortem cerebrospinal fluid and brain tissue levels of F2-isoprostanes (F2-IsoPs especially F4-neuroprotanes (F4-NPs are significantly increased in some neurodegenerative diseases: multiple sclerosis, Alzheimer's disease, Huntington's disease, and Creutzfeldt-Jakob disease. Central nervous system is the most metabolically active organ of the body characterized by high requirement for oxygen and relatively low antioxidative activity, what makes neurons and glia highly susceptible to destruction by reactive oxygen/nitrogen species and neurodegeneration. The discovery of F2-IsoPs and F4-NPs as markers of lipid peroxidation caused by the free radicals has opened up new areas of investigation regarding the role of oxidative stress in the pathogenesis of human neurodegenerative diseases. This review focuses on the relationship between F2-IsoPs and F4-NPs as biomarkers of oxidative stress and neurodegenerative diseases. We summarize the knowledge of these novel biomarkers of oxidative stress and the advantages of monitoring their formation to better define the involvement of oxidative stress in neurological diseases.

  19. Lack of miRNA misregulation at early pathological stages in Drosophila neurodegenerative disease models

    Anita eReinhardt

    2012-10-01

    Full Text Available Late onset neurodegenerative diseases represent a major public health concern as the population in many countries ages. Both frequent diseases such as Alzheimer disease (AD, 14% incidence for 80-84 year old Europeans or Parkinson disease (PD, 1.4% prevalence for > 55 years old share, with other low-incidence neurodegenerative pathologies such as spinocerebellar ataxias (SCAs, 0.01% prevalence and frontotemporal lobar degeneration (FTLD, 0.02% prevalence, a lack of efficient treatment in spite of important research efforts. Besides significant progress, studies with animal models have revealed unexpected complexities in the degenerative process, emphasizing a need to better understand the underlying pathological mechanisms. Recently, microRNAs, a class of small regulatory non-coding RNAs, have been implicated in some neurodegenerative diseases. The current data supporting a role of miRNAs in PD, tauopathies, dominant ataxias and FTLD will first be discussed to emphasize the different levels of the pathological processes which may be affected by miRNAs. To investigate a potential involvement of miRNA dysregulation in the early stages of these neurodegenerative diseases we have used Drosophila models for 7 diseases (PD, 3 FTLD, 3 dominant ataxias that recapitulate many features of the human diseases. We performed deep sequencing of head small RNAs after 3 days of pathological protein expression in the fly head neurons. We found no evidence for a statistically significant difference in miRNA expression in this early stage of the pathological process. In addition, we could not identify small non coding CAG repeat RNAs (sCAG in polyQ disease models. Thus our data suggest that transcriptional deregulation of miRNAs or sCAG is unlikely to play a significant role in the initial stages of neurodegenerative diseases.

  20. A knowledge based approach to matching human neurodegenerative disease and animal models

    Martone, Maryann E.; Mungall, Christopher J.

    2013-01-01

    Neurodegenerative diseases present a wide and complex range of biological and clinical features. Animal models are key to translational research, yet typically only exhibit a subset of disease features rather than being precise replicas of the disease. Consequently, connecting animal to human conditions using direct data-mining strategies has proven challenging, particularly for diseases of the nervous system, with its complicated anatomy and physiology. To address this challenge we have expl...

  1. Residential Distance to High-voltage Power Lines and Risk of Neurodegenerative Diseases

    Frei, Patrizia; Poulsen, Aslak Harbo; Mezei, Gabor;

    2013-01-01

    The aim of this study was to investigate the possible association between residential distance to high-voltage power lines and neurodegenerative diseases, especially Alzheimer's disease. A Swiss study previously found increased risk of Alzheimer's disease for people living within 50 m of a power...... line. A register-based case-control study including all patients diagnosed with neurodegenerative diseases during the years 1994-2010 was conducted among the entire adult population of Denmark. Using conditional logistic regression models, hazard ratios for ever living close to a power line in the time...... period 5-20 years before diagnosis were computed. The risks for developing dementia, Parkinson's disease, multiple sclerosis, and motor neuron disease were not increased in persons living within close vicinity of a power line. The risk of Alzheimer's disease was not increased for ever living within 50 m...

  2. Drug discovery of neurodegenerative disease through network pharmacology approach in herbs.

    Ke, Zhipeng; Zhang, Xinzhuang; Cao, Zeyu; Ding, Yue; Li, Na; Cao, Liang; Wang, Tuanjie; Zhang, Chenfeng; Ding, Gang; Wang, Zhenzhong; Xu, Xiaojie; Xiao, Wei

    2016-03-01

    Neurodegenerative diseases, referring to as the progressive loss of structure and function of neurons, constitute one of the major challenges of modern medicine. Traditional Chinese herbs have been used as a major preventive and therapeutic strategy against disease for thousands years. The numerous species of medicinal herbs and Traditional Chinese Medicine (TCM) compound formulas in nervous system disease therapy make it a large chemical resource library for drug discovery. In this work, we collected 7362 kinds of herbs and 58,147 Traditional Chinese medicinal compounds (Tcmcs). The predicted active compounds in herbs have good oral bioavailability and central nervous system (CNS) permeability. The molecular docking and network analysis were employed to analyze the effects of herbs on neurodegenerative diseases. In order to evaluate the predicted efficacy of herbs, automated text mining was utilized to exhaustively search in PubMed by some related keywords. After that, receiver operator characteristic (ROC) curves was used to estimate the accuracy of predictions. Our study suggested that most herbs were distributed in family of Asteraceae, Fabaceae, Lamiaceae and Apocynaceae. The predictive model yielded good sensitivity and specificity with the AUC values above 0.800. At last, 504 kinds of herbs were obtained by using the optimal cutoff values in ROC curves. These 504 herbs would be the most potential herb resources for neurodegenerative diseases treatment. This study would give us an opportunity to use these herbs as a chemical resource library for drug discovery of anti-neurodegenerative disease. PMID:26898452

  3. Pathophysiological Role of Neuroinflammation in Neurodegenerative Diseases and Psychiatric Disorders

    2016-01-01

    Brain diseases and disorders such as Alzheimer disease, Parkinson disease, depression, schizophrenia, autism, and addiction lead to reduced quality of daily life through abnormal thoughts, perceptions, emotional states, and behavior. While the underlying mechanisms remain poorly understood, human and animal studies have supported a role of neuroinflammation in the etiology of these diseases. In the central nervous system, an increased inflammatory response is capable of activating microglial cells, leading to the release of pro-inflammatory cytokines including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α. In turn, the pro-inflammatory cytokines aggravate and propagate neuroinflammation, degenerating healthy neurons and impairing brain functions. Therefore, activated microglia may play a key role in neuroinflammatory processes contributing to the pathogenesis of psychiatric disorders and neurodegeneration. PMID:27230456

  4. Protein Modification by Dicarbonyl Molecular Species in Neurodegenerative Diseases

    Williams, Wesley M.; Aaron Weinberg; Smith, Mark A.

    2011-01-01

    Neurodegeneration results from abnormalities in cerebral metabolism and energy balance within neurons, astrocytes, microglia, or microvascular endothelial cells of the blood-brain barrier. In Alzheimer's disease, -amyloid is considered the primary contributor to neuropathology and neurodegeneration. It now is believed that certain systemic diseases, such as diabetes mellitus, can contribute to neurodegeneration through the effects of chronic hyperglycemia/insulin resistance resulting in pro...

  5. Strategies for molecular imaging dementia and neurodegenerative diseases

    Schaller, Bernhard

    2008-01-01

    Bernhard J SchallerDepartment of Neurosurgery, University of Paris, Paris, FranceAbstract: Dementia represents a heterogeneous term that has evolved to describe the behavioral syndromes associated with a variety of clinical and neuropathological changes during continuing degenerative disease of the brain. As such, there lacks a clear consensus regarding the neuropsychological and other constituent characteristics associated with various cerebrovascular changes in this disease process. But inc...

  6. Understanding complexity in neurodegenerative diseases: in silico reconstruction of emergence.

    Kolodkin, Alexey; Simeonidis, Evangelos; Balling, Rudi; Westerhoff, Hans V.

    2012-01-01

    Healthy functioning is an emergent property of the network of interacting biomolecules that comprise an organism. It follows that disease (a network shift that causes malfunction) is also an emergent property, emerging from a perturbation of the network. On the one hand, the biomolecular network of every individual is unique and this is evident when similar disease-producing agents cause different individual pathologies. Consequently, a personalized model and approach for every patient may be...

  7. Understanding complexity in neurodegenerative diseases: in silico reconstruction of emergence

    AlexeyKolodkin; HansWesterhoff

    2012-01-01

    Healthy functioning is an emergent property of the network of interacting biomolecules that comprise an organism. It follows that disease (a network shift that causes malfunction) is also an emergent property, emerging from a perturbation of the network. On the one hand, the biomolecular network of every individual is unique and this is evident when similar disease-producing agents cause different individual pathologies. Consequently, a personalized model and approach for every patient may be...

  8. Non-coding RNA and pseudogenes in neurodegenerative diseases: "The (unUsual Suspects"

    Valerio eCosta

    2012-10-01

    Full Text Available Neurodegenerative disorders and cancer are severe diseases threatening human health. The glaring differences between neurons and cancer cells mask the processes involved in their pathogenesis. Defects in cell cycle, DNA repair and cell differentiation can determine unlimited proliferation in cancer, or conversely, compromise neuronal plasticity, leading to cell death and neurodegeneration.Alteration in regulatory networks affecting gene expression contribute to human diseases' onset, including neurodegenerative disorders, and deregulation of non-coding RNAs - particularly microRNAs - is supposed to have a significant impact.Recently, competitive endogenous RNAs - acting as sponges - have been identified in cancer, indicating a new and intricate regulatory network. Given that neurodegenerative disorders and cancer share altered genes and pathways, and considering the emerging role of microRNAs in neurogenesis, we hypothesize competitive endogenous RNAs may be implicated in neurodegenerative diseases. Here we propose, and computationally predict, such regulatory mechanism may be shared between the diseases. It is predictable that similar regulation occurs in other complex diseases, and further investigation is needed.

  9. Association between environmental exposure to pesticides and neurodegenerative diseases

    Preliminary studies have shown associations between chronic pesticide exposure in occupational settings and neurological disorders. However, data on the effects of long-term non-occupational exposures are too sparse to allow any conclusions. This study examines the influence of environmental pesticide exposure on a number of neuropsychiatric conditions and discusses their underlying pathologic mechanisms. An ecological study was conducted using averaged prevalence rates of Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebral degeneration, polyneuropathies, affective psychosis and suicide attempts in selected Andalusian health districts categorized into areas of high and low environmental pesticide exposure based on the number of hectares devoted to intensive agriculture and pesticide sales per capita. A total of 17,429 cases were collected from computerized hospital records (minimum dataset) between 1998 and 2005. Prevalence rates and the risk of having Alzheimer's disease, Parkinson's disease, multiple sclerosis and suicide were significantly higher in districts with greater pesticide use as compared to those with lower pesticide use. The multivariate analyses showed that the population living in areas with high pesticide use had an increased risk for Alzheimer's disease and suicide attempts and that males living in these areas had increased risks for polyneuropathies, affective disorders and suicide attempts. In conclusion, this study supports and extends previous findings and provides an indication that environmental exposure to pesticides may affect the human health by increasing the incidence of certain neurological disorders at the level of the general population. -- Highlights: ► Environmental exposure to pesticides and neurodegenerative–psychiatric disorders. ► Increased risk for Alzheimer's disease and suicide attempts in high exposure areas. ► Males from areas with high pesticide exposure had a higher risk of polyneuropathy.

  10. Role of Epigenetics in Stem Cell Proliferation and Differentiation: Implications for Treating Neurodegenerative Diseases

    Bhairavi Srinageshwar; Panchanan Maiti; Gary L. Dunbar; Julien Rossignol

    2016-01-01

    The main objectives of this review are to survey the current literature on the role of epigenetics in determining the fate of stem cells and to assess how this information can be used to enhance the treatment strategies for some neurodegenerative disorders, like Huntington’s disease, Parkinson’s disease and Alzheimer’s disease. Some of these epigenetic mechanisms include DNA methylation and histone modifications, which have a direct impact on the way that genes are expressed in stem cells and...

  11. Small-Molecule Theranostic Probes: A Promising Future in Neurodegenerative Diseases

    Suzana Aulić; Maria Laura Bolognesi; Giuseppe Legname

    2013-01-01

    Prion diseases are fatal neurodegenerative illnesses, which include Creutzfeldt-Jakob disease in humans and scrapie, chronic wasting disease, and bovine spongiform encephalopathy in animals. They are caused by unconventional infectious agents consisting primarily of misfolded, aggregated, β -sheet-rich isoforms, denoted prions, of the physiological cellular prion protein (PrPC). Many lines of evidence suggest that prions (PrPSc) act both as a template for this conversion and as a neurotoxic a...

  12. INTERRUPTION OF AMINO ACIDS MOLECULAR ASYMMETRY (D/L- ENANTIOMERS DURING NORMAL AGING AND NEURODEGENERATIVE DISEASES

    A.V. Chervyakov

    2010-05-01

    Full Text Available Some facts about D-amino acids, their diffusion in human’s and animal’s organisms, metabolism, identification methods, involving in ageing and pathogenesis of some neurodegenerative diseases are show in this review. Also there is discussing the role of amino acid molecular asymmetry (D and L enantiomers ratio as a fundamental asymmetry of living matter.

  13. Content analysis of neurodegenerative and mental diseases social groups.

    Martínez-Pérez, Borja; de la Torre-Díez, Isabel; Bargiela-Flórez, Beatriz; López-Coronado, Miguel; Rodrigues, Joel J P C

    2015-12-01

    This article aims to characterize the different types of Facebook and Twitter groups for different mental diseases, their purposes, and their functions. We focused the search on depressive disorders, dementia, and Alzheimer's and Parkinson's diseases and examined the Facebook (www.facebook.com) and Twitter (www.twitter.com) groups. We used four assessment criteria: (1) purpose, (2) type of creator, (3) telehealth content, and (4) free-text responses in surveys and interviews. We observed a total of 357 Parkinson groups, 325 dementia groups, 853 Alzheimer groups, and 1127 depression groups on Facebook and Twitter. Moreover, we analyze the responses provided by different users. The survey and interview responses showed that many people were interested in using social networks to support and help in the fight against these diseases. The results indicate that social networks are acceptable by users in terms of simplicity and utility. People use them for finding support, information, self-help, advocacy and awareness, and for collecting funds. PMID:24698768

  14. A Chaperome Subnetwork Safeguards Proteostasis in Aging and Neurodegenerative Disease

    Marc Brehme

    2014-11-01

    Full Text Available Chaperones are central to the proteostasis network (PN and safeguard the proteome from misfolding, aggregation, and proteotoxicity. We categorized the human chaperome of 332 genes into network communities using function, localization, interactome, and expression data sets. During human brain aging, expression of 32% of the chaperome, corresponding to ATP-dependent chaperone machines, is repressed, whereas 19.5%, corresponding to ATP-independent chaperones and co-chaperones, are induced. These repression and induction clusters are enhanced in the brains of those with Alzheimer’s, Huntington’s, or Parkinson’s disease. Functional properties of the chaperome were assessed by perturbation in C. elegans and human cell models expressing Aβ, polyglutamine, and Huntingtin. Of 219 C. elegans orthologs, knockdown of 16 enhanced both Aβ and polyQ-associated toxicity. These correspond to 28 human orthologs, of which 52% and 41% are repressed, respectively, in brain aging and disease and 37.5% affected Huntingtin aggregation in human cells. These results identify a critical chaperome subnetwork that functions in aging and disease.

  15. AUTOMATIC CLASSIFICATION OF STRUCTURAL MRI FOR DIAGNOSIS OF NEURODEGENERATIVE DISEASES

    Hernández-Tamames Juan Antonio

    2010-12-01

    Full Text Available This paper presents an automatic approach which classifies structural Magnetic Resonance images into pathological or healthy controls. A classification model was trained to find the boundaries that allow to separate the study groups. The method uses the deformation values from a set of regions, automatically identified as relevant, in a process that selects the statistically significant regions of a t-test under the restriction that this significance must be spatially coherent within a neighborhood of 5 voxels. The proposed method was assessed to distinguish healthy controls from schizophrenia patients. Classification results showed accuracy between 74% and 89%, depending on the stage of the disease and number of training samples.

  16. Subspace Regularized Sparse Multitask Learning for Multiclass Neurodegenerative Disease Identification.

    Zhu, Xiaofeng; Suk, Heung-Il; Lee, Seong-Whan; Shen, Dinggang

    2016-03-01

    The high feature-dimension and low sample-size problem is one of the major challenges in the study of computer-aided Alzheimer's disease (AD) diagnosis. To circumvent this problem, feature selection and subspace learning have been playing core roles in the literature. Generally, feature selection methods are preferable in clinical applications due to their ease for interpretation, but subspace learning methods can usually achieve more promising results. In this paper, we combine two different methodological approaches to discriminative feature selection in a unified framework. Specifically, we utilize two subspace learning methods, namely, linear discriminant analysis and locality preserving projection, which have proven their effectiveness in a variety of fields, to select class-discriminative and noise-resistant features. Unlike previous methods in neuroimaging studies that mostly focused on a binary classification, the proposed feature selection method is further applicable for multiclass classification in AD diagnosis. Extensive experiments on the Alzheimer's disease neuroimaging initiative dataset showed the effectiveness of the proposed method over other state-of-the-art methods. PMID:26276982

  17. Imaging in cell-based therapy for neurodegenerative diseases

    Fetal cell transplantation for the treatment of Parkinson's and Huntington's diseases has been developed over the past two decades and is now in early clinical testing phase. Direct assessment of the graft's survival, integration into the host brain and impact on neuronal functions requires advanced in vivo neuroimaging techniques. Owing to its high sensitivity, positron emission tomography is today the most widely used tool to evaluate the viability and function of the transplanted tissue in the brain. Nuclear magnetic resonance techniques are opening new possibilities for imaging neurochemical events in the brain. The ultimate goal will be to use the combination of multiple imaging modalities for complete functional monitoring of the repair processes in the central nervous system. (orig.)

  18. Potential of cystamine and cysteamine in the treatment of neurodegenerative diseases.

    Gibrat, C; Cicchetti, F

    2011-03-30

    Neurodegenerative disorders are a subset of disabling pathologies characterized, in part, by a progressive and specific loss of certain brain cell populations. Current therapeutic approaches for the treatment of these disorders are mainly designed towards symptom management and do not manifestly block their typified neuronal loss. However, research conducted over the past decade has reflected the increasing interest and need to find disease-modifying molecules. Among the several neuroprotective agents emerging from experimental animal work, cystamine, as well as its reduced form cysteamine, have been identified as potential candidate drugs. Given the significant benefits observed in a Huntington's disease (HD) model, cysteamine has recently leaped to clinical trial. Here, we review the beneficial properties of these compounds as reported in animal studies, their mechanistic underpinnings, and their potential implications for the future treatment of patients suffering from neurodegenerative diseases, and more specifically for HD and Parkinson's disease (PD). PMID:21111020

  19. The basics of preclinical drug development for neurodegenerative disease indications.

    Steinmetz, Karen L; Spack, Edward G

    2009-01-01

    Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA) Good Laboratory Practices and international guidelines, including the International Conference on Harmonization. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s). Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot Program provide funding and

  20. The basics of preclinical drug development for neurodegenerative disease indications

    Spack Edward G

    2009-06-01

    Full Text Available Abstract Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA Good Laboratory Practices and international guidelines, including the International Conference on Harmonisation. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s. Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot

  1. The BMP signaling pathway at the Drosophila neuromuscular junction and its links to neurodegenerative diseases

    Bayat, Vafa; Jaiswal, Manish; Bellen, Hugo J

    2010-01-01

    The Drosophila neuromuscular junction (NMJ) has recently provided new insights into the roles of various proteins in neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), Multiple Sclerosis (MS) Hereditary Spastic Paraplegia (HSP), and Huntington’s Disease (HD). Several developmental signaling pathways including WNT, MAPK and BMP/TGF-β signaling play important roles in the formation and growth of the Drosophila NMJ. Studies of the fly homolog...

  2. Role of paraoxonase 1 (PON1) in organophosphate metabolism: Implications in neurodegenerative diseases

    Organophosphate pesticides are a class of compounds that are widely used in agricultural and rural areas. Paraoxonase 1 (PON1) is a phase-I enzyme that is involved in the hydrolysis of organophosphate esters. Environmental poisoning by organophosphate compounds has been the main driving force of previous research on PON1 enzymes. Recent discoveries in animal models have revealed the important role of the enzyme in lipid metabolism. However although PON1 function is well established in experimental models, the contribution of PON1 in neurodegenerative diseases remains unclear. In this minireview we summarize the involvement of PON1 genotypes in the occurrence of Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. A brief overview of latest epidemiological studies, regarding the two most important PON1 coding region polymorphisms PON1-L55M and PON1-Q192R is presented. Positive and negative associations of PON1 with disease occurrence are reported. Notably the MM and RR alleles contribute a risk enhancing effect for the development of some neurodegenerative diseases, which may be explained by the reduced lipoprotein free radical scavenging activity that may give rise to neuronal damage, through distinct mechanism. Conflicting findings that fail to support this postulate may represent the human population ethnic heterogeneity, different sample size and environmental parameters affecting PON1 status. We conclude that further epidemiological studies are required in order to address the exact contribution of PON1 genome in combination with organophosphate exposure in populations with neurodegenerative diseases.

  3. Spinocerebellar ataxia type 2 olfactory impairment shows a pattern similar to other major neurodegenerative diseases.

    Velázquez-Pérez, Luis; Fernandez-Ruiz, Juan; Díaz, Rosalinda; González, Ruth Pérez; Ochoa, Nalia Canales; Cruz, Gilberto Sánchez; Mederos, Luis Enrique Almaguer; Góngora, Edilberto Martínez; Hudson, Robyn; Drucker-Colin, René

    2006-09-01

    Olfactory function is affected in different neurodegenerative diseases. Recently, it has been found that some hereditary ataxias are also associated with significant olfactory impairment. However, the initial findings did not examine the nature of the olfactory impairment associated with these ataxias. In the present article the effect of spinocerebellar ataxia type 2 (SCA2) on olfactory function was studied in 53 SCA2 patients and 53 healthy control subjects from Holguín, Cuba. Several tests were applied to evaluate olfactory threshold, description, identification and discrimination. The results show significant impairment in SCA2 patients on all olfactory measurements, and the pattern of olfactory deficits found suggests that they have much in common with those reported for other neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. PMID:16609806

  4. Decrease in Hurst exponent of human gait with aging and neurodegenerative diseases

    Zhuang Jian-Jun; Ning Xin-Bao; Yang Xiao-Dong; Hou Feng-Zhen; Huo Cheng-Yu

    2008-01-01

    In this paper the decrease in the Hurst exponent of human gait with aging and neurodegenerative diseases was observed by using an improved rescaled range (R/S) analysis method. It indicates that the long-range correlations of gait rhythm from young healthy people are stronger than those from the healthy elderly and the diseased.The result further implies that fractal dynamics in human gait will be altered due to weakening or impairment of neural control on locomotion resulting from aging and neurodegenerative diseases. Due to analysing short-term data sequences rather than long datasets required by most nonlinear methods, the algorithm has the characteristics of simplicity and sensitivity, most importantly, fast calculation as well as powerful anti-noise capacities. These findings have implications for modelling locomotor control and also for quantifying gait dynamics in varying physiologic and pathologic states.

  5. Histochemical approaches to assess cell-to-cell transmission of misfolded proteins in neurodegenerative diseases

    Natale, G.; Pompili, E.; Biagioni, F.; Paparelli, S.; Lenzi, P.; Fornai, F.

    2013-01-01

    Formation, aggregation and transmission of abnormal proteins are common features in neurodegenerative disorders including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease. The mechanisms underlying protein alterations in neurodegenerative diseases remain controversial. Novel findings highlighted altered protein clearing systems as common biochemical pathways which generate protein misfolding, which in turn causes protein aggregation and protein spreading. In fact, proteinaceous aggregates are prone to cell-tocell propagation. This is reminiscent of what happens in prion disorders, where the prion protein misfolds thus forming aggregates which spread to neighbouring cells. For this reason, the term prionoids is currently used to emphasize how several misfolded proteins are transmitted in neurodegenerative diseases following this prion-like pattern. Histochemical techniques including the use of specific antibodies covering both light and electron microscopy offer a powerful tool to describe these phenomena and investigate specific molecular steps. These include: prion like protein alterations; glycation of prion-like altered proteins to form advanced glycation end-products (AGEs); mechanisms of extracellular secretion; interaction of AGEs with specific receptors placed on neighbouring cells (RAGEs). The present manuscript comments on these phenomena aimed to provide a consistent scenario of the available histochemical approaches to dissect each specific step. PMID:23549464

  6. Mitochondrial Dysfunction in Cancer and Neurodegenerative Diseases: Spotlight on Fatty Acid Oxidation and Lipoperoxidation Products

    Barrera, Giuseppina; Gentile, Fabrizio; Pizzimenti, Stefania; Canuto, Rosa Angela; Daga, Martina; Arcaro, Alessia; Cetrangolo, Giovanni Paolo; Lepore, Alessio; Ferretti, Carlo; Dianzani, Chiara; Muzio, Giuliana

    2016-01-01

    In several human diseases, such as cancer and neurodegenerative diseases, the levels of reactive oxygen species (ROS), produced mainly by mitochondrial oxidative phosphorylation, is increased. In cancer cells, the increase of ROS production has been associated with mtDNA mutations that, in turn, seem to be functional in the alterations of the bioenergetics and the biosynthetic state of cancer cells. Moreover, ROS overproduction can enhance the peroxidation of fatty acids in mitochondrial membranes. In particular, the peroxidation of mitochondrial phospholipid cardiolipin leads to the formation of reactive aldehydes, such as 4-hydroxynonenal (HNE) and malondialdehyde (MDA), which are able to react with proteins and DNA. Covalent modifications of mitochondrial proteins by the products of lipid peroxidation (LPO) in the course of oxidative cell stress are involved in the mitochondrial dysfunctions observed in cancer and neurodegenerative diseases. Such modifications appear to affect negatively mitochondrial integrity and function, in particular energy metabolism, adenosine triphosphate (ATP) production, antioxidant defenses and stress responses. In neurodegenerative diseases, indirect confirmation for the pathogenetic relevance of LPO-dependent modifications of mitochondrial proteins comes from the disease phenotypes associated with their genetic alterations. PMID:26907355

  7. Histochemical approaches to assess cell-to-cell transmission of misfolded proteins in neurodegenerative diseases

    G. Natale

    2013-03-01

    Full Text Available Formation, aggregation and transmission of abnormal proteins are common features in neurodegenerative disorders including Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. The mechanisms underlying protein alterations in neurodegenerative diseases remain controversial. Novel findings highlighted altered protein clearing systems as common biochemical pathways which generate protein misfolding, which in turn causes protein aggregation and protein spreading. In fact, proteinaceous aggregates are prone to cell-to-cell propagation. This is reminiscent of what happens in prion disorders, where the prion protein misfolds thus forming aggregates which spread to neighbouring cells. For this reason, the term prionoids is currently used to emphasize how several misfolded proteins are transmitted in neurodegenerative diseases following this prion-like pattern. Histochemical techniques including the use of specific antibodies covering both light and electron microscopy offer a powerful tool to describe these phenomena and investigate specific molecular steps. These include: prion like protein alterations; glycation of prion-like altered proteins to form advanced glycation end-products (AGEs; mechanisms of extracellular secretion; interaction of AGEs with specific receptors placed on neighbouring cells (RAGEs. The present manuscript comments on these phenomena aimed to provide a consistent scenario of the available histochemical approaches to dissect each specific step.

  8. Mitochondrial Dysfunction in Cancer and Neurodegenerative Diseases: Spotlight on Fatty Acid Oxidation and Lipoperoxidation Products

    Giuseppina Barrera

    2016-02-01

    Full Text Available In several human diseases, such as cancer and neurodegenerative diseases, the levels of reactive oxygen species (ROS, produced mainly by mitochondrial oxidative phosphorylation, is increased. In cancer cells, the increase of ROS production has been associated with mtDNA mutations that, in turn, seem to be functional in the alterations of the bioenergetics and the biosynthetic state of cancer cells. Moreover, ROS overproduction can enhance the peroxidation of fatty acids in mitochondrial membranes. In particular, the peroxidation of mitochondrial phospholipid cardiolipin leads to the formation of reactive aldehydes, such as 4-hydroxynonenal (HNE and malondialdehyde (MDA, which are able to react with proteins and DNA. Covalent modifications of mitochondrial proteins by the products of lipid peroxidation (LPO in the course of oxidative cell stress are involved in the mitochondrial dysfunctions observed in cancer and neurodegenerative diseases. Such modifications appear to affect negatively mitochondrial integrity and function, in particular energy metabolism, adenosine triphosphate (ATP production, antioxidant defenses and stress responses. In neurodegenerative diseases, indirect confirmation for the pathogenetic relevance of LPO-dependent modifications of mitochondrial proteins comes from the disease phenotypes associated with their genetic alterations.

  9. Mitochondrial Dysfunction in Cancer and Neurodegenerative Diseases: Spotlight on Fatty Acid Oxidation and Lipoperoxidation Products.

    Barrera, Giuseppina; Gentile, Fabrizio; Pizzimenti, Stefania; Canuto, Rosa Angela; Daga, Martina; Arcaro, Alessia; Cetrangolo, Giovanni Paolo; Lepore, Alessio; Ferretti, Carlo; Dianzani, Chiara; Muzio, Giuliana

    2016-01-01

    In several human diseases, such as cancer and neurodegenerative diseases, the levels of reactive oxygen species (ROS), produced mainly by mitochondrial oxidative phosphorylation, is increased. In cancer cells, the increase of ROS production has been associated with mtDNA mutations that, in turn, seem to be functional in the alterations of the bioenergetics and the biosynthetic state of cancer cells. Moreover, ROS overproduction can enhance the peroxidation of fatty acids in mitochondrial membranes. In particular, the peroxidation of mitochondrial phospholipid cardiolipin leads to the formation of reactive aldehydes, such as 4-hydroxynonenal (HNE) and malondialdehyde (MDA), which are able to react with proteins and DNA. Covalent modifications of mitochondrial proteins by the products of lipid peroxidation (LPO) in the course of oxidative cell stress are involved in the mitochondrial dysfunctions observed in cancer and neurodegenerative diseases. Such modifications appear to affect negatively mitochondrial integrity and function, in particular energy metabolism, adenosine triphosphate (ATP) production, antioxidant defenses and stress responses. In neurodegenerative diseases, indirect confirmation for the pathogenetic relevance of LPO-dependent modifications of mitochondrial proteins comes from the disease phenotypes associated with their genetic alterations. PMID:26907355

  10. Gap junctions and hemichannels composed of connexins: potential therapeutic targets for neurodegenerative diseases

    Hideyuki Takeuchi

    2014-09-01

    Full Text Available Microglia are macrophage-like resident immune cells that contribute to the maintenance of homeostasis in the central nervous system (CNS. Abnormal activation of microglia can cause damage in the CNS, and accumulation of activated microglia is a characteristic pathological observation in neurologic conditions such as trauma, stroke, inflammation, epilepsy, and neurodegenerative diseases. Activated microglia secrete high levels of glutamate, which damages CNS cells and has been implicated as a major cause of neurodegeneration in these conditions. Glutamate-receptor blockers and microglia inhibitors (e.g. minocycline have been examined as therapeutic candidates for several neurodegenerative diseases; however, these compounds exerted little therapeutic benefit because they either perturbed physiological glutamate signals or suppressed the actions of protective microglia. The ideal therapeutic approach would hamper the deleterious roles of activated microglia without diminishing their protective effects. We recently found that abnormally activated microglia secrete glutamate via gap-junction hemichannels on the cell surface. Moreover, administration of gap-junction inhibitors significantly suppressed excessive microglial glutamate release and improved disease symptoms in animal models of neurologic conditions such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer’s disease. Recent evidence also suggests that neuronal and glial communication via gap junctions amplifies neuroinflammation and neurodegeneration. Elucidation of the precise pathologic roles of gap junctions and hemichannels may lead to a novel therapeutic strategies that can slow and halt the progression of neurodegenerative diseases.

  11. Transglutaminase inhibition as a possible therapeutical approach to protect cells from death in neurodegenerative diseases.

    Iannaccone, Martina; Serretiello, Enrica; De Vivo, Giulia; Martin, Antonio; Stefanile, Alessandro; Titta, Federica; Gentile, Vittorio

    2013-08-01

    Transglutaminases are ubiquitous enzymes which catalyze post-translational modifications of proteins. The main activity of these enzymes is the cross-linking of glutaminyl residues of a protein/peptide substrate to lysyl residues of a protein/peptide co-substrate. In addition to lysyl residues, other second nucleophilic co-substrates may include monoamines or polyamines (to form mono- or bi-substituted /crosslinked adducts) or -OH groups (to form ester linkages). In absence of co-substrates, the nucleophile may be water, resulting in the net deamidation of the glutaminyl residue. Recently, "tissue" transglutaminase (transglutaminase 2), a member of the transglutaminase family of enzymes, has been shown to be involved in the molecular mechanisms responsible for some human pathologies, including celiac disease, a very widespread human pathology. Transglutaminase activity has also been hypothesized to be involved in the pathogenetic mechanisms responsible for other several human diseases, including neurodegenerative diseases, often associated to celiac disease. Neurodegenerative diseases, such as Alzheimer's Disease, Parkinson's Disease, supranuclear palsy, Huntington's Disease and other polyglutamine diseases, are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains. This review focuses on the possible therapeutic effects of selective transglutaminase inhibitors for patients with diseases characterized by aberrant transglutaminase activity and on the strategies to design such transglutaminase inhibitors. In addition, the review also examines available patents that relates to cysteamine and derivatives. PMID:23688272

  12. The clinical and pathophysiological relevance of REM sleep behavior disorder in neurodegenerative diseases.

    Iranzo, Alex; Santamaria, Joan; Tolosa, Eduard

    2009-12-01

    REM sleep behavior disorder (RBD) is characterized by vigorous movements associated with unpleasant dreams and increased electromyographic activity during REM sleep. Polysomnography with audiovisual recording is needed to confirm the diagnosis of RBD and to exclude other sleep disorders that can mimic its symptoms including obstructive sleep apnea, nocturnal hallucinations and confusional awakenings. RBD may be idiopathic or related to neurodegenerative diseases, particularly multiple system atrophy, Parkinson's disease and dementia with Lewy bodies. RBD may be the first manifestation of these disorders, antedating the onset of parkinsonism, cerebellar syndrome, dysautonomia, and dementia by several years. RBD should thus be considered an integral part of the disease process. When effective, neuroprotective strategies should be considered in subjects with idiopathic RBD. Patients with other neurodegenerative diseases, though, such as spinocerebellar ataxias, may also present with RBD. When clinically required, clonazepam at bedtime is effective in decreasing the intensity of dream-enacting behaviors and unpleasant dreams in both the idiopathic and secondary forms. When part of a neurodegenerative disorder the development of RBD is thought to reflect the location and extent of the underlying lesions involving the REM sleep centers of the brain (e.g., locus subceruleus, amygdala, etc.), leading to a complex multiple neurotransmitter dysfunction that involves GABAergic, glutamatergic and monoaminergic systems. RBD is mediated neither by direct abnormal alpha-synuclein inclusions nor by striatonigral dopaminergic deficiency alone. PMID:19362028

  13. Physical Exercise-Induced Adult Neurogenesis: A Good Strategy to Prevent Cognitive Decline in Neurodegenerative Diseases?

    Suk-yu Yau

    2014-01-01

    Full Text Available Cumulative evidence has indicated that there is an important role for adult hippocampal neurogenesis in cognitive function. With the increasing prevalence of cognitive decline associated with neurodegenerative diseases among the ageing population, physical exercise, a potent enhancer of adult hippocampal neurogenesis, has emerged as a potential preventative strategy/treatment to reduce cognitive decline. Here we review the functional role of adult hippocampal neurogenesis in learning and memory, and how this form of structural plasticity is altered in neurodegenerative diseases known to involve cognitive impairment. We further discuss how physical exercise may contribute to cognitive improvement in the ageing brain by preserving adult neurogenesis, and review the recent approaches for measuring changes in neurogenesis in the live human brain.

  14. Potential Role of Olive Oil Phenolic Compounds in the Prevention of Neurodegenerative Diseases

    Jose Rodríguez-Morató

    2015-03-01

    Full Text Available Adherence to the Mediterranean Diet (MD has been associated with a reduced incidence of neurodegenerative diseases and better cognitive performance. Virgin olive oil, the main source of lipids in the MD, is rich in minor phenolic components, particularly hydroxytyrosol (HT. HT potent antioxidant and anti-inflammatory actions have attracted researchers’ attention and may contribute to neuroprotective effects credited to MD. In this review HT bioavailability and pharmacokinetics are presented prior to discussing health beneficial effects. In vitro and in vivo neuroprotective effects together with its multiple mechanisms of action are reviewed. Other microconstituents of olive oil are also considered due to their potential neuroprotective effects (oleocanthal, triterpenic acids. Finally, we discuss the potential role of HT as a therapeutic tool in the prevention of neurodegenerative diseases.

  15. Dysregulation of cholesterol balance in the brain: contribution to neurodegenerative diseases

    Jean E. Vance

    2012-11-01

    Full Text Available Dysregulation of cholesterol homeostasis in the brain is increasingly being linked to chronic neurodegenerative disorders, including Alzheimer’s disease (AD, Huntington’s disease (HD, Parkinson’s disease (PD, Niemann-Pick type C (NPC disease and Smith-Lemli Opitz syndrome (SLOS. However, the molecular mechanisms underlying the correlation between altered cholesterol metabolism and the neurological deficits are, for the most part, not clear. NPC disease and SLOS are caused by mutations in genes involved in the biosynthesis or intracellular trafficking of cholesterol, respectively. However, the types of neurological impairments, and the areas of the brain that are most affected, differ between these diseases. Some, but not all, studies indicate that high levels of plasma cholesterol correlate with increased risk of developing AD. Moreover, inheritance of the E4 isoform of apolipoprotein E (APOE, a cholesterol-carrying protein, markedly increases the risk of developing AD. Whether or not treatment of AD with statins is beneficial remains controversial, and any benefit of statin treatment might be due to anti-inflammatory properties of the drug. Cholesterol balance is also altered in HD and PD, although no causal link between dysregulated cholesterol homeostasis and neurodegeneration has been established. Some important considerations for treatment of neurodegenerative diseases are the impermeability of the blood-brain barrier to many therapeutic agents and difficulties in reversing brain damage that has already occurred. This article focuses on how cholesterol balance in the brain is altered in several neurodegenerative diseases, and discusses some commonalities and differences among the diseases.

  16. Neural basis of motivational approach and withdrawal behaviors in neurodegenerative disease

    Shinagawa, Shunichiro; Babu, Adhimoolam; Sturm, Virginia; Shany-Ur, Tal; Toofanian Ross, Parnian; Zackey, Diana; Poorzand, Pardis; Grossman, Scott; Miller, Bruce L.; Rankin, Katherine P.

    2015-01-01

    Introduction The Behavioral Inhibition System (BIS) and the Behavioral Activation System (BAS) have been theorized as neural systems that regulate approach/withdrawal behaviors. Behavioral activation/inhibition balance may change in neurodegenerative disease based on underlying alterations in systems supporting motivation and approach/withdrawal behaviors, which may in turn be reflected in neuropsychiatric symptoms. Method A total of 187 participants (31 patients diagnosed with behavioral var...

  17. The two faces of protein misfolding: gain- and loss-of-function in neurodegenerative diseases

    Winklhofer, Konstanze F.; Tatzelt, Jörg; Haass, Christian

    2008-01-01

    The etiologies of neurodegenerative diseases may be diverse; however, a common pathological denominator is the formation of aberrant protein conformers and the occurrence of pathognomonic proteinaceous deposits. Different approaches coming from neuropathology, genetics, animal modeling and biophysics have established a crucial role of protein misfolding in the pathogenic process. However, there is an ongoing debate about the nature of the harmful proteinaceous species and how toxic conformers...

  18. Automated longitudinal monitoring of in vivo protein aggregation in neurodegenerative disease C. elegans models

    Cornaglia, Matteo; Krishnamani, Gopalan; Mouchiroud, Laurent; Sorrentino, Vincenzo; Lehnert, Thomas; Auwerx, Johan; Gijs, Martin A. M.

    2016-01-01

    Background While many biological studies can be performed on cell-based systems, the investigation of molecular pathways related to complex human dysfunctions – e.g. neurodegenerative diseases – often requires long-term studies in animal models. The nematode Caenorhabditis elegans represents one of the best model organisms for many of these tests and, therefore, versatile and automated systems for accurate time-resolved analyses on C. elegans are becoming highly desirable tools in the field. ...

  19. Molecular Modeling Studies of Piperidine Derivatives as New Acetylcholinesterase Inhibitors against Neurodegenerative Diseases

    2013-01-01

    Neurodegenerative disorders are related to the progressive loss of structure or function and, eventually, death of neurons. These processes are responsible for diseases like Parkinson’s, Alzheimer’s, and Huntington’s, and the main molecular target for the drug design against these illnesses today is the enzyme acetylcholinesterase (AChE). Following this line, in the present work, we applied docking techniques to study some piperidine derivative inhibitors of AChE and further propose structure...

  20. Nano-Drugs Based on Nano Sterically Stabilized Liposomes for the Treatment of Inflammatory Neurodegenerative Diseases

    Keren Turjeman; Yaelle Bavli; Pablo Kizelsztein; Yaelle Schilt; Nahum Allon; Tamar Blumenfeld Katzir; Efrat Sasson; Uri Raviv; Haim Ovadia; Yechezkel Barenholz

    2015-01-01

    The present study shows the advantages of liposome-based nano-drugs as a novel strategy of delivering active pharmaceutical ingredients for treatment of neurodegenerative diseases that involve neuroinflammation. We used the most common animal model for multiple sclerosis (MS), mice experimental autoimmune encephalomyelitis (EAE). The main challenges to overcome are the drugs' unfavorable pharmacokinetics and biodistribution, which result in inadequate therapeutic efficacy and in drug toxicity...

  1. O-GlcNAc cycling shows neuroprotective potential in C. elegans models of neurodegenerative disease

    John A Hanover; Wang, Peng

    2013-01-01

    C. elegans has proven to be an excellent organism in which to model human neurodegenerative disease.1–7 The worm’s simple nervous system, lineage, and neural maps, easily scored movement phenotypes, and robust forward and reverse genetics make it optimal for studying age-dependent processes on a reasonable time scale. A popular approach has been the introduction of transgenes expressing GFP-tagged proteotoxic human proteins into neurons leading to visible aggregation or movement phenotypes.2,...

  2. Determination of the olfactory threshold using a piezoelectric microdispenser for neurodegenerative disease diagnostics

    Wallace, David B.; Taylor, David; Antohe, Bogdan V.; Achiriloaie, Ioan; Comparini, Norman; Stewart, R. Malcolm; Sanghera, Manjit K.

    2006-11-01

    Ink-jet microdispensing technology was used to develop an instrument for the quantitative determination of the olfactory threshold. An electrical pulse applied to the piezoelectric element produces a deformation that is transmitted to the fluid which results in a drop of fluid being ejected through the orifice mounted at one end of a piezoelectric tube. An electronic console actuates the piezoelectric dispensing elements and controls the number of drops that are dispensed and evaporated to create a fragrance cloud. The number of drops that are generated, evaporated and presented to the patient's nose for detection is adjusted according to a preset algorithm until the patient's threshold is discovered. Neurodegenerative disease patients tested with the developed olfactometer showed a significant elevation of their olfactory threshold as compared to normal controls. This result agrees with literature studies that indicate the sense of smell is one of the first affected by neurodegenerative disease. Through its precise control and detection capability, the digital olfactometer described in this paper can be used as an early screening tool for neurodegenerative disease through olfactory threshold determination.

  3. Genistein Improves Neuropathology and Corrects Behaviour in a Mouse Model of Neurodegenerative Metabolic Disease

    Langford-Smith, Kia J.; Langford-Smith, Alex; Brown, Jillian R.; Crawford, Brett E.; Vanier, Marie T.; Grynkiewicz, Grzegorz; Wynn, Rob F.; Wraith, J. Ed; Wegrzyn, Grzegorz; Bigger, Brian W.

    2010-01-01

    Background Neurodegenerative metabolic disorders such as mucopolysaccharidosis IIIB (MPSIIIB or Sanfilippo disease) accumulate undegraded substrates in the brain and are often unresponsive to enzyme replacement treatments due to the impermeability of the blood brain barrier to enzyme. MPSIIIB is characterised by behavioural difficulties, cognitive and later motor decline, with death in the second decade of life. Most of these neurodegenerative lysosomal storage diseases lack effective treatments. We recently described significant reductions of accumulated heparan sulphate substrate in liver of a mouse model of MPSIIIB using the tyrosine kinase inhibitor genistein. Methodology/Principal Findings We report here that high doses of genistein aglycone, given continuously over a 9 month period to MPSIIIB mice, significantly reduce lysosomal storage, heparan sulphate substrate and neuroinflammation in the cerebral cortex and hippocampus, resulting in correction of the behavioural defects observed. Improvements in synaptic vesicle protein expression and secondary storage in the cerebral cortex were also observed. Conclusions/Significance Genistein may prove useful as a substrate reduction agent to delay clinical onset of MPSIIIB and, due to its multimodal action, may provide a treatment adjunct for several other neurodegenerative metabolic diseases. PMID:21152017

  4. Genistein improves neuropathology and corrects behaviour in a mouse model of neurodegenerative metabolic disease.

    Marcelina Malinowska

    Full Text Available BACKGROUND: Neurodegenerative metabolic disorders such as mucopolysaccharidosis IIIB (MPSIIIB or Sanfilippo disease accumulate undegraded substrates in the brain and are often unresponsive to enzyme replacement treatments due to the impermeability of the blood brain barrier to enzyme. MPSIIIB is characterised by behavioural difficulties, cognitive and later motor decline, with death in the second decade of life. Most of these neurodegenerative lysosomal storage diseases lack effective treatments. We recently described significant reductions of accumulated heparan sulphate substrate in liver of a mouse model of MPSIIIB using the tyrosine kinase inhibitor genistein. METHODOLOGY/PRINCIPAL FINDINGS: We report here that high doses of genistein aglycone, given continuously over a 9 month period to MPSIIIB mice, significantly reduce lysosomal storage, heparan sulphate substrate and neuroinflammation in the cerebral cortex and hippocampus, resulting in correction of the behavioural defects observed. Improvements in synaptic vesicle protein expression and secondary storage in the cerebral cortex were also observed. CONCLUSIONS/SIGNIFICANCE: Genistein may prove useful as a substrate reduction agent to delay clinical onset of MPSIIIB and, due to its multimodal action, may provide a treatment adjunct for several other neurodegenerative metabolic diseases.

  5. The Enemy within: Innate Surveillance-Mediated Cell Death, the Common Mechanism of Neurodegenerative Disease

    Richards, Robert I.; Robertson, Sarah A.; O'Keefe, Louise V.; Fornarino, Dani; Scott, Andrew; Lardelli, Michael; Baune, Bernhard T.

    2016-01-01

    Neurodegenerative diseases comprise an array of progressive neurological disorders all characterized by the selective death of neurons in the central nervous system. Although, rare (familial) and common (sporadic) forms can occur for the same disease, it is unclear whether this reflects several distinct pathogenic pathways or the convergence of different causes into a common form of nerve cell death. Remarkably, neurodegenerative diseases are increasingly found to be accompanied by activation of the innate immune surveillance system normally associated with pathogen recognition and response. Innate surveillance is the cell's quality control system for the purpose of detecting such danger signals and responding in an appropriate manner. Innate surveillance is an “intelligent system,” in that the manner of response is relevant to the magnitude and duration of the threat. If possible, the threat is dealt with within the cell in which it is detected, by degrading the danger signal(s) and restoring homeostasis. If this is not successful then an inflammatory response is instigated that is aimed at restricting the spread of the threat by elevating degradative pathways, sensitizing neighboring cells, and recruiting specialized cell types to the site. If the danger signal persists, then the ultimate response can include not only the programmed cell death of the original cell, but the contents of this dead cell can also bring about the death of adjacent sensitized cells. These responses are clearly aimed at destroying the ability of the detected pathogen to propagate and spread. Innate surveillance comprises intracellular, extracellular, non-cell autonomous and systemic processes. Recent studies have revealed how multiple steps in these processes involve proteins that, through their mutation, have been linked to many familial forms of neurodegenerative disease. This suggests that individuals harboring these mutations may have an amplified response to innate

  6. Computational Modelling Approaches on Epigenetic Factors in Neurodegenerative and Autoimmune Diseases and Their Mechanistic Analysis

    Afroza Khanam Irin

    2015-01-01

    Full Text Available Neurodegenerative as well as autoimmune diseases have unclear aetiologies, but an increasing number of evidences report for a combination of genetic and epigenetic alterations that predispose for the development of disease. This review examines the major milestones in epigenetics research in the context of diseases and various computational approaches developed in the last decades to unravel new epigenetic modifications. However, there are limited studies that systematically link genetic and epigenetic alterations of DNA to the aetiology of diseases. In this work, we demonstrate how disease-related epigenetic knowledge can be systematically captured and integrated with heterogeneous information into a functional context using Biological Expression Language (BEL. This novel methodology, based on BEL, enables us to integrate epigenetic modifications such as DNA methylation or acetylation of histones into a specific disease network. As an example, we depict the integration of epigenetic and genetic factors in a functional context specific to Parkinson’s disease (PD and Multiple Sclerosis (MS.

  7. New strategies for the treatment of Parkinson's disease hold considerable promise for future management of neurodegenerative disorders

    Bjarkam, Carsten Reidies; Sørensen, Jens Christian; Sunde, Niels Å;

    2001-01-01

    Neurodegenerative diseases are often consideredincurable with no efficient therapies to modifyor halt the progress of disease, and ultimatelylead to reduced quality of life and to death.Our knowledge of the nervous system in healthand disease has, however, increasedconsiderably during the last...... fifty years andtoday, neuroscience reveals promising newstrategies to deal with disorders of thenervous system.Some of these results have been implementedwith success in the treatment of Parkinson'sdisease, a common neurodegenerative illnessaffecting approximately 1% of the populationaged seventy or...

  8. The role of macropinocytosis in the propagation of protein aggregation associated with neurodegenerative diseases

    Zeineddine, Rafaa; Yerbury, Justin J.

    2015-01-01

    With the onset of the rapidly aging population, the impact of age related neurodegenerative diseases is becoming a predominant health and economic concern. Neurodegenerative diseases such as Alzheimer's disease, Creutzfeldt-Jakob disease (CJD), Parkinson's disease, Huntington's disease, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) result from the loss of a specific subsets of neurons, which is closely associated with accumulation and deposition of specific protein aggregates. Protein aggregation, or fibril formation, is a well-studied phenomenon that occurs in a nucleation-dependent growth reaction. Recently, there has been a swell of literature implicating protein aggregation and its ability to propagate cell-to-cell in the rapid progression of these diseases. In order for protein aggregation to be kindled in recipient cells it is a requisite that aggregates must be able to be released from one cell and then taken up by others. In this article we will explore the relationship between protein aggregates, their propagation and the role of macropinocytosis in their uptake. We highlight the ability of neurons to undergo stimulated macropinocytosis and identify potential therapeutic targets. PMID:26528186

  9. The Role of MAPT in Neurodegenerative Diseases: Genetics, Mechanisms and Therapy.

    Zhang, Cheng-Cheng; Xing, Ang; Tan, Meng-Shan; Tan, Lan; Yu, Jin-Tai

    2016-09-01

    Microtubule-associated protein tau (MAPT) is a gene responsible for encoding tau protein, which is tightly implicated in keeping the function of microtubules and axonal transport. Hyperphosphorylated tau protein participates in the formation of neurofibrillary tangles (NFTs), which characterize many neurodegenerative disorders termed tauopathies. Genome-wide association studies (GWAS) have demonstrated numerous single nucleotide polymorphisms (SNPs) located in MAPT associated with various neurodegenerative diseases. Thus, it has been presumed that MAPT plays a crucial role in pathogenesis of neurodegeneration via affecting the structure and function of tau. Here, we review the advanced studies to summarize the biochemical properties of MAPT and its encoded protein, as well as the genetics and epigenetics of MAPT in neurodegeneration. Finally, given the potential mechanisms of MAPT to neurodegeneration pathogenesis, targeting MAPT and tau might present significant treatments of MAPT mutation-related neurodegeneration. Affirmatively, the identification of MAPT is extremely beneficial for improving our understanding of the pathogenesis of various neurodegenerative diseases and developing the mechanism-based therapies. PMID:26363795

  10. Analysis of optical neural stimulation effects on neural networks affected by neurodegenerative diseases

    Zverev, M.; Fanjul-Vélez, F.; Salas-García, I.; Ortega-Quijano, N.; Arce-Diego, J. L.

    2016-03-01

    The number of people in risk of developing a neurodegenerative disease increases as the life expectancy grows due to medical advances. Multiple techniques have been developed to improve patient's condition, from pharmacological to invasive electrodes approaches, but no definite cure has yet been discovered. In this work Optical Neural Stimulation (ONS) has been studied. ONS stimulates noninvasively the outer regions of the brain, mainly the neocortex. The relationship between the stimulation parameters and the therapeutic response is not totally clear. In order to find optimal ONS parameters to treat a particular neurodegenerative disease, mathematical modeling is necessary. Neural networks models have been employed to study the neural spiking activity change induced by ONS. Healthy and pathological neocortical networks have been considered to study the required stimulation to restore the normal activity. The network consisted of a group of interconnected neurons, which were assigned 2D spatial coordinates. The optical stimulation spatial profile was assumed to be Gaussian. The stimulation effects were modeled as synaptic current increases in the affected neurons, proportional to the stimulation fluence. Pathological networks were defined as the healthy ones with some neurons being inactivated, which presented no synaptic conductance. Neurons' electrical activity was also studied in the frequency domain, focusing specially on the changes of the spectral bands corresponding to brain waves. The complete model could be used to determine the optimal ONS parameters in order to achieve the specific neural spiking patterns or the required local neural activity increase to treat particular neurodegenerative pathologies.

  11. Precision Modulation of Neurodegenerative Disease-Related Gene Expression in Human iPSC-Derived Neurons.

    Heman-Ackah, Sabrina Mahalia; Bassett, Andrew Roger; Wood, Matthew John Andrew

    2016-01-01

    The ability to reprogram adult somatic cells into induced pluripotent stem cells (iPSCs) and the subsequent development of protocols for their differentiation into disease-relevant cell types have enabled in-depth molecular analyses of multiple disease states as hitherto impossible. Neurons differentiated from patient-specific iPSCs provide a means to recapitulate molecular phenotypes of neurodegenerative diseases in vitro. However, it remains challenging to conduct precise manipulations of gene expression in iPSC-derived neurons towards modeling complex human neurological diseases. The application of CRISPR/Cas9 to mammalian systems is revolutionizing the utilization of genome editing technologies in the study of molecular contributors to the pathogenesis of numerous diseases. Here, we demonstrate that CRISPRa and CRISPRi can be used to exert precise modulations of endogenous gene expression in fate-committed iPSC-derived neurons. This highlights CRISPRa/i as a major technical advancement in accessible tools for evaluating the specific contributions of critical neurodegenerative disease-related genes to neuropathogenesis. PMID:27341390

  12. ELF electromagnetic fields and neurodegenerative disease. Report of an Advisory Group on Non-ionising radiation

    There are continuing concerns about the possible health effects that may arise as a consequence of exposure to electromagnetic fields and radiations (EMFs). In relation to exposures to power frequency (extremely low frequency, ELF) electromagnetic fields, the principal concern has been the possibility that they may be implicated in the development of cancer. In developing its advice for the Board of NRPB on the possible health effects of electromagnetic fields, the Advisory Group has reviewed a number of studies that have examined associations between Alzheimer's disease, motor neuron disease and Parkinson's disease and exposure to electromagnetic fields. These diseases may be classed as neurodegenerative disease as all involve the death of neurons, although their aetiology is different. This report examines first the biological basis of these neurodegenerative diseases, the location of the nerve cells implicated in their development, and the pathological changes that become manifest as they develop. lt then reviews the relevant epidemiological studies. These have examined the possibility of a relationship with exposure to ELF electromagnetic fields, particularly as a consequence of work involving the use of electricity (eg electric power line/cable workers, welders, electricians and dressmakers)

  13. Mitochondrial dysfunction and cell death in neurodegenerative diseases through nitroxidative stress.

    Akbar, Mohammed; Essa, Musthafa Mohamed; Daradkeh, Ghazi; Abdelmegeed, Mohamed A; Choi, Youngshim; Mahmood, Lubna; Song, Byoung-Joon

    2016-04-15

    Mitochondria are important for providing cellular energy ATP through the oxidative phosphorylation pathway. They are also critical in regulating many cellular functions including the fatty acid oxidation, the metabolism of glutamate and urea, the anti-oxidant defense, and the apoptosis pathway. Mitochondria are an important source of reactive oxygen species leaked from the electron transport chain while they are susceptible to oxidative damage, leading to mitochondrial dysfunction and tissue injury. In fact, impaired mitochondrial function is commonly observed in many types of neurodegenerative diseases, including Alzheimer's disease, Parkinson׳s disease, Huntington׳s disease, alcoholic dementia, brain ischemia-reperfusion related injury, and others, although many of these neurological disorders have unique etiological factors. Mitochondrial dysfunction under many pathological conditions is likely to be promoted by increased nitroxidative stress, which can stimulate post-translational modifications (PTMs) of mitochondrial proteins and/or oxidative damage to mitochondrial DNA and lipids. Furthermore, recent studies have demonstrated that various antioxidants, including naturally occurring flavonoids and polyphenols as well as synthetic compounds, can block the formation of reactive oxygen and/or nitrogen species, and thus ultimately prevent the PTMs of many proteins with improved disease conditions. Therefore, the present review is aimed to describe the recent research developments in the molecular mechanisms for mitochondrial dysfunction and tissue injury in neurodegenerative diseases and discuss translational research opportunities. PMID:26883165

  14. [Changes in olfaction during ageing and in certain neurodegenerative diseases: up-to-date].

    Bianchi, A-J; Guépet-Sordet, H; Manckoundia, P

    2015-01-01

    Olfaction is a complex sensory system, and increasing interest is being shown in the link between olfaction and cognition, notably in the elderly. In this literature review, we revisit the specific neurophysiological features of the olfactory system and odorants that lead to a durable olfactory memory and an emotional memory, for which the implicit component produces subconscious olfactory conditioning. Olfaction is known to affect cognitive abilities and mood. We also consider the impairment of olfactory function due to ageing and to neurodegenerative diseases, in particular Alzheimer's disease and Parkinson's disease, through anatomopathological changes in the peripheral and central olfactory structures. The high frequency of these olfactory disorders as well as their early occurrence in Alzheimer disease and Parkinson disease are in favour of their clinical detection in subjects suffering from these two neurodegenerative diseases. Finally, we analyse the impact of olfactory stimulation on cognitive performance and attention. Current observational data from studies in elderly patients with Alzheimer-type dementia are limited to multiple sensory stimulation methods, such as the Snoezelen method, and aromatherapy. These therapies have shown benefits for dementia-related mood and behaviour disorders in the short term, with few side effects. Since olfactory chemosensory stimulation may be beneficial, it may be proposed in patients with dementia, especially Alzheimer-type dementia, as a complementary or even alternative therapy to existing medical strategies. PMID:25304170

  15. Neural stem cells could serve as a therapeutic material forage-related neurodegenerative diseases

    Sarawut Suksuphew; Parinya Noisa

    2015-01-01

    Progressively loss of neural and glial cells is the keyevent that leads to nervous system dysfunctions anddiseases. Several neurodegenerative diseases, forinstance Alzheimer's disease, Parkinson's disease, andHuntington's disease, are associated to aging andsuggested to be a consequence of deficiency of neuralstem cell pool in the affected brain regions. Endogenousneural stem cells exist throughout life and are found inspecific niches of human brain. These neural stem cellsare responsible for the regeneration of new neurons torestore, in the normal circumstance, the functions of thebrain. Endogenous neural stem cells can be isolated,propagated, and, notably, differentiated to most celltypes of the brain. On the other hand, other types ofstem cells, such as mesenchymal stem cells, embryonicstem cells, and induced pluripotent stem cells can alsoserve as a source for neural stem cell production, thathold a great promise for regeneration of the brain. Thereplacement of neural stem cells, either endogenousor stem cell-derived neural stem cells, into impairedbrain is highly expected as a possible therapeutic meanfor neurodegenerative diseases. In this review, clinicalfeatures and current routinely treatments of agerelatedneurodegenerative diseases are documented.Noteworthy, we presented the promising evidence ofneural stem cells and their derivatives in curing suchdiseases, together with the remaining challenges toachieve the best outcome for patients.

  16. Themes From the Special Issue on Neurodegenerative Diseases: What Have We Learned, and Where Can We Go From Here?

    Foster, Erin R.

    2014-01-01

    This issue of AJOT adds to the growing and evolving understanding of the effectiveness of occupational therapy—related interventions to meet the needs of people living with neurodegenerative diseases.

  17. Mitochondrial ferritin in the regulation of brain iron homeostasis and neurodegenerative diseases

    Guofen eGao

    2014-02-01

    Full Text Available Mitochondrial ferritin (FtMt is a novel iron-storage protein in mitochondria. Evidences have shown that FtMt is structurally and functionally similar to the cytosolic H-chain ferritin. It protects mitochondria from iron-induced oxidative damage presumably through sequestration of potentially harmful excess free iron. It also participates in the regulation of iron distribution between cytosol and mitochondrial contents. Unlike the ubiquitously expressed H-ferritin, FtMt is mainly expressed in testis and brain, which suggests its tissue-related roles. FtMt is involved in pathogenesis of neurodegenerative diseases, as its increased expression has been observed in Alzheimer’s disease, restless legs syndrome and Friedreich’s ataxia. Studies from our laboratory showed that in Alzheimer’s disease, FtMt overexpression attenuated the β-amyloid induced neurotoxicity, which on the other hand increased significantly when FtMt expression was knocked down. It is also found that, by maintaining mitochondrial iron homeostasis, FtMt could prevent 6-hydroxydopamine induced dopaminergic cell damage in Parkinson’s disease. These recent findings on FtMt regarding its functions in regulation of brain iron homeostasis and its protective role in pathogenesis of neurodegenerative diseases are summarized and reviewed.

  18. Insight into the Dissociation of Behavior from Histology in Synucleinopathies and in Related Neurodegenerative Diseases.

    Sekiyama, Kazunari; Takamatsu, Yoshiki; Koike, Wakako; Waragai, Masaaki; Takenouchi, Takato; Sugama, Shuei; Hashimoto, Makoto

    2016-03-31

    Recent clinical trials using immunization approaches against Alzheimer's disease (AD) have failed to demonstrate improved cognitive functions in patients, despite potent suppression in the formation of both senile plaques and other amyloid-β deposits in postmortem brains. Similarly, we observed that treatment with ibuprofen, a non-steroidal anti-inflammatory drug, was effective in improving the histopathology, such as reducing both protein aggregation and glial activation, in the brains of transgenic mice expressing dementia with Lewy bodies-linked P123H β-synuclein. In contrast, only a small improvement in cognitive functions was observed in these mice. Collectively, it is predicted that histology does not correlate with behavior that is resilient and resistant to therapeutic stimuli. Notably, such a 'discrepancy between histology and behavior' is reminiscent of AD-like pathologies and incidental Lewy bodies, which are frequently encountered in postmortem brains of the elderly who had been asymptomatic for memory loss and Parkinsonism during their lives. We suggest that 'the discrepancy between histology and behavior' may be a universal feature that is associated with various aspects of neurodegenerative diseases. Furthermore, given that the cognitive reserve is specifically observed in human brains, human behavior may be evolutionally distinct from that in other animals, thus, contributing to the differential efficiency of therapy between human and lower animals, an important issue in the therapy of neurodegenerative diseases. Overall, it is important to better understand 'the discrepancy between histology and behavior' in the mechanism of neurodegeneration for the development of effective therapies against neurodegenerative diseases. PMID:27031478

  19. Infectivity versus Seeding in Neurodegenerative Diseases Sharing a Prion-Like Mechanism

    Natalia Fernández-Borges

    2013-01-01

    Full Text Available Prions are considered the best example to prove that the biological information can be transferred protein to protein through a conformational change. The term “prion-like” is used to describe molecular mechanisms that share similarities with the mammalian prion protein self-perpetuating aggregation and spreading characteristics. Since prions are presumably composed only of protein and are infectious, the more similar the mechanisms that occur in the different neurodegenerative diseases, the more these processes will resemble an infection. In vitro and in vivo experiments carried out during the last decade in different neurodegenerative disorders such as Alzheimer's disease (AD, Parkinson's diseases (PD, and amyotrophic lateral sclerosis (ALS have shown a convergence toward a unique mechanism of misfolded protein propagation. In spite of the term “infection” that could be used to explain the mechanism governing the diversity of the pathological processes, other concepts as “seeding” or “de novo induction” are being used to describe the in vivo propagation and transmissibility of misfolded proteins. The current studies are demanding an extended definition of “disease-causing agents” to include those already accepted as well as other misfolded proteins. In this new scenario, “seeding” would be a type of mechanism by which an infectious agent can be transmitted but should not be used to define a whole “infection” process.

  20. Brain Cholesterol Metabolism and Its Defects: Linkage to Neurodegenerative Diseases and Synaptic Dysfunction.

    Petrov, A M; Kasimov, M R; Zefirov, A L

    2016-01-01

    Cholesterol is an important constituent of cell membranes and plays a crucial role in the compartmentalization of the plasma membrane and signaling. Brain cholesterol accounts for a large proportion of the body's total cholesterol, existing in two pools: the plasma membranes of neurons and glial cells and the myelin membranes . Cholesterol has been recently shown to be important for synaptic transmission, and a link between cholesterol metabolism defects and neurodegenerative disorders is now recognized. Many neurodegenerative diseases are characterized by impaired cholesterol turnover in the brain. However, at which stage the cholesterol biosynthetic pathway is perturbed and how this contributes to pathogenesis remains unknown. Cognitive deficits and neurodegeneration may be associated with impaired synaptic transduction. Defects in cholesterol biosynthesis can trigger dysfunction of synaptic transmission. In this review, an overview of cholesterol turnover under physiological and pathological conditions is presented (Huntington's, Niemann-Pick type C diseases, Smith-Lemli-Opitz syndrome). We will discuss possible mechanisms by which cholesterol content in the plasma membrane influences synaptic processes. Changes in cholesterol metabolism in Alzheimer's disease, Parkinson's disease, and autistic disorders are beyond the scope of this review and will be summarized in our next paper. PMID:27099785

  1. Does inactivation of USP14 enhance degradation of proteasomal substrates that are associated with neurodegenerative diseases?

    Ortuno, Daniel; Carlisle, Holly J.; Miller, Silke

    2016-01-01

    A common pathological hallmark of age-related neurodegenerative diseases is the intracellular accumulation of protein aggregates such as α-synuclein in Parkinson’s disease, TDP-43 in ALS, and tau in Alzheimer’s disease. Enhancing intracellular clearance of aggregation-prone proteins is a plausible strategy for slowing progression of neurodegenerative diseases and there is great interest in identifying molecular targets that control protein turnover. One of the main routes for protein degradation is through the proteasome, a multisubunit protease that degrades proteins that have been tagged with a polyubiquitin chain by ubiquitin activating and conjugating enzymes. Published data from cellular models indicate that Ubiquitin-specific protease 14 (USP14), a deubiquitinating enzyme (DUB), slows the degradation of tau and TDP-43 by the proteasome and that an inhibitor of USP14 increases the degradation of these substrates. We conducted similar experiments designed to evaluate tau, TDP-43, or α-synuclein levels in cells after overexpressing USP14 or knocking down endogenous expression by siRNA. PMID:26998235

  2. Chronic glutamate toxicity in neurodegenerative diseases-what is the evidence?

    Pamela eMaher

    2015-12-01

    Full Text Available Together with aspartate, glutamate is the major excitatory neurotransmitter in the brain. Glutamate binds and activates both ligand-gated ion channels (ionotropic glutamate receptors and a class of G-protein coupled receptors (metabotropic glutamate receptors. Although the intracellular glutamate concentration in the brain is in the millimolar range, the extracellular glutamate concentration is kept in the low micromolar range by the action of excitatory amino acid transporters that import glutamate and aspartate into astrocytes and neurons. Excess extracellular glutamate may lead to excitotoxicity in vitro and in vivo in acute insults like ischemic stroke via the overactivation of ionotropic glutamate receptors. In addition, chronic excitotoxicity has been hypothesized to play a role in numerous neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer’s disease and Huntington’s disease. Based on this hypothesis, a good deal of effort has been devoted to develop and test drugs that either inhibit glutamate receptors or decrease extracellular glutamate. In this review, we provide an overview of the different pathways that are thought to lead to an over-activation of the glutamatergic system and glutamate toxicity in neurodegeneration. In addition, we summarize the available experimental evidence for glutamate toxicity in animal models of neurodegenerative diseases.

  3. Ethical Perspectives on Stem Cell-based Cellular Therapies for Neurodegenerative Diseases

    Ebbesen, Mette; Pedersen, Finn Skou; Andersen, Svend;

    2012-01-01

    have benefits for patients. The side effect described most commonly in the literature is the risk of tumor formation by stem cells not fully differentiated into neurons when transplanted or following viral transduction and subsequent differentiation to create induced pluripotent stem cells. This risk...... may be avoided by differentiating stem cells in culture before transplantation. Here we argue that the following ethical considerations are important for clinical trials: Informed consent of research subjects or patients, specification of possible therapeutic effects, risk analysis of possible side......The effect of stem cell-based therapies for neurodegenerative diseases such as Alzheimer disease, Huntington disease, and Parkinson disease are currently being investigated. Here we specify possible therapeutic effects and possible side effects for patients and conclude that cellular therapies may...

  4. Targeting Specific HATs for Neurodegenerative Disease Treatment: Translating Basic Biology to Therapeutic Possibilities

    Sheila K. Pirooznia

    2013-03-01

    Full Text Available Dynamic epigenetic regulation of neurons is emerging as a fundamental mechanism by which neurons adapt their transcriptional responses to specific developmental and environmental cues. While defects within the neural epigenome have traditionally been studied in the context of early developmental and heritable cognitive disorders, recent studies point to aberrant histone acetylation status as a key mechanism underlying acquired inappropriate alterations of genome structure and function in post-mitotic neurons during the aging process. Indeed, it is becoming increasingly evident that chromatin acetylation status can be impaired during the lifetime of neurons through mechanisms related to loss of function of histone acetyltransferase (HATs activity. Several HATs have been shown to participate in vital neuronal functions such as regulation of neuronal plasticity and memory formation. As such, dysregulation of such HATs has been implicated in the pathogenesis associated with age-associated neurodegenerative diseases and cognitive decline. In order to counteract the loss of HAT function in neurodegenerative diseases, the current therapeutic strategies involve the use of small molecules called histone deacetylase (HDAC inhibitors that antagonize HDAC activity and thus enhance acetylation levels. Although this strategy has displayed promising therapeutic effects, currently used HDAC inhibitors lack target specificity, raising concerns about their applicability. With rapidly evolving literature on HATs and their respective functions in mediating neuronal survival and higher order brain function such as learning and memory, modulating the function of specific HATs holds new promises as a therapeutic tool in neurodegenerative diseases. In this review, we focus on the recent progress in research regarding epigenetic histone acetylation mechanisms underlying neuronal activity and cognitive function. We discuss the current understanding of specific HDACs and

  5. Network Analysis of Neurodegenerative Disease Highlights a Role of Toll-Like Receptor Signaling

    Thanh-Phuong Nguyen

    2014-01-01

    Full Text Available Despite significant advances in the study of the molecular mechanisms altered in the development and progression of neurodegenerative diseases (NDs, the etiology is still enigmatic and the distinctions between diseases are not always entirely clear. We present an efficient computational method based on protein-protein interaction network (PPI to model the functional network of NDs. The aim of this work is fourfold: (i reconstruction of a PPI network relating to the NDs, (ii construction of an association network between diseases based on proximity in the disease PPI network, (iii quantification of disease associations, and (iv inference of potential molecular mechanism involved in the diseases. The functional links of diseases not only showed overlap with the traditional classification in clinical settings, but also offered new insight into connections between diseases with limited clinical overlap. To gain an expanded view of the molecular mechanisms involved in NDs, both direct and indirect connector proteins were investigated. The method uncovered molecular relationships that are in common apparently distinct diseases and provided important insight into the molecular networks implicated in disease pathogenesis. In particular, the current analysis highlighted the Toll-like receptor signaling pathway as a potential candidate pathway to be targeted by therapy in neurodegeneration.

  6. CRISPR/Cas9: Implications for Modeling and Therapy of Neurodegenerative Diseases

    Yang, Weili; Tu, Zhuchi; Sun, Qiang; Li, Xiao-Jiang

    2016-01-01

    CRISPR/Cas9 is now used widely to genetically modify the genomes of various species. The ability of CRISPR/Cas9 to delete DNA sequences and correct DNA mutations opens up a new avenue to treat genetic diseases that are caused by DNA mutations. In this review, we describe the advantages of using CRISPR/Cas9 to engineer genomic DNAs in animal embryos, as well as in specific regions or cell types in the brain. We also discuss how to apply CRISPR/Cas9 to establish animal models of neurodegenerative diseases, such as Parkinson’s and Huntington’s disease (HD), and to treat these disorders that are caused by genetic mutations. PMID:27199655

  7. Therapeutic Approach of Nanotechnology for Oxidative Stress Induced Ocular Neurodegenerative Diseases.

    Mitra, Rajendra N; Conley, Shannon M; Naash, Muna I

    2016-01-01

    Oxidative stress plays a role in many different forms of neurodegenerative ocular disease. The imbalance between the generation of endogenous reactive oxygen species (ROS) and their corresponding neutralization by endogenous antioxidant defense systems leads to cellular oxidative stress, oxidation of different bio-macromolecules, and eventually retinal disease. As a result, the administration of supplemental endogenous antioxidant materials or exogenous ROS scavengers is an interesting therapeutic approach for the treatment of forms of ocular disease associated with oxidative stress. Thus far, different dietary antioxidant supplements have been proven to be clinically reliable and effective, and different antioxidant gene therapy approaches are under investigation. In addition, various metal oxide nanoparticles were shown to be effective in defending against oxidative stress-associated injury. These benefits are due to free radical scavenging properties of the materials arising from non-stoichiometric crystal defects and oxygen deficiencies. Here we discuss the application of this approach to the protection of the retina. PMID:26427447

  8. The 5-HT2A serotonin receptor in executive function: Implications for neuropsychiatric and neurodegenerative diseases.

    Aznar, Susana; Hervig, Mona El-Sayed

    2016-05-01

    Executive function entails the interplay of a group of cognitive processes enabling the individual to anticipate consequences, attain self-control, and undertake appropriate goal-directed behaviour. Serotonin signalling at serotonin 2A receptors (5-HT2AR) has important effects on these behavioural and cognitive pathways, with the prefrontal cortex (PFC) as the central actor. Indeed, the 5-HT2ARs are highly expressed in PFC, where they modulate cortical activity and local network oscillations (brain waves). Numerous psychiatric and neurodegenerative diseases result in disrupted executive function. Animal and human studies have linked these disorders with alterations in the 5-HT2AR system, making this an important pharmacological target for the treatment of disorders with impaired cognitive function. This review aims to describe the current state of knowledge on the role of 5-HT2AR signalling in components of executive function, and how 5-HT2AR systems may relate to executive dysfunctions occurring in psychiatric and neurodegenerative diseases. We hope thereby to provide insight into how pharmacotherapy targeting the 5-HT2AR may ameliorate (or exacerbate) aspects of these disorders. PMID:26891819

  9. A faulty interaction between SOD1 and hCCS in neurodegenerative disease.

    Wright, Gareth S A; Antonyuk, Svetlana V; Hasnain, S Samar

    2016-01-01

    A proportion of Amyotrophic lateral sclerosis (ALS) cases result from impaired mutant superoxide dismutase-1 (SOD1) maturation. The copper chaperone for SOD1 (hCCS) forms a transient complex with SOD1 and catalyses the final stages of its maturation. We find that a neurodegenerative disease-associated hCCS mutation abrogates the interaction with SOD1 by inhibiting hCCS zinc binding. Analogously, SOD1 zinc loss has a detrimental effect on the formation, structure and disassociation of the hCCS-SOD1 heterodimer. This suggests that hCCS functionality is impaired by ALS mutations that reduce SOD1 zinc affinity. Furthermore, stabilization of wild-type SOD1 by chemical modification including cisplatination, inhibits complex formation. We hypothesize that drug molecules designed to stabilize ALS SOD1 mutants that also target the wild-type form will lead to characteristics common in SOD1 knock-outs. Our work demonstrates the applicability of chromatographic SAXS when studying biomolecules predisposed to aggregation or dissociation; attributes frequently reported for complexes involved in neurodegenerative disease. PMID:27282955

  10. Effect of meditation on cognitive functions in context of aging and neurodegenerative diseases

    Rafał Marciniak

    2014-01-01

    Full Text Available Effect of different meditation practices on various aspects of mental and physical health is receiving growing attention. The present paper reviews evidence about effects of several mediation practices on cognitive functions in the context of aging and neurodegenerative diseases. The effect of meditation in this area is still poorly explored. Seven studies were detected through the databases search which explores the effect of meditation on attention, memory, executive functions and other miscellaneous measures of cognition in a sample of older people and people suffering from neurodegenerative diseases. Overall, reviewed studies suggested a positive effect of meditation techniques, particularly in the area of attention, as well as memory, verbal fluency and cognitive flexibility. These findings are discussed in the context of MRI studies suggesting structural correlates of the effects. Meditation can be a potentially suitable non-pharmacological intervention aimed at the prevention of cognitive decline in the elderly. However, the conclusions of these studies are limited by their methodological flaws and differences of various types of meditation techniques. Further research in this direction could help to verify the validity of the findings and clarify the problematic aspects.

  11. Exosomes: vehicles for the transfer of toxic proteins associated with neurodegenerative diseases?

    Shayne Anthony Bellingham

    2012-05-01

    Full Text Available Exosomes are small membranous vesicles secreted by a number of cell types including neurons and can be isolated from conditioned cell media or bodily fluids such as urine and plasma. Exosome biogenesis involves the inward budding of endosomes to form multivesicular bodies (MVB. When fused with the plasma membrane, the MVB releases the vesicles into the extracellular environment as exosomes. Proposed functions of these vesicles include roles in cell-cell signaling, removal of unwanted proteins, and the transfer of pathogens between cells. One such pathogen which exploits this pathway is the prion, the infectious particle responsible for the transmissible neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD of humans or bovine spongiform encephalopathy (BSE of cattle. Similarly, exosomes are also involved in the processing of the amyloid precursor protein (APP which is associated with Alzheimer's disease (AD. Exosomes have been shown to contain full-length APP and several distinct proteolytically cleaved products of APP, including Aβ. In addition, these fragments can be modulated using inhibitors of the proteases involved in APP cleavage. These observations provide further evidence for a novel pathway in which PrP and APP fragments are released from cells. Other proteins such as superoxide dismutase I (SOD-1 and alpha-synuclein (involved in Amyotrophic Lateral Sclerosis (ALS and Parkinson’s disease respectively are also found associated with exosomes. This review will focus on the role of exosomes in neurodegenerative disorders and discuss the potential of these vesicles for the spread of neurotoxicity, therapeutics and diagnostics for these diseases.

  12. Melatonin and Other Tryptophan Metabolites Produced by Yeasts: Implications in Cardiovascular and Neurodegenerative Diseases

    Hornedo-Ortega, Ruth; Cerezo, Ana B.; Troncoso, Ana M.; Garcia-Parrilla, M. Carmen; Mas, Albert

    2016-01-01

    Yeast metabolism produces compounds derived from tryptophan, which are found in fermented beverages, such as wine and beer. In particular, melatonin and serotonin, may be relevant due to their bioactivity in humans. Indeed, the former is a neurohormone related to circadian rhythms, which also has a putative protective effect against degenerative diseases. Moreover, serotonin is a neurotransmitter itself, in addition to being a precursor of melatonin synthesis. This paper summarizes data reported on fermented beverages, to evaluate dietary intake. Additionally, the article reviews observed effects of yeast amino acid metabolites on the prevention of neurodegenerative diseases (Alzheimer’s and Parkinson’s) and angiogenesis, focusing on evidence of the molecular mechanism involved and identification of molecular targets. PMID:26834716

  13. Computed tomography of neurodegenerative disease in childhood. Serial CT findings and their diagnostic values

    Kataoka, Kenkichi; Nakagawa, Yoshihiro; Hojo, Hiroatsu

    1984-12-01

    Serial computed tomographic scans were performed on seven children with neurodegenerative disorders. In two cases of white-matter diseases (Krabbe's disease and metachromatic leukodystrophy), diffuse, low-density lesions of white matter were visible in the early stage of the diseases. In one case of adrenoleukodystrophy, regional low-density lesions of the white matter around the posterior horns and peculiar high-density strip lesions were visible in the early stage. In two cases of storage-type gray-matter diseases (Tay-Sachs' and infantile Gaucher's disease), there were no abnormalities in the early stage, but diffuse cortical atrophies in the late stage. In one case of Leigh's disease, there were small, low-density lesions of the basal ganglia and multiple low-density lesions of the gray matter in the early stage. In one case of subacute sclerosing panencephalitis, there were no abnormalities in the early stage, but small, low-density lesions of the basal ganglia and diffuse cerebral atrophies in the late stage. Diagnostic values were recognized dominantly in two cases of adrenoleukodystrophy and Leigh's disease. In the other cases, however, serial CT scans were useful in the diagnostic process. (author).

  14. Niemann-Pick C disease gene mutations and age-related neurodegenerative disorders.

    Michael Zech

    Full Text Available Niemann-Pick type C (NPC disease is a rare autosomal-recessively inherited lysosomal storage disorder caused by mutations in NPC1 (95% or NPC2. Given the highly variable phenotype, diagnosis is challenging and particularly late-onset forms with predominantly neuropsychiatric presentations are likely underdiagnosed. Pathophysiologically, genetic alterations compromising the endosomal/lysosomal system are linked with age-related neurodegenerative disorders. We sought to examine a possible association of rare sequence variants in NPC1 and NPC2 with Parkinson's disease (PD, frontotemporal lobar degeneration (FTLD and progressive supranuclear palsy (PSP, and to genetically determine the proportion of potentially misdiagnosed NPC patients in these neurodegenerative conditions. By means of high-resolution melting, we screened the coding regions of NPC1 and NPC2 for rare genetic variation in a homogenous German sample of patients clinically diagnosed with PD (n = 563, FTLD (n = 133 and PSP (n = 94, and 846 population-based controls. The frequencies of rare sequence variants in NPC1/2 did not differ significantly between patients and controls. Disease-associated NPC1/2 mutations were found in six PD patients (1.1% and seven control subjects (0.8%, but not in FTLD or PSP. All rare variation was detected in the heterozygous state and no compound heterozygotes were observed. Our data do not support the hypothesis that rare NPC1/2 variants confer susceptibility for PD, FTLD, or PSP in the German population. Misdiagnosed NPC patients were not present in our samples. However, further assessment of NPC disease genes in age-related neurodegeneration is warranted.

  15. Knockdown of cytosolic glutaredoxin 1 leads to loss of mitochondrial membrane potential: implication in neurodegenerative diseases.

    Uzma Saeed

    Full Text Available Mitochondrial dysfunction including that caused by oxidative stress has been implicated in the pathogenesis of neurodegenerative diseases. Glutaredoxin 1 (Grx1, a cytosolic thiol disulfide oxido-reductase, reduces glutathionylated proteins to protein thiols and helps maintain redox status of proteins during oxidative stress. Grx1 downregulation aggravates mitochondrial dysfunction in animal models of neurodegenerative diseases, such as Parkinson's and motor neuron disease. We examined the mechanism underlying the regulation of mitochondrial function by Grx1. Downregulation of Grx1 by shRNA results in loss of mitochondrial membrane potential (MMP, which is prevented by the thiol antioxidant, alpha-lipoic acid, or by cyclosporine A, an inhibitor of mitochondrial permeability transition. The thiol groups of voltage dependent anion channel (VDAC, an outer membrane protein in mitochondria but not adenosine nucleotide translocase (ANT, an inner membrane protein, are oxidized when Grx1 is downregulated. We then examined the effect of beta-N-oxalyl amino-L-alanine (L-BOAA, an excitatory amino acid implicated in neurolathyrism (a type of motor neuron disease, that causes mitochondrial dysfunction. Exposure of cells to L-BOAA resulted in loss of MMP, which was prevented by overexpression of Grx1. Grx1 expression is regulated by estrogen in the CNS and treatment of SH-SY5Y cells with estrogen upregulated Grx1 and protected from L-BOAA mediated MMP loss. Our studies demonstrate that Grx1, a cytosolic oxido-reductase, helps maintain mitochondrial integrity and prevents MMP loss caused by oxidative insult. Further, downregulation of Grx1 leads to mitochondrial dysfunction through oxidative modification of the outer membrane protein, VDAC, providing support for the critical role of Grx1 in maintenance of MMP.

  16. Neurofilament Light Chain in Blood and CSF as Marker of Disease Progression in Mouse Models and in Neurodegenerative Diseases.

    Bacioglu, Mehtap; Maia, Luis F; Preische, Oliver; Schelle, Juliane; Apel, Anja; Kaeser, Stephan A; Schweighauser, Manuel; Eninger, Timo; Lambert, Marius; Pilotto, Andrea; Shimshek, Derya R; Neumann, Ulf; Kahle, Philipp J; Staufenbiel, Matthias; Neumann, Manuela; Maetzler, Walter; Kuhle, Jens; Jucker, Mathias

    2016-07-01

    A majority of current disease-modifying therapeutic approaches for age-related neurodegenerative diseases target their characteristic proteopathic lesions (α-synuclein, Tau, Aβ). To monitor such treatments, fluid biomarkers reflecting the underlying disease process are crucial. We found robust increases of neurofilament light chain (NfL) in CSF and blood in murine models of α-synucleinopathies, tauopathy, and β-amyloidosis. Blood and CSF NfL levels were strongly correlated, and NfL increases coincided with the onset and progression of the corresponding proteopathic lesions in brain. Experimental induction of α-synuclein lesions increased CSF and blood NfL levels, while blocking Aβ lesions attenuated the NfL increase. Consistently, we also found NfL increases in CSF and blood of human α-synucleinopathies, tauopathies, and Alzheimer's disease. Our results suggest that CSF and particularly blood NfL can serve as a reliable and easily accessible biomarker to monitor disease progression and treatment response in mouse models and potentially in human proteopathic neurodegenerative diseases. PMID:27292537

  17. Tool use disorders in neurodegenerative diseases: Roles of semantic memory and technical reasoning.

    Baumard, Josselin; Lesourd, Mathieu; Jarry, Christophe; Merck, Catherine; Etcharry-Bouyx, Frédérique; Chauviré, Valérie; Belliard, Serge; Moreaud, Olivier; Croisile, Bernard; Osiurak, François; Le Gall, Didier

    2016-09-01

    In the field of apraxia, it has been suggested that the ability to use tools and objects in daily life depends not only on semantic knowledge about tool function and context of use but also on technical reasoning about mechanical properties of tools and objects. The aim of the present work was to assess tool use abilities regarding these hypotheses in patients with neurodegenerative diseases and reduced autonomy. Performance of patients with Alzheimer's disease (AD) (n = 31), semantic dementia (SD) (n = 16) and corticobasal syndrome (CBS) (n = 7) was compared to that of healthy control participants (n = 31) in familiar tool use tasks, functional/contextual associations and mechanical problem solving (MPS). A conversion method was applied to data in order to avoid ceiling effects. Tool use disorders were found in all patient groups but the underlying reasons were different. Patients with SD had difficulties in imagining and selecting familiar tools due to the semantic loss but they performed in normal range in MPS tasks. Interestingly, they performed better with only one tool and its corresponding object, which is interpreted as a partial compensation of semantic loss by spared technical reasoning. Patients with CBS exhibited the reverse pattern, that is, MPS deficits without semantic loss. However, additional qualitative research is needed to disentangle the relative contributions of motor and technical reasoning deficits to this pattern. Both of these profiles were found in patients with AD. For all that, these patients did not commit the same errors as stroke patients with left brain-damage documented in previous works. Several hypotheses are proposed to account for the specificity of tool use disorders in neurodegenerative diseases, and recommendations are provided to caregivers. PMID:27376932

  18. Uncoupling neuronal death and dysfunction in Drosophila models of neurodegenerative disease.

    Chouhan, Amit K; Guo, Caiwei; Hsieh, Yi-Chen; Ye, Hui; Senturk, Mumine; Zuo, Zhongyuan; Li, Yarong; Chatterjee, Shreyasi; Botas, Juan; Jackson, George R; Bellen, Hugo J; Shulman, Joshua M

    2016-01-01

    Common neurodegenerative proteinopathies, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are characterized by the misfolding and aggregation of toxic protein species, including the amyloid beta (Aß) peptide, microtubule-associated protein Tau (Tau), and alpha-synuclein (αSyn) protein. These factors also show toxicity in Drosophila; however, potential limitations of prior studies include poor discrimination between effects on the adult versus developing nervous system and neuronal versus glial cell types. In addition, variable expression paradigms and outcomes hinder systematic comparison of toxicity profiles. Using standardized conditions and medium-throughput assays, we express human Tau, Aß or αSyn selectively in neurons of the adult Drosophila retina and monitor age-dependent changes in both structure and function, based on tissue histology and recordings of the electroretinogram (ERG), respectively. We find that each protein causes a unique profile of neurodegenerative pathology, demonstrating distinct and separable impacts on neuronal death and dysfunction. Strikingly, expression of Tau leads to progressive loss of ERG responses whereas retinal architecture and neuronal numbers are largely preserved. By contrast, Aß induces modest, age-dependent neuronal loss without degrading the retinal ERG. αSyn expression, using a codon-optimized transgene, is characterized by marked retinal vacuolar change, progressive photoreceptor cell death, and delayed-onset but modest ERG changes. Lastly, to address potential mechanisms, we perform transmission electron microscopy (TEM) to reveal potential degenerative changes at the ultrastructural level. Surprisingly, Tau and αSyn each cause prominent but distinct synaptotoxic profiles, including disorganization or enlargement of photoreceptor terminals, respectively. Our findings highlight variable and dynamic properties of neurodegeneration triggered by these disease-relevant proteins in vivo, and suggest

  19. TDP-43 Proteinopathies: A New Player in Neurodegenerative Diseases with Defective Protein Folding

    Suna Lahut

    2012-03-01

    Full Text Available The proteome is the sum of all proteins inside a cell, and proteostasis (protein homeostasis is the stable condition of the proteome. Proteostasis is essential for the cellular and organismal health. Stress, aging and the chronic expression of misfolded proteins challenge the proteostasis machinery and the vitality of the cell. There is increasing evidence that the accumulation of damaged proteins not only has direct consequences on the efficiency and fidelity of cellular processes but, when not corrected, that they initiate a cascade of dysfunction, which in humans is associated with a plethora of diseases of protein conformation, referred to as proteinopathies. Alzheimer’s Disease (AD, Parkinson’s Disease (PD, Huntington’s Disease (HD, Amyotrophic Lateral Sclerosis (ALS, cancer and diabetes, whose frequencies have drastically increased in countries with aging populations, are all consequences of misfolded proteins. This paper focuses on TDP-43, which excelled as a key protein in neurodegenerative processes because of its association with different diseases, especially with ALS and Frontotemporal Lobar Dementia (FTLD, the two best studied examples of TDP-43 proteinopathies.

  20. The causative role and therapeutic potential of the kynurenine pathway in neurodegenerative disease.

    Amaral, Marta; Outeiro, Tiago F; Scrutton, Nigel S; Giorgini, Flaviano

    2013-06-01

    Metabolites of the kynurenine pathway (KP), which arise from the degradation of tryptophan, have been studied in detail for over a century and garnered the interest of the neuroscience community in the late 1970s and early 1980s with work uncovering the neuromodulatory potential of this pathway. Much research in the following decades has found that perturbations in the levels of KP metabolites likely contribute to the pathogenesis of several neurodegenerative diseases. More recently, it has become apparent that targeting KP enzymes, in particular kynurenine 3-monooxygenase (KMO), may hold substantial therapeutic potential for these disorders. Here we provide an overview of the KP, the neuroactive properties of KP metabolites and their role in neurodegeneration. We also discuss KMO as a therapeutic target for these disorders, and our recent resolution of the crystallographic structure of KMO, which will permit the development of new and improved KMO inhibitors which may ultimately expedite clinical application of these compounds. PMID:23636512

  1. Midkine and Pleiotrophin in the Treatment of Neurodegenerative Diseases and Drug Addiction.

    Alguacil, Luis F; Herradón, Gonzalo

    2015-01-01

    Pleiotrophin (PTN) and Midkine (MK) are neurotrophines with documented protective actions in experimental models of neurodegenerative diseases and beneficial effects on toxicity and addictive behaviours related to drug abuse. Concerning the latter, both PTN and MK prevent the neurotoxic effects of amphetamine on nigrostriatal pathways and endogenous PTN also limits amphetamine reward. Moreover, endogenous PTN overexpression in the prefontral cortex abolishes alcohol- induced conditioned place preference. This review summarizes the existing patents for using PTN and MK in the treatment and diagnosis of neuropsychiatric disorders with a focus on neurotoxicity, neurodegeneration and substance use disorders. We have also reviewed the mechanism of action of PTN and MK and summarized existing patents on downstream modulators in their signaling pathways for the same indications. PMID:25808239

  2. Coenzyme Q10 and its effects in the treatment of neurodegenerative diseases

    Graciela Cristina dos Santos

    2009-12-01

    Full Text Available According to clinical and pre-clinical studies, oxidative stress and its consequences may be the cause or, at least, a contributing factor, to a large number of neurodegenerative diseases. These diseases include common and debilitating disorders, characterized by progressive and irreversible loss of neurons in specific regions of the brain. The most common neurodegenerative diseases are Parkinson's disease, Huntington's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Coenzyme Q10 (CoQ10 has been extensively studied since its discovery in 1957. It is a component of the electron transportation chain and participates in aerobic cellular respiration, generating energy in the form of adenosine triphosphate (ATP. The property of CoQ10 to act as an antioxidant or a pro-oxidant, suggests that it also plays an important role in the modulation of redox cellular status under physiological and pathological conditions, also performing a role in the ageing process. In several animal models of neurodegenerative diseases, CoQ10 has shown beneficial effects in reducing disease progression. However, further studies are needed to assess the outcome and effectiveness of CoQ10 before exposing patients to unnecessary health risks at significant costs.De acordo com estudos clínicos e pré-clínicos, o estresse oxidativo e suas conseqüências podem ser a causa, ou, no mínimo, o fator que contribui para grande número de doenças degenerativas. Estas doenças incluem problemas comuns e debilitantes, caracterizados por perda progressiva e irreversível de neurônios em regiões específicas do cérebro. As doenças degenerativas mais comuns são doença de Parkinson, de Hutington, de Alzheimer e esclerose amiotrófica lateral. A Coenzima Q10 (CoQ10 tem sido intensamente estudada desde sua descoberta, em 1957. É um componente da cadeia de transporte eletrônico e participa da respiração aeróbica celular, gerando energia na forma de trifosfato de

  3. Changes in the mitochondrial antioxidant systems in neurodegenerative diseases and acute brain disorders.

    Ruszkiewicz, Joanna; Albrecht, Jan

    2015-09-01

    Oxidative and nitrosative stress (ONS) contributes to the pathogenesis of most brain maladies, and the magnitude of ONS is related to the ability of cellular antioxidants to neutralize the accumulating reactive oxygen and nitrogen species (ROS/RNS). While the major ROS/RNS scavengers and regenerators of bio-oxidized molecules, superoxide dysmutases (SODs), glutathione (GSH), thioredoxin (Trx) and peroxiredoxin (Prx), are distributed in all cellular compartments. This review specifically focuses on the role of the systems operating in mitochondria. There is a growing consensus that the mitochondrial SOD isoform - SOD2 and GSH are critical for the cellular antioxidant defense. Variable changes of the expression or activities of one or more of the mitochondrial antioxidant systems have been documented in the brains derived from human patients and/or in animal models of neurodegenerative diseases (Alzheimer's disease, Parkinson's disease), cerebral ischemia, toxic brain cell damage associated with overexposure to mercury or excitotoxins, or hepatic encephalopathy. In many cases, ambiguity of the responses of the different antioxidant systems in one and the same disease needs to be more conclusively evaluated before the balance of the changes is viewed as beneficial or detrimental. Modulation of the mitochondrial antioxidant systems may in the future become a target of antioxidant therapy. PMID:25576182

  4. Pharmacological Effects of Active Compounds on Neurodegenerative Disease with Gastrodia and Uncaria Decoction, a Commonly Used Poststroke Decoction

    Stanley C. C. Chik

    2013-01-01

    Full Text Available Neurodegenerative diseases refer to the selective loss of neuronal systems in patients. The diseases cause high morbidity and mortality to approximately 22 million people worldwide and the number is expected to be tripled by 2050. Up to now, there is no effective prevention and treatment for the neurodegenerative diseases. Although some of the clinical therapies target at slowing down the progression of symptoms of the diseases, the general effectiveness of the drugs has been far from satisfactory. Traditional Chinese medicine becomes popular alternative remedies as it has been practiced clinically for more than thousands of years in China. As neurodegenerative diseases are mediated through different pathways, herbal decoction with multiple herbs is used as an effective therapeutic approach to work on multiple targets. Gastrodia and Uncaria Decoction, a popular TCM decoction, has been used to treat stroke in China. The decoction contains compounds including alkaloids, flavonoids, iridoids, carotenoids, and natural phenols, which have been found to possess anti-inflammatory, antioxidative, and antiapoptotic effects. In this review, we will summarize the recent publications of the pharmacological effects of these five groups of compounds. Understanding the mechanisms of action of these compounds may provide new treatment opportunities for the patients with neurodegenerative diseases.

  5. Estimating frontal and parietal involvement in cognitive estimation: a study of focal neurodegenerative diseases

    Teagan Ann Bisbing

    2015-06-01

    Full Text Available We often estimate an unknown value based on available relevant information, a process known as cognitive estimation. In this study, we assess the cognitive and neuroanatomic basis for quantitative estimation by examining deficits in patients with focal neurodegenerative disease in frontal and parietal cortex. Executive function and number knowledge are key components in cognitive estimation. Prefrontal cortex has been implicated in multilevel reasoning and planning processes, and parietal cortex has been associated with number knowledge required for such estimations. We administered the Biber Cognitive Estimation Test (BCET to assess cognitive estimation in 22 patients with prefrontal disease due to behavioral variant frontotemporal dementia (bvFTD, to 17 patients with parietal disease due to corticobasal syndrome (CBS or posterior cortical atrophy (PCA and 11 patients with mild cognitive impairment (MCI. Both bvFTD and CBS/PCA patients had significantly more difficulty with cognitive estimation than controls. MCI were not impaired on BCET relative to controls. Regression analyses related BCET performance to gray matter atrophy in right lateral prefrontal and orbital frontal cortices in bvFTD, and to atrophy in right inferior parietal cortex, right insula and fusiform cortices in CBS/PCA. These results are consistent with the hypothesis that a frontal-parietal network plays a crucial role in cognitive estimation.

  6. Closing the gap between brain banks and proteomics to advance the study of neurodegenerative diseases.

    Paraizo Leite, Renata Elaine; Tenenholz Grinberg, Lea

    2015-10-01

    Neurodegenerative diseases (NDs), such as Alzheimer's disease and Parkinson's disease, are among the most debilitating neurological disorders, and as life expectancy rises quickly around the world, the scientific and clinical challenges of dealing with them will also increase dramatically, putting increased pressure on the biomedical community to come up with innovative solutions for the understanding, diagnosis, and treatment of these conditions. Despite several decades of intensive research, there is still little that can be done to prevent, cure, or even slow down the progression of NDs in most patients. There is an urgent need to develop new lines of basic and applied research that can be quickly translated into clinical application. One way to do this is to apply the tools of proteomics to well-characterized samples of human brain tissue, but a closer partnership must still be forged between proteomic scientists, brain banks, and clinicians to explore the maximum potential of this approach. Here, we analyze the challenges and potential benefits of using human brain tissue for proteomics research toward NDs. PMID:26059592

  7. Redox reactions induced by nitrosative stress mediate protein misfolding and mitochondrial dysfunction in neurodegenerative diseases.

    Gu, Zezong; Nakamura, Tomohiro; Lipton, Stuart A

    2010-06-01

    Overstimulation of N-methyl-D-aspartate (NMDA)-type glutamate receptors accounts, at least in part, for excitotoxic neuronal damage, potentially contributing to a wide range of acute and chronic neurologic diseases. Neurodegenerative disorders including Alzheimer's disease (AD) and Parkinson's disease (PD), manifest deposits of misfolded or aggregated proteins, and result from synaptic injury and neuronal death. Recent studies have suggested that nitrosative stress due to generation of excessive nitric oxide (NO) can mediate excitotoxicity in part by triggering protein misfolding and aggregation, and mitochondrial fragmentation in the absence of genetic predisposition. S-Nitrosylation, or covalent reaction of NO with specific protein thiol groups, represents a convergent signal pathway contributing to NO-induced protein misfolding and aggregation, compromised dynamics of mitochondrial fission-fusion process, thus leading to neurotoxicity. Here, we review the effect of S-nitrosylation on protein function under excitotoxic conditions, and present evidence suggesting that NO contributes to protein misfolding and aggregation via S-nitrosylating protein-disulfide isomerase or the E3 ubiquitin ligase parkin, and mitochondrial fragmentation through beta-amyloid-related S-nitrosylation of dynamin-related protein-1. Moreover, we also discuss that inhibition of excessive NMDA receptor activity by memantine, an uncompetitive/fast off-rate (UFO) drug can ameliorate excessive production of NO, protein misfolding and aggregation, mitochondrial fragmentation, and neurodegeneration. PMID:20333559

  8. TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease

    Tansey Malú G

    2008-10-01

    Full Text Available Abstract The role of tumor necrosis factor (TNF as an immune mediator has long been appreciated but its function in the brain is still unclear. TNF receptor 1 (TNFR1 is expressed in most cell types, and can be activated by binding of either soluble TNF (solTNF or transmembrane TNF (tmTNF, with a preference for solTNF; whereas TNFR2 is expressed primarily by microglia and endothelial cells and is preferentially activated by tmTNF. Elevation of solTNF is a hallmark of acute and chronic neuroinflammation as well as a number of neurodegenerative conditions including ischemic stroke, Alzheimer's (AD, Parkinson's (PD, amyotrophic lateral sclerosis (ALS, and multiple sclerosis (MS. The presence of this potent inflammatory factor at sites of injury implicates it as a mediator of neuronal damage and disease pathogenesis, making TNF an attractive target for therapeutic development to treat acute and chronic neurodegenerative conditions. However, new and old observations from animal models and clinical trials reviewed here suggest solTNF and tmTNF exert different functions under normal and pathological conditions in the CNS. A potential role for TNF in synaptic scaling and hippocampal neurogenesis demonstrated by recent studies suggest additional in-depth mechanistic studies are warranted to delineate the distinct functions of the two TNF ligands in different parts of the brain prior to large-scale development of anti-TNF therapies in the CNS. If inactivation of TNF-dependent inflammation in the brain is warranted by additional pre-clinical studies, selective targeting of TNFR1-mediated signaling while sparing TNFR2 activation may lessen adverse effects of anti-TNF therapies in the CNS.

  9. Chronic exposure to low benzo[a]pyrene level causes neurodegenerative disease-like syndromes in zebrafish (Danio rerio).

    Gao, Dongxu; Wu, Meifang; Wang, Chonggang; Wang, Yuanchuan; Zuo, Zhenghong

    2015-10-01

    Previous epidemiological and animal studies report that exposure to environmental pollutant exposure links to neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. Benzo[a]pyrene (BaP), a neurotoxic polycyclic aromatic hydrocarbon, has been increasingly released into the environment during recent decades. So far, the role of BaP on the development of neurodegenerative diseases remaind unclear. This study aimed to determine whether chronic exposure to low dose BaP would cause neurodegenerative disease-like syndromes in zebrafish (Danio rerio). We exposed zebrafish, from early embryogenesis to adults, to environmentally relevant concentrations of BaP for 230 days. Our results indicated that BaP decreased the brain weight to body weight ratio, locomotor activity and cognitive ability; induced the loss of dopaminergic neurons; and resulted in neurodegeneration. In addition, obvious cell apoptosis in the brain was found. Furthermore, the neurotransmitter levels of dopamine and 3,4-dihydroxyphenylacetic acid, the mRNA levels of the genes encoding dopamine transporter, Parkinson protein 7, phosphatase and tensin-induced putative kinase 1, ubiquitin carboxy-terminal hydrolase L1, leucine-rich repeat serine/threonine kinase 2, amyloid precursor protein b, presenilin 1 and presenilin 2 were significantly down-regulated by BaP exposure. These findings suggest that chronic exposure to low dose BaP could cause the behavioral, neuropathological, neurochemical, and genetic features of neurodegenerative diseases. This study provides clues that BaP may constitute an important environmental risk factor for neurodegenerative diseases in humans. PMID:26349946

  10. Subpicomolar diphenyleneiodonium inhibits microglial NADPH oxidase with high specificity and shows great potential as a therapeutic agent for neurodegenerative diseases

    Wang, Qingshan; Chu, Chun-Hsien; Oyarzabal, Esteban; Jiang, Lulu; Chen, Shih-Heng; Wilson, Belinda; Qian, Li; Hong, Jau-Shyong

    2014-01-01

    Activation of microglial NADPH oxidase (NOX2) plays a critical role in mediating neuroinflammation, which is closely linked with the pathogenesis of a variety of neurodegenerative diseases, including Parkinson’s disease (PD). The inhibition of NOX2-generated superoxide has become an effective strategy for developing disease-modifying therapies for PD. However, the lack of specific and potent NOX2 inhibitors has hampered the progress of this approach. Diphenyleneiodonium (DPI) is a widely used...

  11. Neuro degenerative diseases: clinical concerns; Les maladies neuro-degeneratives: problemes cliniques

    Ibanez, V. [Hopitaux Universitaires de Geneve (HUG), Unite de Neuroimagerie, Dept. de Psychiatrie (Switzerland)

    2005-04-15

    Idiopathic Parkinson's disease (PD) and Alzheimer's disease (AD) are the main neuro-degenerative diseases (NDDs) seen clinically. They share some common clinical symptoms and neuro-pathological findings. The increase of life expectancy in the developed countries will inevitably contribute to enhance the prevalence of these diseases. Behavioral disorders, common in NDDs, will produce major care management challenges. Idiopathic Parkinson's disease corresponds to a histopathological diagnosis, based on the observation of a de-pigmentation and a neuronal loss in the substantia nigra, as well as on the presence of intra-neuronal inclusion bodies. AD is insidious with slowly progressive dementia in which the decline in memory constitutes the main complaint. The diagnosis of definite AD requires the presence of clinical criteria as well as the histopathological confirmation of brain lesions. The two main lesions are the presence of senile plaques and neuro-fibrillary tangles. Positron emission tomography (PET) explores cerebral metabolism and neurotransmitter kinetics in NDDs using principally [{sup 18}F]-deoxyglucose and [{sup 18}F]-dopa. Nigrostriatal dopaminergic function is altered in PD, as evidenced by the low uptake of [{sup 18}F]-dopa in the posterior putamen as compared to anterior putamen and caudate nucleus. In contrast, [{sup 18}F]-dopa uptake is equally depressed in all striatal structures in progressive supra-nuclear palsy. Regional glucose metabolism at rest is preserved in elderly once cerebral atrophy is taken into account. On the contrary, glucose metabolism is globally reduced in AD, with marked decrease in the parietal and temporal regions. PET has proved to be useful to study in vivo neurochemical processes in patients suffering from NDDs. The potential of this approach is still largely unexploited, and depends on new ligand production to establish early diagnosis and treatment follow-up. (author)

  12. Transgenic Rat Model of Huntington's Disease: A Histopathological Study and Correlations with Neurodegenerative Process in the Brain of HD Patients.

    Mazurová, Y.; Anděrová, Miroslava; Němečková, I.; Bezrouk, A.

    2014-01-01

    Roč. 2014, Aug 03 (2014), s. 291531. ISSN 2314-6133 R&D Projects: GA ČR(CZ) GBP304/12/G069 Grant ostatní: GA MŠk(CZ) Prvouk P37 Institutional support: RVO:68378041 Keywords : Huntington's Disease * neurodegenerative process in the brain Subject RIV: FH - Neurology Impact factor: 1.579, year: 2014

  13. Exosomes and other extracellular vesicles in neural cells and neurodegenerative diseases.

    Janas, Anna M; Sapoń, Karolina; Janas, Teresa; Stowell, Michael H B; Janas, Tadeusz

    2016-06-01

    The function of human nervous system is critically dependent on proper interneuronal communication. Exosomes and other extracellular vesicles are emerging as a novel form of information exchange within the nervous system. Intraluminal vesicles within multivesicular bodies (MVBs) can be transported in neural cells anterogradely or retrogradely in order to be released into the extracellular space as exosomes. RNA loading into exosomes can be either via an interaction between RNA and the raft-like region of the MVB limiting membrane, or via an interaction between an RNA-binding protein-RNA complex with this raft-like region. Outflow of exosomes from neural cells and inflow of exosomes into neural cells presumably take place on a continuous basis. Exosomes can play both neuro-protective and neuro-toxic roles. In this review, we characterize the role of exosomes and microvesicles in normal nervous system function, and summarize evidence for defective signaling of these vesicles in disease pathogenesis of some neurodegenerative diseases. PMID:26874206

  14. The armadillo: a model for the neuropathy of leprosy and potentially other neurodegenerative diseases

    Rahul Sharma

    2013-01-01

    Full Text Available Leprosy (also known as Hansen’s disease is an infectious peripheral neurological disorder caused by Mycobacterium leprae that even today leaves millions of individuals worldwide with life-long disabilities. The specific mechanisms by which this bacterium induces nerve injury remain largely unknown, mainly owing to ethical and practical limitations in obtaining affected human nerve samples. In addition to humans, nine-banded armadillos (Dasypus novemcinctus are the only other natural host of M. leprae, and they develop a systemically disseminated disease with extensive neurological involvement. M. leprae is an obligate intracellular parasite that cannot be cultivated in vitro. Because of the heavy burdens of bacilli they harbor, nine-banded armadillos have become the organism of choice for propagating large quantities of M. leprae, and they are now advancing as models of leprosy pathogenesis and nerve damage. Although armadillos are exotic laboratory animals, the recently completed whole genome sequence for this animal is enabling researchers to undertake more sophisticated molecular studies and to develop armadillo-specific reagents. These advances will facilitate the use of armadillos in piloting new therapies and diagnostic regimens, and will provide new insights into the oldest known infectious neurodegenerative disorder.

  15. Relevance of the Anti-Inflammatory Properties of Curcumin in Neurodegenerative Diseases and Depression

    Yousef Tizabi

    2014-12-01

    Full Text Available This review is an attempt to summarize our current understanding of curcumin’s potential as a neuroprotectant and an antidepressant. This dual property confers a unique advantage to this herbal medication, believed to be devoid of any major side effects, to combat commonly observed co-morbid conditions of a neurodegenerative and a neuropsychiatric disorder. Moreover, in line with the theme of this series, the role of inflammation and stress in these diseases and possible anti-inflammatory effects of curcumin, as well as its interaction with signal transduction proteins as a common denominator in its varied mechanisms of action, are also discussed. Thus, following a brief introduction of curcumin’s pharmacology, we present research suggesting how its anti-inflammatory properties have therapeutic potential in treating a devastating neurological disorder (Parkinson’s disease = PD and a debilitating neuropsychiatric disorder (major depressive disorder = MDD. It is concluded that curcumin, or better yet, an analog with better and longer bioavailability could be of important therapeutic potential in PD and/or major depression.

  16. Recent Advances in Neurogenic Small Molecules as Innovative Treatments for Neurodegenerative Diseases.

    Herrera-Arozamena, Clara; Martí-Marí, Olaia; Estrada, Martín; de la Fuente Revenga, Mario; Rodríguez-Franco, María Isabel

    2016-01-01

    The central nervous system of adult mammals has long been considered as a complex static structure unable to undergo any regenerative process to refurbish its dead nodes. This dogma was challenged by Altman in the 1960s and neuron self-renewal has been demonstrated ever since in many species, including humans. Aging, neurodegenerative, and some mental diseases are associated with an exponential decrease in brain neurogenesis. Therefore, the controlled pharmacological stimulation of the endogenous neural stem cells (NSCs) niches might counteract the neuronal loss in Alzheimer's disease (AD) and other pathologies, opening an exciting new therapeutic avenue. In the last years, druggable molecular targets and signalling pathways involved in neurogenic processes have been identified, and as a consequence, different drug types have been developed and tested in neuronal plasticity. This review focuses on recent advances in neurogenic agents acting at serotonin and/or melatonin systems, Wnt/β-catenin pathway, sigma receptors, nicotinamide phosphoribosyltransferase (NAMPT) and nuclear erythroid 2-related factor (Nrf2). PMID:27598108

  17. Orally Bioavailable Metal Chelators and Radical Scavengers: Multifunctional Antioxidants for the Coadjutant Treatment of Neurodegenerative Diseases.

    Kawada, Hiroyoshi; Kador, Peter F

    2015-11-25

    Neurodegenerative diseases are associated with oxidative stress that is induced by the presence of reactive oxygen species and the abnormal cellular accumulation of transition metals. Here, a new series of orally bioavailable multifunctional antioxidants (MFAO-2s) possessing a 2-diacetylamino-5-hydroxypyrimidine moiety is described. These MFAO-2s demonstrate both free radical and metal attenuating properties that are similar to the original published MFAO-1s that are based on 1-N,N'-dimethylsulfamoyl-1-4-(2-pyrimidyl)piperazine. Oral bioavailability studies in C57BL/6 mice demonstrate that the MFAO-2s accumulate in the brain at significantly higher levels than the MFAO-1s while achieving similar neural retina levels. The MFAO-2s protect human neuroblastoma and retinal pigmented epithelial cells against hydroxyl radicals in a dose-dependent manner by maintaining cell viability and intracellular glutathione levels. The MFAO-2s outperform clioquinol, a metal attenuator that has been investigated for the treatment of Alzheimer's disease. PMID:26068053

  18. Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function.

    Esteras, Noemí; Dinkova-Kostova, Albena T; Abramov, Andrey Y

    2016-05-01

    The nuclear factor erythroid-derived 2 (NF-E2)-related factor 2 (Nrf2) is a transcription factor well-known for its function in controlling the basal and inducible expression of a variety of antioxidant and detoxifying enzymes. As part of its cytoprotective activity, increasing evidence supports its role in metabolism and mitochondrial bioenergetics and function. Neurodegenerative diseases are excellent candidates for Nrf2-targeted treatments. Most neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia and Friedreich's ataxia are characterized by oxidative stress, misfolded protein aggregates, and chronic inflammation, the common targets of Nrf2 therapeutic strategies. Together with them, mitochondrial dysfunction is implicated in the pathogenesis of most neurodegenerative disorders. The recently recognized ability of Nrf2 to regulate intermediary metabolism and mitochondrial function makes Nrf2 activation an attractive and comprehensive strategy for the treatment of neurodegenerative disorders. This review aims to focus on the potential therapeutic role of Nrf2 activation in neurodegeneration, with special emphasis on mitochondrial bioenergetics and function, metabolism and the role of transporters, all of which collectively contribute to the cytoprotective activity of this transcription factor. PMID:26812787

  19. Nano-Drugs Based on Nano Sterically Stabilized Liposomes for the Treatment of Inflammatory Neurodegenerative Diseases.

    Turjeman, Keren; Bavli, Yaelle; Kizelsztein, Pablo; Schilt, Yaelle; Allon, Nahum; Katzir, Tamar Blumenfeld; Sasson, Efrat; Raviv, Uri; Ovadia, Haim; Barenholz, Yechezkel

    2015-01-01

    The present study shows the advantages of liposome-based nano-drugs as a novel strategy of delivering active pharmaceutical ingredients for treatment of neurodegenerative diseases that involve neuroinflammation. We used the most common animal model for multiple sclerosis (MS), mice experimental autoimmune encephalomyelitis (EAE). The main challenges to overcome are the drugs' unfavorable pharmacokinetics and biodistribution, which result in inadequate therapeutic efficacy and in drug toxicity (due to high and repeated dosage). We designed two different liposomal nano-drugs, i.e., nano sterically stabilized liposomes (NSSL), remote loaded with: (a) a "water-soluble" amphipathic weak acid glucocorticosteroid prodrug, methylprednisolone hemisuccinate (MPS) or (b) the amphipathic weak base nitroxide, Tempamine (TMN). For the NSSL-MPS we also compared the effect of passive targeting alone and of active targeting based on short peptide fragments of ApoE or of β-amyloid. Our results clearly show that for NSSL-MPS, active targeting is not superior to passive targeting. For the NSSL-MPS and the NSSL-TMN it was demonstrated that these nano-drugs ameliorate the clinical signs and the pathology of EAE. We have further investigated the MPS nano-drug's therapeutic efficacy and its mechanism of action in both the acute and the adoptive transfer EAE models, as well as optimizing the perfomance of the TMN nano-drug. The highly efficacious anti-inflammatory therapeutic feature of these two nano-drugs meets the criteria of disease-modifying drugs and supports further development and evaluation of these nano-drugs as potential therapeutic agents for diseases with an inflammatory component. PMID:26147975

  20. Cystamine metabolism and brain transport properties: clinical implications for neurodegenerative diseases.

    Bousquet, Mélanie; Gibrat, Claire; Ouellet, Mélissa; Rouillard, Claude; Calon, Frédéric; Cicchetti, Francesca

    2010-09-01

    Cystamine has shown significant neuroprotective properties in preclinical studies of Parkinson's disease (PD) and Huntington's disease (HD). Cysteamine, its FDA-approved reduced form, is scheduled to be tested for clinical efficacy in HD patients. Here, we studied the key cystamine metabolites, namely cysteamine, hypotaurine and taurine, as well as cysteine, in order to identify which one is more distinctively responsible for the neuroprotective action of cystamine. After a single administration of cystamine (10, 50 or 200 mg/kg), naïve mice were perfused with phosphate-buffered saline (PBS) at 1, 3, 12, 24 or 48 h post-injection and brain and plasma samples were analyzed by two distinct HPLC methods. Although plasma levels remained under the detection threshold, significant increases in cysteamine brain levels were detected with the 50 and 200 mg/kg doses in mice perfused 1 and 3 h following cystamine injection. To further assess cysteamine as the candidate molecule for pre-clinical and clinical trials in PD, we evaluated its capacity to cross the blood brain barrier. Using an in situ cerebral perfusion technique, we determined that the brain transport coefficient (Clup) of cysteamine (259 μM) was 0.15 ± 0.02 μL/g/s and was increased up to 0.34 ± 0.07 μL/g/s when co-perfused in the presence of cysteine. Taken together, these results strongly suggest that cysteamine is the neuroactive metabolite of cystamine and may further support its therapeutic use in neurodegenerative diseases, particularly in HD and PD. PMID:20569301

  1. Nano-Drugs Based on Nano Sterically Stabilized Liposomes for the Treatment of Inflammatory Neurodegenerative Diseases.

    Keren Turjeman

    Full Text Available The present study shows the advantages of liposome-based nano-drugs as a novel strategy of delivering active pharmaceutical ingredients for treatment of neurodegenerative diseases that involve neuroinflammation. We used the most common animal model for multiple sclerosis (MS, mice experimental autoimmune encephalomyelitis (EAE. The main challenges to overcome are the drugs' unfavorable pharmacokinetics and biodistribution, which result in inadequate therapeutic efficacy and in drug toxicity (due to high and repeated dosage. We designed two different liposomal nano-drugs, i.e., nano sterically stabilized liposomes (NSSL, remote loaded with: (a a "water-soluble" amphipathic weak acid glucocorticosteroid prodrug, methylprednisolone hemisuccinate (MPS or (b the amphipathic weak base nitroxide, Tempamine (TMN. For the NSSL-MPS we also compared the effect of passive targeting alone and of active targeting based on short peptide fragments of ApoE or of β-amyloid. Our results clearly show that for NSSL-MPS, active targeting is not superior to passive targeting. For the NSSL-MPS and the NSSL-TMN it was demonstrated that these nano-drugs ameliorate the clinical signs and the pathology of EAE. We have further investigated the MPS nano-drug's therapeutic efficacy and its mechanism of action in both the acute and the adoptive transfer EAE models, as well as optimizing the perfomance of the TMN nano-drug. The highly efficacious anti-inflammatory therapeutic feature of these two nano-drugs meets the criteria of disease-modifying drugs and supports further development and evaluation of these nano-drugs as potential therapeutic agents for diseases with an inflammatory component.

  2. Mechanisms of Oxidative Damage in Multiple Sclerosis and Neurodegenerative Diseases: Therapeutic Modulation via Fumaric Acid Esters

    Ralf Gold

    2012-09-01

    Full Text Available Oxidative stress plays a crucial role in many neurodegenerative conditions such as Alzheimer’s disease, amyotrophic lateral sclerosis and Parkinson’s as well as Huntington’s disease. Inflammation and oxidative stress are also thought to promote tissue damage in multiple sclerosis (MS. Recent data point at an important role of anti-oxidative pathways for tissue protection in chronic-progressive MS, particularly involving the transcription factor nuclear factor (erythroid-derived 2-related factor 2 (Nrf2. Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for MS treatment. Here, fumaric acid esters (FAE are a new, orally available treatment option which had already been tested in phase II/III MS trials demonstrating beneficial effects on relapse rates and magnetic resonance imaging markers. In vitro, application of dimethylfumarate (DMF leads to stabilization of Nrf2, activation of Nrf2-dependent transcriptional activity and abundant synthesis of detoxifying proteins. Furthermore, application of FAE involves direct modification of the inhibitor of Nrf2, Kelch-like ECH-associated protein 1. On cellular levels, the application of FAE enhances neuronal survival and protects astrocytes against oxidative stress. Increased levels of Nrf2 are detected in the central nervous system of DMF treated mice suffering from experimental autoimmune encephalomyelitis (EAE, an animal model of MS. In EAE, DMF ameliorates the disease course and improves preservation of myelin, axons and neurons. Finally, Nrf2 is also up-regulated in the spinal cord of autopsy specimens from untreated patients with MS, probably as part of a naturally occurring anti-oxidative response. In summary, oxidative stress and anti-oxidative pathways are important players in MS pathophysiology and constitute a promising target for future MS therapies like FAE.

  3. Visual saliency maps for studies of behavior of patients with neurodegenerative diseases: Observer's versus Actor's points of view

    Boujut, Hugo; Buso, Vincent; Benois-Pineau, Jenny; Gaëstel, Yann; Dartigues, Jean-François

    2013-01-01

    We are interested in finding the relation between the visual saliency maps of the viewer of visual content and the actors (person executing the actions) in the context of studies of neurodegenerative diseases such as Alzheimer's disease. From results of eye-trackers worn by the actors and used when recording observers, and on the basis of hand-eye interactions from motor control studies we established a time shift between actor's and viewer's saliency maps. This time shift corresponds to the ...

  4. Plasma-Enabled Carbon Nanostructures for Early Diagnosis of Neurodegenerative Diseases

    Shafique Pineda

    2014-06-01

    Full Text Available Carbon nanostructures (CNs are amongst the most promising biorecognition nanomaterials due to their unprecedented optical, electrical and structural properties. As such, CNs may be harnessed to tackle the detrimental public health and socio-economic adversities associated with neurodegenerative diseases (NDs. In particular, CNs may be tailored for a specific determination of biomarkers indicative of NDs. However, the realization of such a biosensor represents a significant technological challenge in the uniform fabrication of CNs with outstanding qualities in order to facilitate a highly-sensitive detection of biomarkers suspended in complex biological environments. Notably, the versatility of plasma-based techniques for the synthesis and surface modification of CNs may be embraced to optimize the biorecognition performance and capabilities. This review surveys the recent advances in CN-based biosensors, and highlights the benefits of plasma-processing techniques to enable, enhance, and tailor the performance and optimize the fabrication of CNs, towards the construction of biosensors with unparalleled performance for the early diagnosis of NDs, via a plethora of energy-efficient, environmentally-benign, and inexpensive approaches.

  5. Specific transfection of inflamed brain by macrophages: a new therapeutic strategy for neurodegenerative diseases.

    Matthew J Haney

    Full Text Available The ability to precisely upregulate genes in inflamed brain holds great therapeutic promise. Here we report a novel class of vectors, genetically modified macrophages that carry reporter and therapeutic genes to neural cells. Systemic administration of macrophages transfected ex vivo with a plasmid DNA (pDNA encoding a potent antioxidant enzyme, catalase, produced month-long expression levels of catalase in the brain resulting in three-fold reductions in inflammation and complete neuroprotection in mouse models of Parkinson's disease (PD. This resulted in significant improvements in motor functions in PD mice. Mechanistic studies revealed that transfected macrophages secreted extracellular vesicles, exosomes, packed with catalase genetic material, pDNA and mRNA, active catalase, and NF-κb, a transcription factor involved in the encoded gene expression. Exosomes efficiently transfer their contents to contiguous neurons resulting in de novo protein synthesis in target cells. Thus, genetically modified macrophages serve as a highly efficient system for reproduction, packaging, and targeted gene and drug delivery to treat inflammatory and neurodegenerative disorders.

  6. Nanoparticle-mediated brain drug delivery: Overcoming blood-brain barrier to treat neurodegenerative diseases.

    Saraiva, Cláudia; Praça, Catarina; Ferreira, Raquel; Santos, Tiago; Ferreira, Lino; Bernardino, Liliana

    2016-08-10

    The blood-brain barrier (BBB) is a vital boundary between neural tissue and circulating blood. The BBB's unique and protective features control brain homeostasis as well as ion and molecule movement. Failure in maintaining any of these components results in the breakdown of this specialized multicellular structure and consequently promotes neuroinflammation and neurodegeneration. In several high incidence pathologies such as stroke, Alzheimer's (AD) and Parkinson's disease (PD) the BBB is impaired. However, even a damaged and more permeable BBB can pose serious challenges to drug delivery into the brain. The use of nanoparticle (NP) formulations able to encapsulate molecules with therapeutic value, while targeting specific transport processes in the brain vasculature, may enhance drug transport through the BBB in neurodegenerative/ischemic disorders and target relevant regions in the brain for regenerative processes. In this review, we will discuss BBB composition and characteristics and how these features are altered in pathology, namely in stroke, AD and PD. Additionally, factors influencing an efficient intravenous delivery of polymeric and inorganic NPs into the brain as well as NP-related delivery systems with the most promising functional outcomes will also be discussed. PMID:27208862

  7. The influence of Na+,K+-ATPase on glutamate signaling in neurodegenerative diseases and senescence

    Paula Fernanda Kinoshita

    2016-06-01

    Full Text Available Decreased Na+,K+-ATPase (NKA activity causes energy deficiency, which is commonly observed in neurodegenerative diseases. The NKA is constituted of three subunits: α, β and γ, with four distinct isoforms of the catalytic α subunit (α1-4. Genetic mutations in the ATP1A2 gene and ATP1A3 gene, encoding the α2 and α3 subunit isoforms, respectively can cause distinct neurological disorders, concurrent to impaired NKA activity. Within the central nervous system (CNS, the α2 isoform is expressed mostly in glial cells and the α3 isoform is neuron-specific. Mutations in ATP1A2 gene can result in familial hemiplegic migraine (FHM2, while mutations in the ATP1A3 gene can cause Rapid-onset dystonia-Parkinsonism (RDP and alternating hemiplegia of childhood (AHC, as well as the cerebellar ataxia, areflexia, pescavus, optic atrophy and sensorineural hearing loss (CAPOS syndrome. Data indicates that the central glutamatergic system is affected by mutations in the α2 isoform, however further investigations are required to establish a connection to mutations in the α3 isoform, especially given the diagnostic confusion and overlap with glutamate transporter disease. The age-related decline in brain α2/3 activity may arise from changes in the cyclic guanosine monophosphate (cGMP and cGMP‐dependent protein kinase (PKG pathway. Glutamate, through nitric oxide synthase (NOS, cGMP and PKG, stimulates brain α2/3 activity, with the glutamatergic N-methyl-D-aspartate (NMDA receptor cascade able to drive an adaptive, neuroprotective response to inflammatory and challenging stimuli, including amyloid‐β. Here we review the NKA, both as an ion pump as well as a receptor that interacts with NMDA, including the role of NKA subunits mutations. Failure of the NKA-associated adaptive response mechanisms may render neurons more susceptible to degeneration over the course of aging.

  8. Diffusion tensor magnetic resonance imaging in the analysis of neurodegenerative diseases.

    Müller, Hans-Peter; Kassubek, Jan

    2013-01-01

    Diffusion tensor imaging (DTI) techniques provide information on the microstructural processes of the cerebral white matter (WM) in vivo. The present applications are designed to investigate differences of WM involvement patterns in different brain diseases, especially neurodegenerative disorders, by use of different DTI analyses in comparison with matched controls. DTI data analysis is performed in a variate fashion, i.e. voxelwise comparison of regional diffusion direction-based metrics such as fractional anisotropy (FA), together with fiber tracking (FT) accompanied by tractwise fractional anisotropy statistics (TFAS) at the group level in order to identify differences in FA along WM structures, aiming at the definition of regional patterns of WM alterations at the group level. Transformation into a stereotaxic standard space is a prerequisite for group studies and requires thorough data processing to preserve directional inter-dependencies. The present applications show optimized technical approaches for this preservation of quantitative and directional information during spatial normalization in data analyses at the group level. On this basis, FT techniques can be applied to group averaged data in order to quantify metrics information as defined by FT. Additionally, application of DTI methods, i.e. differences in FA-maps after stereotaxic alignment, in a longitudinal analysis at an individual subject basis reveal information about the progression of neurological disorders. Further quality improvement of DTI based results can be obtained during preprocessing by application of a controlled elimination of gradient directions with high noise levels. In summary, DTI is used to define a distinct WM pathoanatomy of different brain diseases by the combination of whole brain-based and tract-based DTI analysis. PMID:23928996

  9. A new look at auranoifn, dextromethorphan and rosiglitazone for reduction of glia-mediated inlfammation in neurodegenerative diseases

    Jocelyn M. Madeira; Stephanie M. Schindler; Andis Klegeris

    2015-01-01

    Neurodegenerative disorders including Alzheimer’s disease are characterized by chronic in-lfammation in the central nervous system. The two main glial types involved in inlfammatory reactions are microglia and astrocytes. While these cells normally protect neurons by providing nutrients and growth factors, disease speciifc stimuli can induce glial secretion of neurotoxins. It has been hypothesized that reducing glia-mediated inlfammation could diminish neuronal loss. This hypothesis is supported by observations that chronic use of non-steroidal anti-inlfamma-tory drugs (NSAIDs) is linked with lower incidences of neurodegenerative disease. It is possible that the NSAIDs are not potent enough to appreciably reduce chronic neuroinlfammation after disease processes are fully established. Gold thiol compounds, including auranoifn, comprise an-other class of medications effective at reducing peripheral inlfammation. We have demonstrated that auranofin inhibits human microglia- and astrocyte-mediated neurotoxicity. Other drugs which are currently used to treat peripheral inlfammatory conditions could be helpful in neu-rodegenerative disease. Three different classes of anti-inlfammatory compounds, which have a potential to inhibit neuroinlfammation are highlighted below.

  10. A new look at auranofin, dextromethorphan and rosiglitazone for reduction of glia-mediated inflammation in neurodegenerative diseases

    Jocelyn M Madeira

    2015-01-01

    Full Text Available Neurodegenerative disorders including Alzheimer′s disease are characterized by chronic inflammation in the central nervous system. The two main glial types involved in inflammatory reactions are microglia and astrocytes. While these cells normally protect neurons by providing nutrients and growth factors, disease specific stimuli can induce glial secretion of neurotoxins. It has been hypothesized that reducing glia-mediated inflammation could diminish neuronal loss. This hypothesis is supported by observations that chronic use of non-steroidal anti-inflammatory drugs (NSAIDs is linked with lower incidences of neurodegenerative disease. It is possible that the NSAIDs are not potent enough to appreciably reduce chronic neuroinflammation after disease processes are fully established. Gold thiol compounds, including auranofin, comprise another class of medications effective at reducing peripheral inflammation. We have demonstrated that auranofin inhibits human microglia- and astrocyte-mediated neurotoxicity. Other drugs which are currently used to treat peripheral inflammatory conditions could be helpful in neurodegenerative disease. Three different classes of anti-inflammatory compounds, which have a potential to inhibit neuroinflammation are highlighted below.

  11. Structural elucidation of the interaction between neurodegenerative disease-related tau protein with model lipid membranes

    Jones, Emmalee M.

    A protein's sequence of amino acids determines how it folds. That folded structure is linked to protein function, and misfolding to dysfunction. Protein misfolding and aggregation into beta-sheet rich fibrillar aggregates is connected with over 20 neurodegenerative diseases, including Alzheimer's disease (AD). AD is characterized in part by misfolding, aggregation and deposition of the microtubule associated tau protein into neurofibrillary tangles (NFTs). However, two questions remain: What is tau's fibrillization mechanism, and what is tau's cytotoxicity mechanism? Tau is prone to heterogeneous interactions, including with lipid membranes. Lipids have been found in NFTs, anionic lipid vesicles induced aggregation of the microtubule binding domain of tau, and other protein aggregates induced ion permeability in cells. This evidence prompted our investigation of tau's interaction with model lipid membranes to elucidate the structural perturbations those interactions induced in tau protein and in the membrane. We show that although tau is highly charged and soluble, it is highly surface active and preferentially interacts with anionic membranes. To resolve molecular-scale structural details of tau and model membranes, we utilized X-ray and neutron scattering techniques. X-ray reflectivity indicated tau aggregated at air/water and anionic lipid membrane interfaces and penetrated into membranes. More significantly, membrane interfaces induced tau protein to partially adopt a more compact conformation with density similar to folded protein and ordered structure characteristic of beta-sheet formation. This suggests possible membrane-based mechanisms of tau aggregation. Membrane morphological changes were seen using fluorescence microscopy, and X-ray scattering techniques showed tau completely disrupts anionic membranes, suggesting an aggregate-based cytotoxicity mechanism. Further investigation of protein constructs and a "hyperphosphorylation" disease mimic helped

  12. Improvement of Oxidative and Metabolic Parameters by Cellfood Administration in Patients Affected by Neurodegenerative Diseases on Chelation Treatment

    Alessandro Fulgenzi; Rachele De Giuseppe; Fabrizia Bamonti; Maria Elena Ferrero

    2014-01-01

    Objective. This prospective pilot study aimed at evaluating the effects of therapy with antioxidant compounds (Cellfood, and other antioxidants) on patients affected by neurodegenerative diseases (ND), who displayed toxic metal burden and were subjected to chelation treatment with the chelating agent calcium disodium ethylenediaminetetraacetic acid (CaNa2EDTA or EDTA). Methods. Two groups of subjects were studied: (a) 39 patients affected by ND and (b) 11 subjects unaffected by ND (controls)....

  13. Reaction time impairments in decision-making networks as a diagnostic marker for traumatic brain injuries and neurodegenerative diseases

    Maia, Pedro D; Kutz, J Nathan

    2016-01-01

    The presence of diffuse Focal Axonal Swellings (FAS) is a hallmark cellular feature in many neurodegenerative diseases and traumatic brain injury. Among other things, the FAS have a significant impact on spike-train encodings that propagate through the affected neurons, leading to compromised signal processing on a neuronal network level. This work merges, for the first time, three fields of study: (i) signal processing in excitatory-inhibitory (EI) networks of neurons via population codes, (...

  14. Why are the neurodegenerative disease-related pathways overrepresented in primary HIV-infected peripheral blood mononuclear cells: a genome-wide perspective

    Zhou Li; Conceicao Viviane; Gupta Priyanka; Saksena Nitin K

    2012-01-01

    Abstract We demonstrate for the first time that the genome-wide profiling of HIV-infected peripheral blood mononuclear cells (PBMCs) from HIV-patients free of neurologic disease show overrepresentation of neurodegenerative pathways (Alzheimer’s, Parkinson’s, ALS, Huntington’s and Prion Disease, etc.) in genome-wide microarray analysis, which suggests that this genome-wide representation of neurodegenerative diseases-related pathways in PBMCs could possibly be a subcellular manifestation of ne...

  15. Specific reduction of calcium-binding protein (28-kilodalton calbindin-D) gene expression in aging and neurodegenerative diseases

    The present studies establish that there are specific, significant decreases in the neuronal calcium-binding protein (28-kDa calbindin-D) gene expression in aging and in neurodegenerative diseases. The specificity of the changes observed in calbindin mRNA levels was tested by reprobing blots with calmodulin, cyclophilin, and B-actin cDNAs. Gross brain regions of the aging rat exhibited specific, significant decreases in calbindin·mRNA and protein levels in the cerebellum, corpus striatum, and brain-stem region but not in the cerebral cortex or hippocampus. Discrete areas of the aging human brain exhibited significant decreases in calbindin protein and mRNA in the cerebellum, corpus striatum, and nucleus basalis but not in the neocortex, hippocampus, amygdala, locus ceruleus, or nucleus raphe dorsalis. Comparison of diseased human brain tissue with age- and sex-matched controls yielded significant decreases calbindin protein and mRNA in the substantia nigra (Parkinson disease), in the corpus striatum (Huntington disease), in the nucleus basalis (Alzheimer disease), and in the hippocampus and nucleus raphe dorsalis (Parkinson, Huntington, and Alzheimer diseases) but not in the cerebellum, neocortex, amygdala, or locus ceruleus. These findings suggest that decreased calbindin gene expression may lead to a failure of calcium buffering or intraneuronal calcium homeostasis, which contributes to calcium-mediated cytotoxic events during aging and in the pathogenesis of neurodegenerative diseases

  16. The Mircen project, neuro-degenerative disease: mechanisms, therapeutics and imaging research Unit URA Cea Cnrs 2210

    During the post-genomic era, significant advances in our understanding of the molecular basis of disease have been made. The power of functional and molecular imaging in translating this knowledge into effective therapy is now being more and more recognized. Thus, molecular imaging plays a vital role in the early identification of disease-related molecular markers, in the development of molecular-targeted therapies, and in monitoring phenotypic response to therapy both in experimental animals and in human patients. In this context, MIRCen (acronym for Molecular Imaging Research Center ) provides a comprehensive resource available to empower basic, translational, and clinical research through the application of imaging and drug, cell, and gene based technologies. The MIR center will be dedicated to the development of pre-clinical trials for the treatment of various seriously debilitating diseases such as neuro-degenerative diseases, cardiac and hepatic disorders, and infectious diseases (AIDS). Despite the fact that many of these pathologies are still incurable, recent advances in drug, cell and gene therapy point to the feasibility of new therapeutic approaches. The long term goals of MIRCen are therefore to develop and validate: - pertinent animal models for neuro-degenerative, hepatic, cardiac and infectious diseases in rodents as well as non-human primates, - novel technologies for in vivo sensing and imaging of disease-related molecular events,- drug, gene and cell based palliative and or curative therapeutic strategies aiming at protecting and /or restoring damaged or lost functions. (author)

  17. A review on the cause-effect relationship between oxidative stress and toxic proteins in the pathogenesis of neurodegenerative diseases.

    Borza, Liana Rada

    2014-01-01

    Protein aggregates are the defining pathological feature of human neurodegenerative diseases. Studies have revealed that mutant huntingtin, polyglutamine-expanded ataxin-1 and ataxin-3 can cause elevated levels of reactive oxygen species in neuronal cells. It has also been indicated that the normal host prion protein behaves as an antioxidant, while the neurotoxic peptide based on the sequence of the scrapie isoform increases hydrogen peroxide toxicity in neuronal cultures. Additionally, not only can oxidative stress contribute to the aggregation of beta-amyloid and alpha-synuclein, but both beta-amyloid and alpha-synuclein can induce oxidative damage. Furthermore, oxidative stressors have been shown to play a critical role in neurofibrillary pathology leading to tau hyperphosphorylation. In conclusion, the present review supports a cause-effect relationship between oxidative stress and toxic proteins in the pathogenesis of neurodegenerative disorders. PMID:24741770

  18. Technologies enabling autologous neural stem cell-based therapies for neurodegenerative disease and injury

    Bakhru, Sasha H.

    The intrinsic abilities of mammalian neural stem cells (NSCs) to self-renew, migrate over large distances, and give rise to all primary neural cell types of the brain offer unprecedented opportunity for cell-based treatment of neurodegenerative diseases and injuries. This thesis discusses development of technologies in support of autologous NSC-based therapies, encompassing harvest of brain tissue biopsies from living human patients; isolation of NSCs from harvested tissue; efficient culture and expansion of NSCs in 3D polymeric microcapsule culture systems; optimization of microcapsules as carriers for efficient in vivo delivery of NSCs; genetic engineering of NSCs for drug-induced, enzymatic release of transplanted NSCs from microcapsules; genetic engineering for drug-induced differentiation of NSCs into specific therapeutic cell types; and synthesis of chitosan/iron-oxide nanoparticles for labeling of NSCs and in vivo tracking by cellular MRI. Sub-millimeter scale tissue samples were harvested endoscopically from subventricular zone regions of living patient brains, secondary to neurosurgical procedures including endoscopic third ventriculostomy and ventriculoperitoneal shunt placement. On average, 12,000 +/- 3,000 NSCs were isolated per mm 3 of subventricular zone tissue, successfully demonstrated in 26 of 28 patients, ranging in age from one month to 68 years. In order to achieve efficient expansion of isolated NSCs to clinically relevant numbers (e.g. hundreds of thousands of cells in Parkinson's disease and tens of millions of cells in multiple sclerosis), an extracellular matrix-inspired, microcapsule-based culture platform was developed. Initial culture experiments with murine NSCs yielded unprecedented expansion folds of 30x in 5 days, from initially minute NSC populations (154 +/- 15 NSCs per 450 mum diameter capsule). Within 7 days, NSCs expanded as almost perfectly homogenous populations, with 94.9% +/- 4.1% of cultured cells staining positive for

  19. Mouse models rarely mimic the transcriptome of human neurodegenerative diseases: A systematic bioinformatics-based critique of preclinical models.

    Burns, Terry C; Li, Matthew D; Mehta, Swapnil; Awad, Ahmed J; Morgan, Alexander A

    2015-07-15

    Translational research for neurodegenerative disease depends intimately upon animal models. Unfortunately, promising therapies developed using mouse models mostly fail in clinical trials, highlighting uncertainty about how well mouse models mimic human neurodegenerative disease at the molecular level. We compared the transcriptional signature of neurodegeneration in mouse models of Alzheimer׳s disease (AD), Parkinson׳s disease (PD), Huntington׳s disease (HD) and amyotrophic lateral sclerosis (ALS) to human disease. In contrast to aging, which demonstrated a conserved transcriptome between humans and mice, only 3 of 19 animal models showed significant enrichment for gene sets comprising the most dysregulated up- and down-regulated human genes. Spearman׳s correlation analysis revealed even healthy human aging to be more closely related to human neurodegeneration than any mouse model of AD, PD, ALS or HD. Remarkably, mouse models frequently upregulated stress response genes that were consistently downregulated in human diseases. Among potential alternate models of neurodegeneration, mouse prion disease outperformed all other disease-specific models. Even among the best available animal models, conserved differences between mouse and human transcriptomes were found across multiple animal model versus human disease comparisons, surprisingly, even including aging. Relative to mouse models, mouse disease signatures demonstrated consistent trends toward preserved mitochondrial function protein catabolism, DNA repair responses, and chromatin maintenance. These findings suggest a more complex and multifactorial pathophysiology in human neurodegeneration than is captured through standard animal models, and suggest that even among conserved physiological processes such as aging, mice are less prone to exhibit neurodegeneration-like changes. This work may help explain the poor track record of mouse-based translational therapies for neurodegeneration and provides a path

  20. Breaking peripheral immune tolerance to CNS antigens in neurodegenerative diseases: boosting autoimmunity to fight-off chronic neuroinflammation.

    Schwartz, Michal; Baruch, Kuti

    2014-11-01

    Immune cell infiltration to the brain's territory was considered for decades to reflect a pathological process in which immune cells attack the central nervous system (CNS); such a process is observed in the inflammatory autoimmune disease, multiple sclerosis (MS). As neuroinflammatory processes within the CNS parenchyma are also common to other CNS pathologies, regardless of their etiology, including neurodegenerative disorders such as Alzheimer's disease (AD) and Amyotrophic lateral sclerosis (ALS), these pathologies have often been compared to MS, a disease that benefits from immunosuppressive therapy. Yet, over the last decade, it became clear that autoimmunity has a bright side, and that it plays a pivotal role in CNS repair following damage. Specifically, autoimmune T cells were found to facilitate CNS healing processes, such as in the case of sterile mechanical injuries to the brain or the spinal cord, mental stress, or biochemical insults. Even more intriguingly, autoimmune T cells were found to be involved in supporting fundamental processes of brain functional integrity, such as in the maintenance of life-long brain plasticity, including spatial learning and memory, and neurogenesis. Importantly, autoimmune T cells are part of a cellular network which, to operate efficiently and safely, requires tight regulation by other immune cell populations, such as regulatory T cells, which are indispensable for maintenance of immunological self-tolerance and homeostasis. Here, we suggest that dysregulation of the balance between peripheral immune suppression, on one hand, and protective autoimmunity, on the other, is an underlying mechanism in the emergence and progression of the neuroinflammatory response associated with chronic neurodegenerative diseases and brain aging. Mitigating chronic neuroinflammation under these conditions necessitates activation, rather than suppression, of the peripheral immune response directed against self. Accordingly, we propose that

  1. Blood-Brain Barrier and Breast Cancer Resistance Protein: A Limit to the Therapy of CNS Tumors and Neurodegenerative Diseases

    Iorio, Anna Lisa; da Ros, Martina; Fantappiè, Ornella; Lucchesi, Maurizio; Facchini, Ludovica; Stival, Alessia; Becciani, Sabrina; Guidi, Milena; Favre, Claudio; de Martino, Maurizio; Genitori, Lorenzo; Sardi, Iacopo

    2016-01-01

    The treatment of brain tumors and neurodegenerative diseases, represents an ongoing challenge. In Central Nervous System (CNS) the achievement of therapeutic concentration of chemical agents is complicated by the presence of distinct set of efflux proteins, such as ATP-Binding Cassette (ABC) transporters localized on the Blood-Brain Barrier (BBB). The activity of ABC transporters seems to be a common mechanism that underlies the poor response of CNS diseases to therapies. The molecular characterization of Breast Cancer Resistance Protein (BCRP/ABCG2), as an ABC transporter conferring multidrug resistance (MDR), has stimulated many studies to investigate its activity on the BBB, its involvement in physiology and CNS diseases and its role in limiting the delivery of drugs in CNS. In this review, we highlight the activity and localization of BCRP on the BBB and the action that this efflux pump has on many conventional drugs or latest generation molecules used for the treatment of CNS tumors and other neurodegenerative diseases. PMID:26584727

  2. Toxicity mechanisms of arsenic that are shared with neurodegenerative diseases and cognitive impairment: Role of oxidative stress and inflammatory responses.

    Escudero-Lourdes, Claudia

    2016-03-01

    Arsenic (As) is a worldwide naturally occurring metalloid. Human chronic exposure to inorganic As compounds (iAs), which are at the top of hazardous substances (ATSDR, 2013), is associated with different diseases including cancer and non- cancerous diseases. The neurotoxic effects of iAs and its methylated metabolites have been demonstrated in exposed populations and experimental models. Impaired cognitive abilities have been described in children and adults chronically exposed to iAs through drinking water. Even though different association studies failed to demonstrate that As causes neurodegenerative diseases, several toxicity mechanisms of iAs parallel those mechanisms associated with neurodegeneration, including oxidative stress and inflammation, impaired protein degradation, autophagy, and intracellular accumulation, endoplasmic reticulum stress, and mitochondrial dysfunction. Additionally, different reports have shown that specifically in brain tissue, iAs and its metabolites induce hyper-phosphorylation of the tau protein and over-regulation of the amyloid precursor protein, impaired neurotransmitters synthesis and synaptic transmission, increased glutamate receptors activation, and decreased glutamate transporters expression. Interestingly, increased and sustained pro-inflammatory responses mediated by cytokines and related factors, seems to be the triggering factor for all of such cellular pathological effects. Therefore, this review proposes that iAs-associated cognitive impairment could be the result of the activation of pro-inflammatory responses in the brain tissue, which also may favor neurodegeneration or increase the risk for neurodegenerative diseases in exposed human populations. PMID:26868456

  3. Low-level laser therapy regulates microglial function through Src-mediated signaling pathways: implications for neurodegenerative diseases

    Song Sheng; Zhou Feifan; Chen Wei R

    2012-01-01

    Abstract Background Activated microglial cells are an important pathological component in brains of patients with neurodegenerative diseases. The purpose of this study was to investigate the effect of He-Ne (632.8 nm, 64.6 mW/cm2) low-level laser therapy (LLLT), a non-damaging physical therapy, on activated microglia, and the subsequent signaling events of LLLT-induced neuroprotective effects and phagocytic responses. Methods To model microglial activation, we treated the microglial BV2 cells...

  4. Modulation of heat shock transcription factor 1 as a therapeutic target for small molecule intervention in neurodegenerative disease.

    Daniel W Neef

    2010-01-01

    Full Text Available Neurodegenerative diseases such as Huntington disease are devastating disorders with no therapeutic approaches to ameliorate the underlying protein misfolding defect inherent to poly-glutamine (polyQ proteins. Given the mounting evidence that elevated levels of protein chaperones suppress polyQ protein misfolding, the master regulator of protein chaperone gene transcription, HSF1, is an attractive target for small molecule intervention. We describe a humanized yeast-based high-throughput screen to identify small molecule activators of human HSF1. This screen is insensitive to previously characterized activators of the heat shock response that have undesirable proteotoxic activity or that inhibit Hsp90, the central chaperone for cellular signaling and proliferation. A molecule identified in this screen, HSF1A, is structurally distinct from other characterized small molecule human HSF1 activators, activates HSF1 in mammalian and fly cells, elevates protein chaperone expression, ameliorates protein misfolding and cell death in polyQ-expressing neuronal precursor cells and protects against cytotoxicity in a fly model of polyQ-mediated neurodegeneration. In addition, we show that HSF1A interacts with components of the TRiC/CCT complex, suggesting a potentially novel regulatory role for this complex in modulating HSF1 activity. These studies describe a novel approach for the identification of new classes of pharmacological interventions for protein misfolding that underlies devastating neurodegenerative disease.

  5. Emerging bioinformatics approaches for analysis of NGS-derived coding and non-coding RNAs in neurodegenerative diseases

    Alessandro Guffanti

    2014-03-01

    Full Text Available Neurodegenerative diseases such as late-onset Alzheimer’s disease (LOAD involve a genetically complex and still obscure ensemble of causative and risk factors accompanied by complex feedback responses. The advent of ‘high-throughput’ transcriptome investigation technologies such as deep sequecing is increasingly being combined with statistical and bioinformatics analysis methods complemented by Bayesian Networks or network and graph analyses. Together, such 'integrative' studies are beginning to identify co-regulated gene networks linked with biological pathways and potentially modulating disease predisposition, outcome and progression. Specifically, bioinformatics analyses of integrated microarray and genotyping data in cases and controls reveal changes in gene expression of both protein-coding and small and long regulatory RNAs; highlight relevant quantitative transcriptional differences between LOAD and non-demented control brains and demonstrate reconfiguration of functionally meaningful molecular interaction structures in LOAD. These may be measured as changes in connectivity in ‘hub nodes’ of relevant gene networks. We illustrate here the open analytical questions in the transcriptome investigation of neurodegenerative disease studies, proposing 'ad-hoc' strategies for the evaluation of differential gene expression and hints for a simple analysis of the ncRNA part of such datasets. We then survey the emerging role of long non-coding RNA in the healthy and diseased brain transcriptome and describe the main current methods for computational modeling of gene networks. We propose accessible modular and pathway-oriented methods and guidelines for bioinformatics investigations of whole transcriptome NGS datasets. We finally present methods and databases for functional interpretations of long ncRNAs and propose a simple heuristic approach to visualize and represent physical and and functional interactions of the coding and non

  6. A missense change in the ATG4D gene links aberrant autophagy to a neurodegenerative vacuolar storage disease.

    Kaisa Kyöstilä

    2015-04-01

    Full Text Available Inherited neurodegenerative disorders are debilitating diseases that occur across different species. We have performed clinical, pathological and genetic studies to characterize a novel canine neurodegenerative disease present in the Lagotto Romagnolo dog breed. Affected dogs suffer from progressive cerebellar ataxia, sometimes accompanied by episodic nystagmus and behavioral changes. Histological examination revealed unique pathological changes, including profound neuronal cytoplasmic vacuolization in the nervous system, as well as spheroid formation and cytoplasmic aggregation of vacuoles in secretory epithelial tissues and mesenchymal cells. Genetic analyses uncovered a missense change, c.1288G>A; p.A430T, in the autophagy-related ATG4D gene on canine chromosome 20 with a highly significant disease association (p = 3.8 x 10-136 in a cohort of more than 2300 Lagotto Romagnolo dogs. ATG4D encodes a poorly characterized cysteine protease belonging to the macroautophagy pathway. Accordingly, our histological analyses indicated altered autophagic flux in affected tissues. The knockdown of the zebrafish homologue atg4da resulted in a widespread developmental disturbance and neurodegeneration in the central nervous system. Our study describes a previously unknown canine neurological disease with particular pathological features and implicates the ATG4D protein as an important autophagy mediator in neuronal homeostasis. The canine phenotype serves as a model to delineate the disease-causing pathological mechanism(s and ATG4D function, and can also be used to explore treatment options. Furthermore, our results reveal a novel candidate gene for human neurodegeneration and enable the development of a genetic test for veterinary diagnostic and breeding purposes.

  7. Bullous pemphigoid and neurodegenerative diseases: a study in a setting of a Central European university dermatology department.

    Pietkiewicz, Paweł; Gornowicz-Porowska, Justyna; Bowszyc-Dmochowska, Monika; Bartkiewicz, Paweł; Dmochowski, Marian

    2016-08-01

    Bullous pemphigoid (BP) is an autoimmune blistering dermatosis of the elderly mediated by IgG and IgE antibodies to skin hemidesmosomal proteins, BP180 and/or BP230, that occur physiologically also in neuronal tissue. It was reported that BP is associated with neurodegenerative diseases (ND). We performed a retrospective study in a setting of a Central European university dermatology department on prevalence of ND in 94 BP patients. 26 out of 94 BP patients had at least one ND. ND included: Parkinson's disease, dementia, stroke, hear loss, tinnitus, blindness, vertigo, neurosyphilis, systemic sclerosis, and epilepsy. Since population aging is conceivably responsible for the rising number of BP cases as a result of immunosenescence-related phenomena, the plausible BP-specific immunopathogenetic relationship between BP and ND deserves to be further experimentally explored. PMID:26420424

  8. Copy number variation analysis of the 17q21.31 region and its role in neurodegenerative diseases.

    Cervera-Carles, Laura; Pagonabarraga, Javier; Pascual-Sedano, Berta; Pastor, Pau; Campolongo, Antonia; Fortea, Juan; Blesa, Rafael; Alcolea, Daniel; Morenas-Rodríguez, Estrella; Sala, Isabel; Lleó, Alberto; Kulisevsky, Jaime; Clarimón, Jordi

    2016-03-01

    The H1 haplotype of the 17q21.31 inversion polymorphism has been consistently associated with progressive supranuclear palsy, corticobasal degeneration, and Parkinson's disease in Caucasians. Recently, large polymorphic segmental duplications resulting into complex rearrangements at this locus with a high diversity range in human populations have been revealed. We sought to explore whether the two multi-allelic copy number variants that are present in the H1 clade (with segmental duplications of 300 and 218 kilobases in length) could be responsible for the known H1-related risk of developing these neurodegenerative disorders. A total of 857 Spanish subjects including 330 patients with Parkinson's disease, 96 with progressive supranuclear palsy, 55 with corticobasal degeneration, 51 dementia with Lewy bodies, and 325 neurologically healthy controls, were genotyped for the H1/H2 haplotype. Subsequently, the two copy number variants that are characteristic of the H1 haplotype were evaluated through a high-resolution approach based on droplet digital polymerase chain reaction, in all H1 homozygous subjects. The H1 allele was significantly overrepresented in all diagnostic groups compared with controls (Parkinson's disease, P = 0.0001; progressive supranuclear palsy, P = 1.22 × 10(-6) ; corticobasal degeneration, P = 0.0002; and dementia with Lewy bodies, P = 0.032). However, no dosage differences were found for any of the two copy number variants analyzed. The H1 haplotype is associated with the risk of several neurodegenerative disorders, including dementia with Lewy bodies. However, common structural diversity within the 17q21.31-H1 clade does not explain this genetic association. © 2015 Wiley Periodicals, Inc. PMID:26453547

  9. Diffusion tensor imaging of the cortico-ponto-cerebellar pathway in patients with adult-onset ataxic neurodegenerative disease

    Kitamura, Kaeko; Nakayama, Keiko; Yamada, Eiji; Inoue, Yuichi [Osaka City University Graduate School of Medicine, Department of Radiology, Osaka (Japan); Kosaka, Satoru; Shimada, Hiroyuki; Miki, Takami [Osaka City University Graduate School of Medicine, Department of Neurology, Osaka (Japan)

    2008-04-15

    We sought to determine whether diffusion-tensor imaging (DTI) can detect in vivo axonal damage in the corticopontocerebellar pathway of patients with adult-onset ataxic neurodegenerative disease. Conventional MRI and DTI were performed on 18 patients with adult-onset ataxic neurodegenerative disease and 28 age-matched control subjects. Fractional anisotropy (FA) and the mean diffusivity (MD) were measured in the ventral, central, and dorsal pons, middle cerebellar peduncle (MCP) and internal capsule to evaluate corticopontocerebellar projection. Changes in FA and MD values were compared between patients and controls. Clinical disability was assessed according to the International Cooperative Ataxia Rating Scale (ICARS). The relationship between DTI measurements and ICARS was studied. Follow-up MRI was performed in five patients approximately 1 year later. FA values were significantly lower in the ventral and central portions of the pons, MCP, and internal capsules than in these areas in control subjects (P < 0.05) with the lower FA values correlating with poorer ICARS (r > -0.57, P < 0.05). MD values were elevated in these areas, but the differences were smaller than for the FA values. No relationship was observed between the MD and ICARS. In the five patients who underwent the follow-up study, there were significant decreases between the initial study and the follow-up DTI study for FA in the MCP and internal capsule (P < 0.05). DTI can demonstrate a degenerated corticopontocerebellar pathway in patients, and FA values can be correlated with ataxia severity. DTI may be a clinically useful tool as a quantitative surrogate marker for monitoring disease progression. (orig.)

  10. Structure of an aprataxin-DNA complex with insights into AOA1 neurodegenerative disease

    Tumbale, Percy; Appel, C Denise; Kraehenbuehl, Rolf; Robertson, Patrick D; Williams, Jessica S; Krahn, Joe; Ahel, Ivan; Williams, R Scott [NIEHS; (Manchester)

    2012-09-17

    DNA ligases finalize DNA replication and repair through DNA nick-sealing reactions that can abort to generate cytotoxic 5'-adenylation DNA damage. Aprataxin (Aptx) catalyzes direct reversal of 5'-adenylate adducts to protect genome integrity. Here the structure of a Schizosaccharomyces pombe Aptx-DNA-AMP-Zn2+ complex reveals active site and DNA interaction clefts formed by fusing a histidine triad (HIT) nucleotide hydrolase with a DNA minor groove-binding C2HE zinc finger (Znf). An Aptx helical 'wedge' interrogates the base stack for sensing DNA ends or DNA nicks. The HIT-Znf, the wedge and an '[F/Y]PK' pivot motif cooperate to distort terminal DNA base-pairing and direct 5'-adenylate into the active site pocket. Structural and mutational data support a wedge-pivot-cut HIT-Znf catalytic mechanism for 5'-adenylate adduct recognition and removal and suggest that mutations affecting protein folding, the active site pocket and the pivot motif underlie Aptx dysfunction in the neurodegenerative disorder ataxia with oculomotor apraxia 1 (AOA1).

  11. Common pitfalls of stem cell differentiation: a guide to improving protocols for neurodegenerative disease models and research.

    Engel, Martin; Do-Ha, Dzung; Muñoz, Sonia Sanz; Ooi, Lezanne

    2016-10-01

    Induced pluripotent stem cells and embryonic stem cells have revolutionized cellular neuroscience, providing the opportunity to model neurological diseases and test potential therapeutics in a pre-clinical setting. The power of these models has been widely discussed, but the potential pitfalls of stem cell differentiation in this research are less well described. We have analyzed the literature that describes differentiation of human pluripotent stem cells into three neural cell types that are commonly used to study diseases, including forebrain cholinergic neurons for Alzheimer's disease, midbrain dopaminergic neurons for Parkinson's disease and cortical astrocytes for neurodegenerative and psychiatric disorders. Published protocols for differentiation vary widely in the reported efficiency of target cell generation. Additionally, characterization of the cells by expression profile and functionality differs between studies and is often insufficient, leading to highly variable protocol outcomes. We have synthesized this information into a simple methodology that can be followed when performing or assessing differentiation techniques. Finally we propose three considerations for future research, including the use of physiological O2 conditions, three-dimensional co-culture systems and microfluidics to control feeding cycles and growth factor gradients. Following these guidelines will help researchers to ensure that robust and meaningful data is generated, enabling the full potential of stem cell differentiation for disease modeling and regenerative medicine. PMID:27154043

  12. NeuroDNet - an open source platform for constructing and analyzing neurodegenerative disease networks

    Vasaikar Suhas V; Padhi Aditya K; Jayaram Bhyravabhotla; Gomes James

    2013-01-01

    Abstract Background Genetic networks control cellular functions. Aberrations in normal cellular function are caused by mutations in genes that disrupt the fine tuning of genetic networks and cause disease or disorder. However, the large number of signalling molecules, genes and proteins that constitute such networks, and the consequent complexity of interactions, has restrained progress in research elucidating disease mechanisms. Hence, carrying out a systematic analysis of how diseases alter...

  13. Autophagy and neurodegenerative disorders

    Evangelia Kesidou; Roza Lagoudaki; Olga Touloumi; Kyriaki-Nefeli Poulatsidou; Constantina Simeonidou

    2013-01-01

    Accumulation of aberrant proteins and inclusion bodies are hallmarks in most neurodegenerative diseases. Consequently, these aggregates within neurons lead to toxic effects, overproduction of reactive oxygen species and oxidative stress. Autophagy is a significant intracel ular mechanism that removes damaged organelles and misfolded proteins in order to maintain cel homeostasis. Excessive or insufficient autophagic activity in neurons leads to altered homeostasis and influences their survival rate, causing neurodegeneration. The review article provides an update of the role of autophagic process in representative chronic and acute neurodegenerative disorders.

  14. Links among glaucoma, neurodegenerative, and vascular diseases of the central nervous system.

    Nucci, Carlo; Martucci, Alessio; Cesareo, Massimo; Garaci, Francesco; Morrone, Luigi Antonio; Russo, Rossella; Corasaniti, Maria Tiziana; Bagetta, Giacinto; Mancino, Raffaele

    2015-01-01

    Glaucoma is the leading cause of irreversible blindness worldwide. Although the intraocular pressure (IOP) has been considered for long time the key point and the only treatable risk factor of the disease, there are cases in which glaucoma continues to progress despite normal IOP values. Vision loss in glaucoma is related to a selective decrease in the number of retinal ganglion cells by apoptosis that is associated to alterations of the central visual pathways. Interestingly, similar events have been also described in disorders of the central nervous system (CNS), such as Alzheimer's disease, Parkinson's disease, Leber's hereditary optic neuropathy, and cerebrovascular diseases. In this review, we discuss recent evidence supporting pathological links between glaucoma and disorders of the CNS. PMID:26518072

  15. Dysregulation of the HPA axis as a core pathophysiology mediating co-morbid depression in neurodegenerative diseases

    Xin eDu

    2015-03-01

    Full Text Available There is increasing evidence of prodromal manifestation of neuropsychiatric symptoms in a variety of neurodegenerative diseases such as Parkinson’s disease and Huntington’s disease. These affective symptoms may be observed many years before the core diagnostic symptoms of the neurological condition. It is becoming more apparent that depression is a significant modifying factor of the trajectory of disease progression, and even treatment outcomes. It is therefore crucial that we understand the potential pathophysiologies related to the primary condition, which could contribute to the development of depression. The hypothalamic-pituitary-adrenal (HPA axis is a key neuroendocrine signaling system involved in physiological homeostasis and stress response. Disturbances of this system lead to severe hormonal imbalances, and the majority of such patients also present with behavioural deficits and/or mood disorders. Dysregulation of the HPA axis is also strongly implicated in the pathology of major depressive disorder. Consistent with this, anti-depressant drugs such as the selective serotonin reuptake inhibitors (SSRI have been shown to alter HPA axis activity. In this review, we will summarize the current state of knowledge regarding HPA axis pathology in Alzheimer’s, Parkinson’s and Huntington’s diseases, differentiating between prodromal and later stages of disease progression where possible. Both clinical and preclinical evidence will be examined, but we highlight animal model studies as being particularly useful for uncovering novel mechanisms of pathology related to co-morbid mood disorders. Finally, we purpose utilizing the pre-clinical evidence to better inform prospective, intervention studies.

  16. Tau imaging in the study of ageing, Alzheimer's disease, and other neurodegenerative conditions.

    Villemagne, Victor L; Okamura, Nobuyuki

    2016-02-01

    In vivo tau imaging allows a deeper understanding of tau deposition in the brain, providing insights into the causes, diagnosis and treatment of primary and secondary tauopathies such as Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, chronic traumatic encephalopathy, and some variants of frontotemporal lobar degeneration. The cross-sectional and longitudinal assessment of the temporal and spatial patterns of tau deposition in the brain will allow a better understanding of the role tau plays in ageing as well as its relationship with cognition, genotype, and neurodegeneration. It is likely that selective tau imaging could be used as a diagnostic and prognostic biomarker of disease progression, as well as a surrogate marker for monitoring of efficacy and patient recruitment for disease-specific therapeutic trials. PMID:26397020

  17. Experimental Evidence of ω-3 Polyunsaturated Fatty Acid Modulation of Inflammatory Cytokines and Bioactive Lipid Mediators: Their Potential Role in Inflammatory, Neurodegenerative, and Neoplastic Diseases

    Gabriella Calviello; Hui-Min Su; Weylandt, Karsten H.; Elena Fasano; Simona Serini; Achille Cittadini

    2013-01-01

    A large body of evidence has emerged over the past years to show the critical role played by inflammation in the pathogenesis of several diseases including some cardiovascular, neoplastic, and neurodegenerative diseases, previously not considered inflammation-related. The anti-inflammatory action of ω-3 polyunsaturated fatty acids (PUFAs), as well as their potential healthy effects against the development and progression of the same diseases, has been widely studied by our and others' laborat...

  18. The beneficial role of curcumin on inflammation, diabetes and neurodegenerative disease: A recent update.

    Ghosh, Shatadal; Banerjee, Sharmistha; Sil, Parames C

    2015-09-01

    The concept of using phytochemicals has ushered in a new revolution in pharmaceuticals. Naturally occurring polyphenols (like curcumin, morin, resveratrol, etc.) have gained importance because of their minimal side effects, low cost and abundance. Curcumin (diferuloylmethane) is a component of turmeric isolated from the rhizome of Curcuma longa. Research for more than two decades has revealed the pleiotropic nature of the biological effects of this molecule. More than 7000 published articles have shed light on the various aspects of curcumin including its antioxidant, hypoglycemic, anti-inflammatory and anti-cancer activities. Apart from these well-known activities, this natural polyphenolic compound also exerts its beneficial effects by modulating different signalling molecules including transcription factors, chemokines, cytokines, tumour suppressor genes, adhesion molecules, microRNAs, etc. Oxidative stress and inflammation play a pivotal role in various diseases like diabetes, cancer, arthritis, Alzheimer's disease and cardiovascular diseases. Curcumin, therefore, could be a therapeutic option for the treatment of these diseases, provided limitations in its oral bioavailability can be overcome. The current review provides an updated overview of the metabolism and mechanism of action of curcumin in various organ pathophysiologies. The review also discusses the potential for multifunctional therapeutic application of curcumin and its recent progress in clinical biology. PMID:26066364

  19. Inflammatory events at blood–brain barrier in neuroinflammatory and neurodegenerative disorders: Implications for clinical disease

    de Vries, Helga E.; Kooij, Gijs; Frenkel, Dan; Georgopoulos, Spiros; Monsonego, Alon; Janigro, Damir

    2016-01-01

    Summary Proper function of the neurovasculature is required for optimal brain function and preventing neuroinflammation and neurodegeneration. Within this review, we discuss alterations of the function of the blood–brain barrier in neurologic disorders such as multiple sclerosis, epilepsy, and Alzheimer’s disease and address potential underlying mechanisms. PMID:23134495

  20. Possible pathophysiological roles of transglutaminase-catalyzed reactions in the pathogenesis of human neurodegenerative diseases

    Enrica Serretiello

    2015-09-01

    Full Text Available Transglutaminases (TG, E.C. 2.3.2.13 are related and ubiquitous enzymes that catalyze the cross linking of a glutaminyl residue of a protein/peptide substrate to a lysyl residue of a protein/peptide co-substrate. These enzymes are also capable of catalyzing other post-translational reactions important for cell life. The distribution and the physiological roles of human TGs have been widely studied in numerous cell types and tissues and recently their roles in several diseases have begun to be identified. It has been hypothesized that transglutaminase activity is directly involved in the pathogenetic mechanisms responsible for several human diseases. In particular, tissue TG (tTG, TG2, a member of the TG enzyme family, has been recently shown to be involved in the molecular mechanisms responsible for a very widespread human pathology, Celiac Disease (CD, one of the most common food intolerances described in the western population. The main food agent that provokes the strong and diffuse clinical symptoms has been known for several years to be gliadin, a protein present in a very large number of human foods derived from vegetables. Recently, some biochemical and immunological aspects of this very common disease have been clarified, and “tissue” transglutaminase, a multifunctional and ubiquitous enzyme, has been identified as one of the major factors. The aim of this review is to summarize the most recent findings concerning the relationships between the biochemical properties of the transglutaminase activity and the basic molecular mechanisms responsible for some human diseases, with particular reference to neuropsychiatric disorders. Possible molecular links between CD and neuropsychiatric disorders, and the use of transglutaminase inhibitors are also discussed.

  1. Early-Life Toxic Insults and Onset of Sporadic Neurodegenerative Diseases-an Overview of Experimental Studies.

    Tartaglione, Anna Maria; Venerosi, Aldina; Calamandrei, Gemma

    2016-01-01

    The developmental origin of health and disease hypothesis states that adverse fetal and early childhood exposures can predispose to obesity, cardiovascular, and neurodegenerative diseases (NDDs) in adult life. Early exposure to environmental chemicals interferes with developmental programming and induces subclinical alterations that may hesitate in pathophysiology and behavioral deficits at a later life stage. The mechanisms by which perinatal insults lead to altered programming and to disease later in life are still undefined. The long latency between exposure and onset of disease, the difficulty of reconstructing early exposures, and the wealth of factors which the individual is exposed to during the life course make extremely difficult to prove the developmental origin of NDDs in clinical and epidemiological studies. An overview of animal studies assessing the long-term effects of perinatal exposure to different chemicals (heavy metals and pesticides) supports the link between exposure and hallmarks of neurodegeneration at the adult stage. Furthermore, models of maternal immune activation show that brain inflammation in early life may enhance adult vulnerability to environmental toxins, thus supporting the multiple hit hypothesis for NDDs' etiology. The study of prospective animal cohorts may help to unraveling the complex pathophysiology of sporadic NDDs. In vivo models could be a powerful tool to clarify the mechanisms through which different kinds of insults predispose to cell loss in the adult age, to establish a cause-effect relationship between "omic" signatures and disease/dysfunction later in life, and to identify peripheral biomarkers of exposure, effects, and susceptibility, for translation to prospective epidemiological studies. PMID:26695168

  2. Dietary fat and antioxidant vitamin intake in patients of neurodegenerative disease in a rural region of Jalisco, Mexico

    Navarro-Meza, Mónica; Gabriel-Ortiz, Genaro; Pacheco-Moisés, Fermín P.; Cruz-Ramos, José A.; López-Espinoza, Antonio

    2014-01-01

    Objective To evaluate and compare the intake of lipids and (A, E, and C) vitamins in patients with and without possible neurodegenerative diseases. Methods Twenty adults with possible Alzheimer's disease or Parkinson's disease and 41 control subjects (50–89 years old) from a rural region were studied. Dietary intake was evaluated with the analysis of macronutrients and micronutrients conducted by a food frequency questionnaire and 24 hours dietary record. Analyses were adjusted for age, sex, body mass index, and energy intake. Through interrogation and use of medical record form of health secretary we obtained information about the sociodemographic characteristics. Multivariate analysis of variance to allow for covariated adjustment was used. Results Patients had a lower energy intake, vitamin C (P = 0.016), fruits (P < 0.001), vegetables (P = 0.037), and oils and fat (P = 0.002), than the controls. Interestingly, the C vitamin intake in patients was still higher than the recommended. Patients had a higher consumption of cereals (P = 0.017), high-animal fat diet (P = 0.024), and whole milk (P < 0.001); 2.4% of the controls smoke and 5% are alcohol consumers. Eighty-five percent of patients and 78% of the controls do not have physical activity. Family history of subjects in this study indicated chronic diseases. Conclusion The subjects included in this study had a high intake of C vitamin, this is due to the consumption of fruits and vegetables. However, patients with possible Alzheimer's or Parkinson's disease had a lower intake of fruits and vegetables, which could be due to type of food to which they have access. PMID:24257159

  3. Right Anterior Insula: Core Region of Hallucinations in Cognitive Neurodegenerative Diseases

    Blanc, Frédéric; Noblet, Vincent; Philippi, Nathalie; Cretin, Benjamin; Foucher, Jack,; Armspach, Jean-Paul; Rousseau, François; ,

    2014-01-01

    Objectives We investigated the neural basis of hallucinations Alzheimer's disease (AD) by applying voxel-based morphometry (VBM) to anatomical and functional data from the AD Neuroimaging Initiative. Methods AD patients with hallucinations, based on the Neuropsychiatric Inventory (NPI-Q) (AD-hallu group; n = 39), were compared to AD patients without hallucinations matched for age, sex, educational level, handedness and MMSE (AD-c group; n = 39). Focal brain volume on MRI was analyzed and comp...

  4. Selective Activation of mTORC1 Signaling Recapitulates Microcephaly, Tuberous Sclerosis, and Neurodegenerative Diseases

    Hidetoshi Kassai

    2014-06-01

    Full Text Available Mammalian target of rapamycin (mTOR has been implicated in human neurological diseases such as tuberous sclerosis complex (TSC, neurodegeneration, and autism. However, little is known about when and how mTOR is involved in the pathogenesis of these diseases, due to a lack of animal models that directly increase mTOR activity. Here, we generated transgenic mice expressing a gain-of-function mutant of mTOR in the forebrain in a temporally controlled manner. Selective activation of mTORC1 in embryonic stages induced cortical atrophy caused by prominent apoptosis of neuronal progenitors, associated with upregulation of HIF-1α. In striking contrast, activation of the mTORC1 pathway in adulthood resulted in cortical hypertrophy with fatal epileptic seizures, recapitulating human TSC. Activated mTORC1 in the adult cortex also promoted rapid accumulation of cytoplasmic inclusions and activation of microglial cells, indicative of progressive neurodegeneration. Our findings demonstrate that mTORC1 plays different roles in developmental and adult stages and contributes to human neurological diseases.

  5. Recent Advancements in Targeted Delivery of Therapeutic Molecules in Neurodegenerative Disease - Spinocerebellar Ataxia - Opportunities and Challenges

    Satya Prakash

    2008-01-01

    Full Text Available Drug discovery and its methodologies have been very effective in terms of treating cancers and immunological disorders but have not been able to stop genetic diseases as most of the drugs target at the protein level. They merely mitigate the symptoms of the disease. Spinocerebellar ataxia is a neurological genetic disorder that is caused by the formation of an abnormal protein. There have been several reports on ataxic drug development but actual clinical treatment is yet to be achieved. Oligonucleotide therapy called sequence specific siRNA mediated gene silencing has evolved with promising results. This approach emphasizes on suppressing the expression of the diseased gene at mRNA level. However, there is a limitation in delivery of siRNA to the target site. Several methods have been developed over the last decade to enhance the target specific delivery of DNA, siRNA, protein and small drug molecules for therapeutic purpose with less or no side effects. This review discusses the latest upcoming technologies in the field that focus on a number of nonviral nanocarriers for targeted delivery. In this review, we explore the promise and potential of novel therapeutics with interest on ataxia therapy.

  6. Effect of Systemic Iron Overload and a Chelation Therapy in a Mouse Model of the Neurodegenerative Disease Hereditary Ferritinopathy.

    Garringer, Holly J; Irimia, Jose M; Li, Wei; Goodwin, Charles B; Richine, Briana; Acton, Anthony; Chan, Rebecca J; Peacock, Munro; Muhoberac, Barry B; Ghetti, Bernardino; Vidal, Ruben

    2016-01-01

    Mutations in the ferritin light chain (FTL) gene cause the neurodegenerative disease neuroferritinopathy or hereditary ferritinopathy (HF). HF is characterized by a severe movement disorder and by the presence of nuclear and cytoplasmic iron-containing ferritin inclusion bodies (IBs) in glia and neurons throughout the central nervous system (CNS) and in tissues of multiple organ systems. Herein, using primary mouse embryonic fibroblasts from a mouse model of HF, we show significant intracellular accumulation of ferritin and an increase in susceptibility to oxidative damage when cells are exposed to iron. Treatment of the cells with the iron chelator deferiprone (DFP) led to a significant improvement in cell viability and a decrease in iron content. In vivo, iron overload and DFP treatment of the mouse model had remarkable effects on systemic iron homeostasis and ferritin deposition, without significantly affecting CNS pathology. Our study highlights the role of iron in modulating ferritin aggregation in vivo in the disease HF. It also puts emphasis on the potential usefulness of a therapy based on chelators that can target the CNS to remove and redistribute iron and to resolubilize or prevent ferritin aggregation while maintaining normal systemic iron stores. PMID:27574973

  7. β-amyloidopathy in the Pathogenesis of Age-Related Macular Degeneration in Correlation with Neurodegenerative Diseases.

    Ermilov, Victor V; Nesterova, Alla A

    2016-01-01

    Involvement of new biotechnology and genetic engineering methods to the study of the aging organism allowed to select a group of neurodegenerative diseases (NDD) which have a similar mechanism of pathogenesis including pathological processes of protein aggregation and its deposition in the structures of nerve tissue. The development of eye and brain from one embryonic germ layer, community of ethiopathogenetic and morphological manifestations of age-related macular degeneration (AMD) and Alzheimer's disease (AD), a common pathway of β-amyloid precursor protein (APP) are associated with the pathological aggregation of fibrillar β-amyloid (Aβ) protein and the development of β-amyloidopathy in structural elements of the eye and the brain. The review demonstrates the keynote of AMD and AD pathogenesis is β-amyloidopathy that is a manifestation of proteinopathy leading to cytotoxicity, neurodegeneration and the development of pathological apoptosis activated by the formation of intracellular Aβ. This view on the problem predetermines the development of new strategies for the creating of ophthalmogeriatric and neuroprotective drugs affecting the pathogenesis and including all stages of Aβ formation and pathological aggregation. PMID:26427402

  8. CRISPR/Cas9: Implications for Modeling and Therapy of Neurodegenerative Diseases

    Yang, Weili; Tu, Zhuchi; Sun, Qiang; Li, Xiao-Jiang

    2016-01-01

    CRISPR/Cas9 is now used widely to genetically modify the genomes of various species. The ability of CRISPR/Cas9 to delete DNA sequences and correct DNA mutations opens up a new avenue to treat genetic diseases that are caused by DNA mutations. In this review, we describe the advantages of using CRISPR/Cas9 to engineer genomic DNAs in animal embryos, as well as in specific regions or cell types in the brain. We also discuss how to apply CRISPR/Cas9 to establish animal models of neurodegenerati...

  9. Non linear approach to study the dynamics of neurodegenerative diseases by Multifractal Detrended Cross-correlation Analysis-A quantitative assessment on gait disease

    Dutta, Srimonti; Ghosh, Dipak; Samanta, Shukla

    2016-04-01

    This paper studies the human gait pattern of normal people and patients suffering from Parkinson's disease using the MFDXA (Multifractal Detrended Cross-correlation Analysis) methodology. The auto correlation and cross correlation of the time series of the total force under the left foot and right foot were studied. The study reveals that the degree of multifractality (W) and degree of correlation (γ) are generally more for normal patients than the diseased set. It is also observed that the values of W and γ are nearly same for left foot and right. It is also observed that the study of autocorrelation alone is not sufficient, cross correlations should also be studied to get a better concept of neurodegenerative diseases.

  10. Low-level laser therapy regulates microglial function through Src-mediated signaling pathways: implications for neurodegenerative diseases

    Song Sheng

    2012-09-01

    Full Text Available Abstract Background Activated microglial cells are an important pathological component in brains of patients with neurodegenerative diseases. The purpose of this study was to investigate the effect of He-Ne (632.8 nm, 64.6 mW/cm2 low-level laser therapy (LLLT, a non-damaging physical therapy, on activated microglia, and the subsequent signaling events of LLLT-induced neuroprotective effects and phagocytic responses. Methods To model microglial activation, we treated the microglial BV2 cells with lipopolysaccharide (LPS. For the LLLT-induced neuroprotective study, neuronal cells with activated microglial cells in a Transwell™ cell-culture system were used. For the phagocytosis study, fluorescence-labeled microspheres were added into the treated microglial cells to confirm the role of LLLT. Results Our results showed that LLLT (20 J/cm2 could attenuate toll-like receptor (TLR-mediated proinflammatory responses in microglia, characterized by down-regulation of proinflammatory cytokine expression and nitric oxide (NO production. LLLT-triggered TLR signaling inhibition was achieved by activating tyrosine kinases Src and Syk, which led to MyD88 tyrosine phosphorylation, thus impairing MyD88-dependent proinflammatory signaling cascade. In addition, we found that Src activation could enhance Rac1 activity and F-actin accumulation that typify microglial phagocytic activity. We also found that Src/PI3K/Akt inhibitors prevented LLLT-stimulated Akt (Ser473 and Thr308 phosphorylation and blocked Rac1 activity and actin-based microglial phagocytosis, indicating the activation of Src/PI3K/Akt/Rac1 signaling pathway. Conclusions The present study underlines the importance of Src in suppressing inflammation and enhancing microglial phagocytic function in activated microglia during LLLT stimulation. We have identified a new and important neuroprotective signaling pathway that consists of regulation of microglial phagocytosis and inflammation under LLLT

  11. Role of Abca7 in mouse behaviours relevant to neurodegenerative diseases.

    Warren Logge

    Full Text Available ATP-binding cassette transporters of the subfamily A (ABCA are responsible for the translocation of lipids including cholesterol, which is crucial for neurological function. Recent studies suggest that the ABC transporter ABCA7 may play a role in the development of brain disorders such as schizophrenia and Alzheimer's disease. However, Abca7's role in cognition and other behaviours has not been investigated. Therefore, we characterised homozygous Abca7 knockout mice in a battery of tests for baseline behaviours (i.e. physical exam, baseline locomotion and anxiety and behaviours relevant to schizophrenia (i.e. prepulse inhibition and locomotor response to psychotropic drugs and Alzheimer's disease (i.e. cognitive domains. Knockout mice had normal motor functions and sensory abilities and performed the same as wild type-like animals in anxiety tasks. Short-term spatial memory and fear-associated learning was also intact in Abca7 knockout mice. However, male knockout mice exhibited significantly impaired novel object recognition memory. Task acquisition was unaffected in the cheeseboard task. Female mice exhibited impaired spatial reference memory. This phenomenon was more pronounced in female Abca7 null mice. Acoustic startle response, sensorimotor gating and baseline locomotion was unaltered in Abca7 knockout mice. Female knockouts showed a moderately increased motor response to MK-801 than control mice. In conclusion, Abca7 appears to play only a minor role in behavioural domains with a subtle sex-specific impact on particular cognitive domains.

  12. Quantification of muscle activity during sleep for patients with neurodegenerative diseases

    Hanif, Umaer; Trap, Lotte; Jennum, Poul;

    2015-01-01

    Idiopathic REM sleep behavior disorder (iRBD) is a very strong predictor for later development of Parkinson's disease (PD), and is characterized by REM sleep without atonia (RSWA), resulting in increased muscle activity during REM sleep. Abundant studies have shown the loss of atonia during REM...... sleep, but our aim was to investigate whether iRBD and PD patients have increased muscle activity in both REM and NREM sleep compared to healthy controls. This was achieved by developing a semi-automatic algorithm for quantification of mean muscle activity per second during all sleep stages for the...... enrolled patients. The three groups examined included patients suffering from iRBD, PD and healthy control subjects (CO). To determine muscle activity, a baseline and threshold were established after pre-processing of the raw surface electromyography (sEMG) signal. The signal was then segmented according...

  13. CAFFEINE AND CHLOROGENIC ACIDS IN COFFEE AND EFFECTS ON SELECTED NEURODEGENERATIVE DISEASES

    Santos Roseane Maria Maia

    2013-08-01

    Full Text Available Much controversy and misunderstanding has surrounded the disputed health impact of coffee consumption. Recent studies now help clarify the pharmacological and neurological health promoting properties of coffee daily intake. Benefits are shown attributable to coffee’s rich phytochemistry that includes (besides caffeine, phenolic compounds, such as chlorogenic acids, diterpenes, trigonelline, minerals, amino acids and other volatile compounds. It is also a powerful disease fighting antioxidant, the primary source of antioxidants in several countries. The purpose of this article is to review results from current epidemiological and mechanistic studies on the central nervous system attributed to coffee. A primary focus to this review is the activity of caffeine and chlorogenic acids and their implications to CNS health. The discussion will highlight possible molecular mechanisms responsible for the respective pharmacological benefits.

  14. Movement and Other Neurodegenerative Syndromes in Patients with Systemic Rheumatic Diseases: A Case Series of 8 Patients and Review of the Literature.

    Menezes, Rikitha; Pantelyat, Alexander; Izbudak, Izlem; Birnbaum, Julius

    2015-08-01

    Patients with rheumatic diseases can present with movement and other neurodegenerative disorders. It may be underappreciated that movement and other neurodegenerative disorders can encompass a wide variety of disease entities. Such disorders are strikingly heterogeneous and lead to a wider spectrum of clinical injury than seen in Parkinson's disease. Therefore, we sought to stringently phenotype movement and other neurodegenerative disorders presenting in a case series of rheumatic disease patients. We integrated our findings with a review of the literature to understand mechanisms which may account for such a ubiquitous pattern of clinical injury.Seven rheumatic disease patients (5 Sjögren's syndrome patients, 2 undifferentiated connective tissue disease patients) were referred and could be misdiagnosed as having Parkinson's disease. However, all of these patients were ultimately diagnosed as having other movement or neurodegenerative disorders. Findings inconsistent with and more expansive than Parkinson's disease included cerebellar degeneration, dystonia with an alien-limb phenomenon, and nonfluent aphasias.A notable finding was that individual patients could be affected by cooccurring movement and other neurodegenerative disorders, each of which could be exceptionally rare (ie, prevalence of ∼1:1000), and therefore with the collective probability that such disorders were merely coincidental and causally unrelated being as low as ∼1-per-billion. Whereas our review of the literature revealed that ubiquitous patterns of clinical injury were frequently associated with magnetic resonance imaging (MRI) findings suggestive of a widespread vasculopathy, our patients did not have such neuroimaging findings. Instead, our patients could have syndromes which phenotypically resembled paraneoplastic and other inflammatory disorders which are known to be associated with antineuronal antibodies. We similarly identified immune-mediated and inflammatory markers of injury

  15. Blood-brain barrier proteomics: towards the understanding of neurodegenerative diseases.

    Karamanos, Yannis; Gosselet, Fabien; Dehouck, Marie-Pierre; Cecchelli, Roméo

    2014-11-01

    The blood-brain barrier (BBB) regulates the passage of endogenous and exogenous compounds and thus contributes to the brain homeostasis with the help of well-known proteins such as tight junction proteins, plasma membrane transporters and metabolic barrier proteins. In the last decade, proteomics have emerged as supplementary tools for BBB research. The development of proteomic technologies has provided several means to extend knowledge on the BBB and to investigate additional routes for the bypass of this barrier. Proteomics approaches have been used in vivo and also using in vitro BBB models to decipher the physiological characteristics and, under stress conditions, to understand the molecular mechanisms of brain diseases. This work has demonstrated that both quantitative global and targeted proteomics approaches are powerful and provide significant information on the brain microvessel endothelium. However, current knowledge is only partial and it is necessary to increase the studies using proteomics tools that will provide additional information concerning brain pathologies or BBB metabolism. Highly sensitive, accurate and specific protein quantification by quantitative targeted proteomics appears as an essential methodology for human BBB studies. PMID:25446619

  16. The Emerging Role of Guanine Exchange Factors in ALS and other neurodegenerative diseases

    Cristian eDroppelmann

    2014-09-01

    Full Text Available Small GTPases participate in a broad range of cellular processes such as proliferation, differentiation and migration. The exchange of GDP for GTP resulting in the activation of these GTPases is catalyzed by a group of enzymes called guanine nucleotide exchange factors (GEFs, of which two classes: Dbl-related exchange factors and the more recently described Dock family exchange factors. Increasingly, deregulation of normal GEF activity or function has been associated with a broad range of disease states, including neurodegeneration and neurodevelopmental disorders. In this review, we examine this evidence with special emphasis on the novel role of Rho guanine nucleotide exchange factor (RGNEF/p190RhoGEF in the pathogenesis of amyotrophic lateral sclerosis (ALS. RGNEF is the first neurodegeneration-linked GEF that regulates not only RhoA GTPase activation but also functions as an RNA binding protein that directly acts with low molecular weight neurofilament (NEFL mRNA 3’UTR to regulate its stability. This dual role for RGNEF, coupled with the increasing understanding of the key role for GEFs in modulating the GTPase function in cell survival suggests a prominent role for GEFs in mediating a critical balance between cytotoxicity and neuroprotection which, when disturbed, contributes to neuronal loss.

  17. Expression of the Kynurenine Pathway in Human Peripheral Blood Mononuclear Cells: Implications for Inflammatory and Neurodegenerative Disease.

    Jones, Simon P; Franco, Nunzio F; Varney, Bianca; Sundaram, Gayathri; Brown, David A; de Bie, Josien; Lim, Chai K; Guillemin, Gilles J; Brew, Bruce J

    2015-01-01

    The kynurenine pathway is a fundamental mechanism of immunosuppression and peripheral tolerance. It is increasingly recognized as playing a major role in the pathogenesis of a wide variety of inflammatory, neurodegenerative and malignant disorders. However, the temporal dynamics of kynurenine pathway activation and metabolite production in human immune cells is currently unknown. Here we report the novel use of flow cytometry, combined with ultra high-performance liquid chromatography and gas chromatography-mass spectrometry, to sensitively quantify the intracellular expression of three key kynurenine pathway enzymes and the main kynurenine pathway metabolites in a time-course study. This is the first study to show that up-regulation of indoleamine 2,3-dioxygenase (IDO-1), kynurenine 3-monoxygenase (KMO) and quinolinate phosphoribosyltransferase (QPRT) is lacking in lymphocytes treated with interferon gamma. In contrast, peripheral monocytes showed a significant elevation of kynurenine pathway enzymes and metabolites when treated with interferon gamma. Expression of IDO-1, KMO and QPRT correlated significantly with activation of the kynurenine pathway (kynurenine:tryptophan ratio), quinolinic acid concentration and production of the monocyte derived, pro-inflammatory immune response marker: neopterin. Our results also describe an original and sensitive methodological approach to quantify kynurenine pathway enzyme expression in cells. This has revealed further insights into the potential role of these enzymes in disease processes. PMID:26114426

  18. Cyanine dye N744 inhibits tau fibrillization by blocking filament extension: implications for the treatment of tauopathic neurodegenerative diseases.

    Necula, Mihaela; Chirita, Carmen N; Kuret, Jeff

    2005-08-01

    Tau fibrillization is a potential therapeutic target for Alzheimer's and other neurodegenerative diseases. Small molecules capable of both inhibiting aggregation and promoting filament disaggregation have been discovered, but knowledge of their mechanism of action and potential for testing in biological models is fragmentary. To clarify these issues, the interaction between a small-molecule inhibitor of tau fibrillization, 3,3'-bis(beta-hydroxyethyl)-9-ethyl-5,5'-dimethoxythiacarbocyanine iodide (N744), and full-length four-repeat tau protein was characterized in vitro using transmission electron microscopy and fluorescence spectroscopy. Analysis of reaction time courses performed in the presence of anionic fibrillization inducers revealed that increasing concentrations of N744 decreased the total filament length without modulating lag time, indicating that filament extension but not nucleation was affected by inhibitor under the conditions that were investigated. Critical concentration measurements confirmed that N744 shifted equilibria at filament ends away from the fibrillized state, resulting in endwise filament disaggregation when it was added to synthetic filaments. Both increasing bulk tau concentrations and filament stabilizing modifications such as pseudophosphorylation and glycation antagonized N744 activity. The results illustrate the importance of mechanism for the design and interpretation of pharmacological studies in biological models of tau aggregation. PMID:16042400

  19. Validation of soluble amyloid-β precursor protein assays as diagnostic CSF biomarkers for neurodegenerative diseases.

    van Waalwijk van Doorn, Linda J C; Koel-Simmelink, Marleen J; Haußmann, Ute; Klafki, Hans; Struyfs, Hanne; Linning, Philipp; Knölker, Hans-Joachim; Twaalfhoven, Harry; Kuiperij, H Bea; Engelborghs, Sebastiaan; Scheltens, Philip; Verbeek, Marcel M; Vanmechelen, Eugeen; Wiltfang, Jens; Teunissen, Charlotte E

    2016-04-01

    Analytical validation of a biomarker assay is essential before implementation in clinical practice can occur. In this study, we analytically validated the performance of assays detecting soluble amyloid-β precursor protein (sAPP) α and β in CSF in two laboratories according to previously standard operating procedures serving this goal. sAPPα and sAPPβ ELISA assays from two vendors (IBL-international, Meso Scale Diagnostics) were validated. The performance parameters included precision, sensitivity, dilutional linearity, recovery, and parallelism. Inter-laboratory variation, biomarker comparison (sAPPα vs. sAPPβ) and clinical performance was determined in three laboratories using 60 samples of patients with subjective memory complaints, Alzheimer's disease, or frontotemporal dementia. All performance parameters of the assays were similar between labs and within predefined acceptance criteria. The only exceptions were minor out-of-range results for recovery at low concentrations and, despite being within predefined acceptance criteria, non-comparability of the results for evaluation of the dilutional linearity and hook-effect. Based on the inter-laboratory correlation between Lab #1 and Lab #2, the IBL-international assays were more robust (sAPPα: r(2) = 0.92, sAPPβ: r(2) = 0.94) than the Meso Scale Diagnostics (MSD) assay (sAPPα: r(2) = 0.70, sAPPβ: r(2) = 0.80). Specificity of assays was confirmed using assay-specific peptide competitors. Clinical validation showed consistent results across the clinical groups in the different laboratories for all assays. The validated sAPP assays appear to be of sufficient technical quality and perform well. Moreover, the study shows that the newly developed standard operating procedures provide highly useful tools for the validation of new biomarker assays. A recommendation was made for renewed instructions to evaluate the dilutional linearity and hook-effect. We analytically validated the performance of assays

  20. Large cerebral perfusion defects observed in brain perfusion SPECT may herald psychiatric or neurodegenerative diseases of transient global amnesia patients

    So, Young; Kim, Hahn Young; Roh, Hong Gee; Han, Seol Heui [Konkuk University School of Medicine, Seoul (Korea, Republic of)

    2007-07-01

    Transient global amnesia (TGA) is a memory disorder characterized by an episode of antegrade amnesia and bewilderment which persists for several hours. We analyzed brain perfusion SPECT findings and clinical outcome of patients who suffered from TGA. From September 2005 to August 2007, 12 patients underwent Tc-99m ECD brain perfusion SPECT for neuroimaging of TGA. All patients also underwent MRI and MRA including DWI (MRI). Among them, 10 patients who could be chased more than 6 months were included in this study. Their average age was 60.74.0 yrs (M: F = 2: 8) and the average duration of amnesia was 4.42.2 hrs (1 hr {approx} 7 hrs). Duration from episode of amnesia to SPECT was 4.32.4 days (1{approx}9 days). Precipitating factors could be identified in 6 patients: emotional stress 3, hair dyeing 1, taking a nap 1 and angioplasty 1. SPECT and MRI was visually assessed, No cerebral perfusion defect was observed on SPECT in 3 patients and their clinical outcome was all good. Among 7 patients who had cerebral perfusion defects on SPECT, 3 patients had good clinical outcome, while others did not: one had hypercholesterolemia, another had depression, and 2 patients with cerebral perfusion defects at both temporoparetal cortex was later diagnosed as early Alzheimer's disease (AD) and mild cognitive impairment (MCI). MRI was negative in 6 patients and 3 of them had excellent clinical outcome while other 3 were diagnosed as hypercholesterolemia, early AD and MCI. Among 4 patients with positive MRI, 3 showed good clinical outcome and their MRI showed lesions at medial temporal cortex and/or vertebral artery. One patient with microcalcification at left putamen was diagnosed to have depression. Large cerebral perfusion defects on SPECT may herald psychiatric or neurodegenerative diseases of transient global amnesia patients which usually shows negative MRI.

  1. Large cerebral perfusion defects observed in brain perfusion SPECT may herald psychiatric or neurodegenerative diseases of transient global amnesia patients

    Transient global amnesia (TGA) is a memory disorder characterized by an episode of antegrade amnesia and bewilderment which persists for several hours. We analyzed brain perfusion SPECT findings and clinical outcome of patients who suffered from TGA. From September 2005 to August 2007, 12 patients underwent Tc-99m ECD brain perfusion SPECT for neuroimaging of TGA. All patients also underwent MRI and MRA including DWI (MRI). Among them, 10 patients who could be chased more than 6 months were included in this study. Their average age was 60.74.0 yrs (M: F = 2: 8) and the average duration of amnesia was 4.42.2 hrs (1 hr ∼ 7 hrs). Duration from episode of amnesia to SPECT was 4.32.4 days (1∼9 days). Precipitating factors could be identified in 6 patients: emotional stress 3, hair dyeing 1, taking a nap 1 and angioplasty 1. SPECT and MRI was visually assessed, No cerebral perfusion defect was observed on SPECT in 3 patients and their clinical outcome was all good. Among 7 patients who had cerebral perfusion defects on SPECT, 3 patients had good clinical outcome, while others did not: one had hypercholesterolemia, another had depression, and 2 patients with cerebral perfusion defects at both temporoparetal cortex was later diagnosed as early Alzheimer's disease (AD) and mild cognitive impairment (MCI). MRI was negative in 6 patients and 3 of them had excellent clinical outcome while other 3 were diagnosed as hypercholesterolemia, early AD and MCI. Among 4 patients with positive MRI, 3 showed good clinical outcome and their MRI showed lesions at medial temporal cortex and/or vertebral artery. One patient with microcalcification at left putamen was diagnosed to have depression. Large cerebral perfusion defects on SPECT may herald psychiatric or neurodegenerative diseases of transient global amnesia patients which usually shows negative MRI

  2. Context-dependent neural activation: internally and externally guided rhythmic lower limb movement in individuals with and without neurodegenerative disease

    Madeleine Eve Hackney

    2015-12-01

    Full Text Available Parkinson’s Disease (PD is a neurodegenerative disorder that has received considerable attention in allopathic medicine over the past decades. However, it is clear that, to date, pharmacological and surgical interventions do not fully address symptoms of PD and patients’ quality of life. As both an alternative therapy and as an adjuvant to conventional approaches, several types of rhythmic movement (e.g., movement strategies, dance, tandem biking, tai chi have shown improvements to motor symptoms, lower limb control and postural stability in people with PD (Amano, Nocera, Vallabhajosula, Juncos, Gregor, Waddell et al., 2013; Earhart, 2009; M. E. Hackney & Earhart, 2008; Kadivar, Corcos, Foto, & Hondzinski, 2011; Morris, Iansek, & Kirkwood, 2009; Ridgel, Vitek, & Alberts, 2009. However, while these programs are increasing in number, still little is known about the neural mechanisms underlying motor improvements attained with such interventions. Studying limb motor control under task specific contexts can help determine the mechanisms of rehabilitation effectiveness. Both internally guided (IG and externally guided (EG movement strategies have evidence to support their use in rehabilitative programs. However, there appears to be a degree of differentiation in the neural substrates involved in IG versus EG designs. Because of the potential task specific benefits of rhythmic training within a rehabilitative context, this report will consider the use of IG and EG movement strategies, and observations produced by functional magnetic resonance imaging (fMRI and other imaging techniques. This review will present findings from lower limb imaging studies, under IG and EG conditions for populations with and without movement disorders. We will discuss how these studies might inform movement disorders rehabilitation (in the form of rhythmic, music-based movement training and highlight research gaps. We believe better understanding of lower limb neural

  3. Context-Dependent Neural Activation: Internally and Externally Guided Rhythmic Lower Limb Movement in Individuals With and Without Neurodegenerative Disease.

    Hackney, Madeleine E; Lee, Ho Lim; Battisto, Jessica; Crosson, Bruce; McGregor, Keith M

    2015-01-01

    Parkinson's disease is a neurodegenerative disorder that has received considerable attention in allopathic medicine over the past decades. However, it is clear that, to date, pharmacological and surgical interventions do not fully address symptoms of PD and patients' quality of life. As both an alternative therapy and as an adjuvant to conventional approaches, several types of rhythmic movement (e.g., movement strategies, dance, tandem biking, and Tai Chi) have shown improvements to motor symptoms, lower limb control, and postural stability in people with PD (1-6). However, while these programs are increasing in number, still little is known about the neural mechanisms underlying motor improvements attained with such interventions. Studying limb motor control under task-specific contexts can help determine the mechanisms of rehabilitation effectiveness. Both internally guided (IG) and externally guided (EG) movement strategies have evidence to support their use in rehabilitative programs. However, there appears to be a degree of differentiation in the neural substrates involved in IG vs. EG designs. Because of the potential task-specific benefits of rhythmic training within a rehabilitative context, this report will consider the use of IG and EG movement strategies, and observations produced by functional magnetic resonance imaging and other imaging techniques. This review will present findings from lower limb imaging studies, under IG and EG conditions for populations with and without movement disorders. We will discuss how these studies might inform movement disorders rehabilitation (in the form of rhythmic, music-based movement training) and highlight research gaps. We believe better understanding of lower limb neural activity with respect to PD impairment during rhythmic IG and EG movement will facilitate the development of novel and effective therapeutic approaches to mobility limitations and postural instability. PMID:26696952

  4. Development of the CHARIOT Research Register for the Prevention of Alzheimer's Dementia and Other Late Onset Neurodegenerative Diseases.

    Mark E Larsen

    socioeconomically disadvantaged practices (r = 0.68, and practices with a higher proportion of White patients (r = 0.82.Response rates are comparable to other registers reported in the literature, and indicate good interest and support for a research register and for participation in research for the prevention of age-related neurodegenerative diseases and dementia. We consider that the simplicity of the approach means that this system is easily scalable and replicable across the UK and internationally.

  5. Ovarian steroids regulate gene expression related to DNA repair and neurodegenerative diseases in serotonin neurons of macaques.

    Bethea, C L; Reddy, A P

    2015-12-01

    Depression often accompanies the perimenopausal transition and it often precedes overt symptomology in common neurodegenerative diseases (NDDs, such as Alzheimer's, Parkinson's, Huntington, amyotrophic lateral sclerosis). Serotonin dysfunction is frequently found in the different etiologies of depression. We have shown that ovariectomized (Ovx) monkeys treated with estradiol (E) for 28 days supplemented with placebo or progesterone (P) on days 14-28 had reduced DNA fragmentation in serotonin neurons of the dorsal raphe nucleus, and long-term Ovx monkeys had fewer serotonin neurons than intact controls. We questioned the effect of E alone or E+P (estradiol supplemented with progesterone) on gene expression related to DNA repair, protein folding (chaperones), the ubiquitin-proteosome, axon transport and NDD-specific genes in serotonin neurons. Ovx macaques were treated with placebo, E or E+P (n=3 per group) for 1 month. Serotonin neurons were laser captured and subjected to microarray analysis and quantitative real-time PCR (qRT-PCR). Increases were confirmed with qRT-PCR in five genes that code for proteins involved in repair of strand breaks and nucleotide excision. NBN1, PCNA (proliferating nuclear antigen), GADD45A (DNA damage-inducible), RAD23A (DNA damage recognition) and GTF2H5 (gene transcription factor 2H5) significantly increased with E or E+P treatment (all analysis of variance (ANOVA), PPSEN1 (presenilin1) decreased (ANOVA, P<0.02) with treatment. APP decreased 10-fold with E or E+P administration. Newman-Keuls post hoc comparisons indicated variation in the response to E alone versus E+P across the different genes. In summary, E or E+P increased gene expression for DNA repair mechanisms in serotonin neurons, thereby rendering them less vulnerable to stress-induced DNA fragmentation. In addition, E or E+P regulated four genes encoding proteins that are often misfolded or malfunctioning in neuronal populations subserving overt NDD symptomology. The

  6. Paleoneurology: neurodegenerative diseases are age-related diseases of specific brain regions recently developed by Homo sapiens.

    Ghika, J

    2008-11-01

    Bipedal locomotion and fine motility of hand and larynx of humans introduced musculoskeletal adaptations, new pyramidal, corticostriatal, corticobulbar, nigrostriatal, and cerebellar pathways and expansions of prefrontal, cingular, parieto-temporal and occipital cortices with derived new brain capabilities. All selectively degenerate in aged homo sapiens following 16 syndromic presentations: (1) Parkinsonism: nigrostriatal control for fast automatic movements of hand, larynx, bipedal posture and gait ("simian gait and hand"). (2) Frontal (highest level) gait disorders (lower body parkinsonism, gait apraxia, retropulsion): prefrontostriatal executive control of bipedal locomotion. (3) ataxia: new synergistic coordination of bipedal gait and fine motility. (4) Dyskinesias (chorea, dystonia, tremor...): intrusions of simian basal ganglia motor subroutines. (5) motoneuron diseases: new proximo-distal and bulbar motoneurones, preserving older ones (oculomotor, abdominal...). (6) Archaic reflexes: prefrontal disinhibition of old mother/tree-climbing-oriented reflexes (sucking, grasping, Babinski/triple retraction, gegenhalten), group alarms (laughter, crying, yawning, grunting...) or grooming (tremor=scratching). (7) Dysautonomia: contextual regulation (orthostatism...). (8) REM sleep disorders of new cortical functions. (9) Corticobasal syndrome: melokinetic control of hand prehension-manipulation and language (retrocession to simian patterns). (10) Frontal/temporal lobe degeneration: medial-orbitofrontal behavioural variant: self monitoring of internal needs and social context: apathy, loss of personal hygiene, stereotypia, disinhibition, loss of concern for consequences of acts, social rules, danger and empathy; dorsolateral executive variant: inadequacy to the context of action (goal, environmental changes...); progressive non-fluent aphasia: executive and praxic processing of speech; temporal variant: abstract concepts for speech, gestures and vision (semantic

  7. An integral approach to the etiopathogenesis of human neurodegenerative diseases (HNDDs and cancer. Possible therapeutic consequences within the frame of the trophic factor withdrawal syndrome (TFWS

    Enrique Meléndez Hevia

    2008-10-01

    Full Text Available Salvador Harguindey1, Gorka Orive2,6, Ramón Cacabelos3, Enrique Meléndez Hevia4, Ramón Díaz de Otazu5, et al1Institute of Clinical Biology and Metabolism, Vitoria, Spain; 2Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of The Basque Country, Vitoria, Spain; 3Department of Clinical Neuroscience, EuroEspes Biomedical Research Center, Bergondo, La Coruña, Spain; 4Institute for Cellular Metabolism, Tenerife, Spain; 5Department of Pathology, Hospital Txagorritxu, Vitoria, Spain; 6Biotechnology Institute (BTI, Vitoria, SpainAbstract: A novel and integral approach to the understanding of human neurodegenerative diseases (HNDDs and cancer based upon the disruption of the intracellular dynamics of the hydrogen ion (H+ and its physiopathology, is advanced. From an etiopathological perspective, the activity and/or deficiency of different growth factors (GFs in these pathologies are studied, and their relationships to intracellular acid-base homeostasis reviewed. Growth and trophic factor withdrawal in HNDDs indicate the need to further investigate the potential utilization of certain GFs in the treatment of Alzheimer disease and other neurodegenerative diseases.  Platelet abnormalities and the therapeutic potential of platelet-derived growth factors in these pathologies, either through platelet transfusions or other clinical methods, are considered. Finally, the etiopathogenic mechanisms of apoptosis and antiapoptosis in HNDDs and cancer are viewed as opposite biochemical and biological disorders of cellular acid-base balance and their secondary effects on intracellular signaling pathways and aberrant cell metabolism are considered in the light of the both the seminal and most recent data available. The “trophic factor withdrawal syndrome” is described for the first time in English-speaking medical literature, as well as a Darwinian-like interpretation of cellular behavior related to specific and nonspecific

  8. Transmission of Neurodegenerative Disorders Through Blood Transfusion

    Edgren, Gustaf; Hjalgrim, Henrik; Rostgaard, Klaus;

    2016-01-01

    Background: The aggregation of misfolded proteins in the brain occurs in several neurodegenerative disorders. Aberrant protein aggregation is inducible in rodents and primates by intracerebral inoculation. Possible transfusion transmission of neurodegenerative diseases has important public health...... implications. Objective: To investigate possible transfusion transmission of neurodegenerative disorders. Design: Retrospective cohort study. Setting: Nationwide registers of transfusions in Sweden and Denmark. Participants: 1 465 845 patients who received transfusions between 1968 and 2012. Measurements......: Observational study design, underascertainment of the outcome, and possible insufficient statistical power. Conclusion: The data provide no evidence for the transmission of neurodegenerative diseases and suggest that if transmission does occur, it is rare. Primary Funding Source: Swedish Research Council...

  9. Radiopharmaceuticals for SPECT exploration of dopaminergic systems. Diagnosis and surveillance of neuro-degenerative diseases; Les radiopharmaceutiques pour l`exploration des system dopaminergique en TEMP. Interet pour le diagnostic et le suivi des maladies neurodegeneratives

    Gouilloteau, D.; Prunier-Levallon, C.; Zimmer, L.; Autret, A.; Besnard, J-Cl.; Baulieu, J-L. [CHU TOURS (France)

    1997-12-31

    New radiopharmaceuticals were developed to explore the pre- or post-synaptic slopes of the dopaminergic terminations. At present, their interest is recognized for the differential diagnosis of the extra-pyramidal syndromes. Other various applications in neurology and psychiatry are in view. On the pre-synaptic slope, implied in the Parkinson`s disease, the dopamine carrier, able to be visualized due to its iodine derivatives of cocaine, is localized. The {beta}CIT, which is presently the best known specificity-free derivative, has actually an equivalent affinity for the dopamine carrier and the serotonin carrier. Besides, its kinetic does not allow its imaging in the day of injection. We have developed and validated another derivative, the PE2I: N-(3-Iodoprop-(2E)-enyl) -2{beta}-carbometoxy -3{beta}-(4`-methyl-phenyl) nortropane which displays the properties required by kinetic and specificity. On the post-synaptic slope the type-D2 dopaminergic receptors were localized, which can be explored by means of (iodolisuride) ergolenes and benzamide derivatives (IBZM). These ligands have not an AMM yet, therefore their utilization may be approached by magistral preparation. The scintigraphy of the D2 receptors and dopamine carrier could be useful for the earlier diagnosis and the therapeutic surveillance of the neuro-degenerative decease. The coupling of the pre- and post-synaptic scintigraphies may be taken into consideration to augment diagnosis potentiality

  10. Inhibition of myeloperoxidase-mediated oxidative damage by nitrite in SH-SY5Y cells: Relevance to neuroprotection in neurodegenerative diseases.

    Lu, Naihao; Ding, Yun; Tian, Rong; Peng, Yi-Yuan

    2016-06-01

    Myeloperoxidase (MPO) and MPO-catalyzed hypochlorous acid (HOCl) is elevated in many neurodegenerative diseases, and lead to severe tissue injuries. Nitrite (NO2(-)) is a widespread inorganic molecule that has recently been proposed as a direct NO donor to exert antioxidant properties in vivo and vitro. Since NO2(-) and MPO (and/or HOCl) were important mediators in brain function and disease, we investigated the effects of NO2(-) on MPO-mediated damage to human neuroblastoma SH-SY5Y cells. Here, we showed that exposure of SH-SY5Y cells to MPO (or HOCl) resulted in a significant loss in viability, ATP and glutathione levels, and treatment of neuronal cells with NO2(-) substantially attenuated MPO (or HOCl)-dependent cellular toxicity. The protective effects of NO2(-) on MPO (or HOCl)-induced cytotoxicity were because that (1) NO2(-) at high concentrations competed effectively with Cl(-) for MPO, thus limiting OCl(-) production by the enzyme; (2) HOCl was removed by reacting with NO2(-), forming less damaging compound; (3) NO2(-) significantly inhibited MPO-mediated inactivation of brain protein (enolase) and protein oxidation. Therefore, NO2(-) could show novel protective effects in some neurodegenerative diseases by preventing MPO-mediated oxidative damage. PMID:27020551

  11. Molecular diagnostics of neurodegenerative disorders

    Agrawal, Megha; Biswas, Abhijit

    2015-01-01

    Molecular diagnostics provide a powerful method to detect and diagnose various neurological diseases such as Alzheimer's and Parkinson's disease. The confirmation of such diagnosis allows early detection and subsequent medical counseling that help specific patients to undergo clinically important drug trials. This provides a medical pathway to have better insight of neurogenesis and eventual cure of the neurodegenerative diseases. In this short review, we present recent advances in molecular ...

  12. Substance P and Antagonists of the Neurokinin-1 Receptor in Neuroinflammation Associated with Infectious and Neurodegenerative Diseases of the Central Nervous System

    Martinez, Alejandra N.; Philipp, Mario T.

    2016-01-01

    This review addresses the role that substance P (SP) and its preferred receptor neurokinin-1 (NK1R) play in neuroinflammation associated with select bacterial, viral, parasitic, and neurodegenerative diseases of the central nervous system. The SP/NK1R complex is a key player in the interaction between the immune and nervous systems. A common effect of this interaction is inflammation. For this reason and because of the predominance in the human brain of the NK1R, its antagonists are attractive potential therapeutic agents. Preventing the deleterious effects of SP through the use of NK1R antagonists has been shown to be a promising therapeutic strategy, as these antagonists are selective, potent, and safe. Here we evaluate their utility in the treatment of different neuroinfectious and neuroinflammatory diseases, as a novel approach to clinical management of CNS inflammation.

  13. Mitochondrial Medicine and the Neurodegenerative Mitochondriopathies

    Russell H. Swerdlow

    2009-12-01

    Full Text Available Neurodegenerative diseases are a common late-life scourge for which diseasemodifying treatments are sorely needed. Mitochondrial perturbation is commonly observed in these diseases, so pursuing treatment development strategies that target mitochondria or processes affected by mitochondria seems reasonable. This review discusses the rationale underlying past and current efforts to treat neurodegenerative diseases using mitochondrial medicine, and tries to predict how future efforts might proceed.

  14. 神经炎症与神经退行性疾病的关系%Relationship Between Neuroinflammation and Neurodegenerative Diseases

    邱奥望; 刘展; 郭军; 彰聿平

    2011-01-01

    近十多年来的研究表明,在神经退行性疾病的发生与发展中,脑内始终存在着以胶质细胞激活为主要特征的炎症反应.神经炎症是把双刃剑,一方面,它诱发或加重神经系统的退行性病变;另一方面,它在某些特定情况下有利于神经系统损伤的修复.激活的胶质细胞通过释放致炎细胞因子和活性氧自由基等分子介导神经炎症所致的神经元退行性病变,而由调节性T细胞产生的抗炎细胞因子及由神经元释放的抗炎神经肽能保护神经元抵抗神经炎症,从而减缓或减轻神经退行性疾病的进程.%Over recent decade, studies have shown that inflammatory reaction characterized mainly by the activation of microglia in the brain is implicated in the pathogenesis and processes of neurodegenera tive diseases. Neuroinflammation is a double-edged sword. On the one hand, it induces or aggravates the neurodegeneration in the nervous system, and on the other hand, it favors the recovery of the injured neu rons in certain conditions. The activated glial cells release pro-inflammatory cytokines and reactive oxygen species, which mediate the neuroinflammation-induced neurodegenerative diseases. The anti-inflammato ry cytokines synthesized by regulatory T cells and neuropeptides secreted by neurons protect the neurons against neuroinflammation, through which neurodegenerative diseases are alleviated.

  15. Age, gender, and cancer but not neurodegenerative and cardiovascular diseases strongly modulate systemic effect of the Apolipoprotein E4 allele on lifespan

    Kulminski, Alexander M; Arbeev, Konstantin G; Culminskaya, Irina;

    2014-01-01

    Enduring interest in the Apolipoprotein E (ApoE) polymorphism is ensured by its evolutionary-driven uniqueness in humans and its prominent role in geriatrics and gerontology. We use large samples of longitudinally followed populations from the Framingham Heart Study (FHS) original and offspring...... cohorts and the Long Life Family Study (LLFS) to investigate gender-specific effects of the ApoE4 allele on human survival in a wide range of ages from midlife to extreme old ages, and the sensitivity of these effects to cardiovascular disease (CVD), cancer, and neurodegenerative disorders (ND). The...... analyses show that women's lifespan is more sensitive to the e4 allele than men's in all these populations. A highly significant adverse effect of the e4 allele is limited to women with moderate lifespan of about 70 to 95 years in two FHS cohorts and the LLFS with relative risk of death RR = 1.48 (p = 3...

  16. Permanent, bilateral common carotid artery occlusion in the rat : A model for chronic cerebral hypoperfusion-related neurodegenerative diseases

    Farkas, Eszter; Luiten, Paul G. M.; Bari, Ferenc

    2007-01-01

    Chronic cerebral hypoperfusion has been associated with cognitive decline in aging and Alzheimer's disease. Moreover, the pattern of cerebral blood flow in mild cognitive impairment has emerged as a predictive marker for the progression into Alzheimer's disease. The reconstruction of a pathological

  17. Different molecular pathologies result in similar spatial patterns of cellular inclusions in neurodegenerative disease: a comparative study of eight disorders

    Armstrong, Richard A.; Cairns, Nigel J.

    2012-01-01

    Recent research suggests cell-to-cell transfer of pathogenic proteins such as tau and α-synuclein may play a role in neurodegeneration. Pathogenic spread along neural pathways may give rise to specific spatial patterns of the neuronal cytoplasmic inclusions (NCI) characteristic of these disorders. Hence, the spatial patterns of NCI were compared in four tauopathies, viz., Alzheimer’s disease, Pick’s disease, corticobasal degeneration, and progressive supranuclear palsy, two synucleinopathies,...

  18. 蛇床子素对神经退行性疾病的作用及机制%Function and Mechanism of Osthole for Neurodegenerative Diseases

    路遥; 曾常茜

    2013-01-01

    蛇床子素是最先从伞形科植物中提取分离出的天然香豆素类化合物,具有多种药理学活性。近期研究表明,蛇床子素通过其抗炎、抗氧化、抗凋亡等作用对缺血性脑损伤、实验性自身免疫性脑脊髓炎、帕金森病、阿尔茨海默病和癫痫等多种神经退行性疾病均具有保护作用。%Osthole is a natural coumarin derivative that was the first isolated from umbelliferae plants . It possesses a broad spectrum of pharmacological activities . Recent research showed that osthole has neuroprotective effects through its antioxidative , antiinflammatory and antiapoptotic actions on various neurodegenerative diseases such as cerebral ischemia , experimental autoimmune encephalomyelitis , Parkinson disease , Alzheimer disease , epilepsy and so on .

  19. Synthesis and evaluation of gallocyanine dyes as potential agents for the treatment of Alzheimer's disease and related neurodegenerative tauopathies.

    Mpousis, Spyros; Thysiadis, Savvas; Avramidis, Nicolaos; Katsamakas, Sotirios; Efthimiopoulos, Spiros; Sarli, Vasiliki

    2016-01-27

    In search of safe and effective anti-Alzheimer disease agents a series of gallocyanine dyes have been synthesized and evaluated for their ability to inhibit LRPs/DKK1 interactions. Modulation of the interactions between LRPS and DKK1, regulate Wnt signaling pathway and affect Tau phosphorylation. The current efforts resulted in the identification of potent DKK1 inhibitors which are able to inhibit prostaglandin J2-induced tau phosphorylation at serine 396. PMID:26629858

  20. Transgenic Rat Model of Huntington’s Disease: A Histopathological Study and Correlations with Neurodegenerative Process in the Brain of HD Patients

    Yvona Mazurová

    2014-01-01

    Full Text Available Rats transgenic for Huntington’s disease (tgHD51 CAG rats, surviving up to two years, represent an animal model of HD similar to the late-onset form of human disease. This enables us to follow histopathological changes in course of neurodegenerative process (NDP within the striatum and compare them with postmortem samples of human HD brains. A basic difference between HD pathology in human and tgHD51 rats is in the rate of NDP progression that originates primarily from slow neuronal degeneration consequently resulting in lesser extent of concomitant reactive gliosis in the brain of tgHD51 rats. Although larger amount of striatal neurons displays only gradual decrease in their size, their number is significantly reduced in the oldest tgHD51 rats. Our quantitative analysis proved that the end of the first year represents the turn in the development of morphological changes related to the progression of NDP in tgHD51 rats. Our data also support the view that all types of CNS glial cells play an important, irreplaceable role in NDP. To the best of our knowledge, our findings are the first to document that tgHD51 CAG rats can be used as a valid animal model for detailed histopathological studies related to HD in human.

  1. Therapeutic potential of culinary-medicinal mushrooms for the management of neurodegenerative diseases: diversity, metabolite, and mechanism.

    Phan, Chia-Wei; David, Pamela; Naidu, Murali; Wong, Kah-Hui; Sabaratnam, Vikineswary

    2015-01-01

    Mushrooms have long been used not only as food but also for the treatment of various ailments. Although at its infancy, accumulated evidence suggested that culinary-medicinal mushrooms may play an important role in the prevention of many age-associated neurological dysfunctions, including Alzheimer's and Parkinson's diseases. Therefore, efforts have been devoted to a search for more mushroom species that may improve memory and cognition functions. Such mushrooms include Hericium erinaceus, Ganoderma lucidum, Sarcodon spp., Antrodia camphorata, Pleurotus giganteus, Lignosus rhinocerotis, Grifola frondosa, and many more. Here, we review over 20 different brain-improving culinary-medicinal mushrooms and at least 80 different bioactive secondary metabolites isolated from them. The mushrooms (either extracts from basidiocarps/mycelia or isolated compounds) reduced beta amyloid-induced neurotoxicity and had anti-acetylcholinesterase, neurite outgrowth stimulation, nerve growth factor (NGF) synthesis, neuroprotective, antioxidant, and anti-(neuro)inflammatory effects. The in vitro and in vivo studies on the molecular mechanisms responsible for the bioactive effects of mushrooms are also discussed. Mushrooms can be considered as useful therapeutic agents in the management and/or treatment of neurodegeneration diseases. However, this review focuses on in vitro evidence and clinical trials with humans are needed. PMID:24654802

  2. Human T cell lymphotropic virus type I genomic expression and impact on intracellular signaling pathways during neurodegenerative disease and leukemia.

    Yao, J; Wigdahl, B

    2000-01-01

    HTLV-I has been identified as the etiologic agent of neoplasia within the human peripheral blood T lymphocyte population, and a progressive neurologic disorder based primarily within the central nervous system. We have examined the role of HTLV-I in these two distinctly different clinical syndromes by examining the life cycle of the virus, with emphasis on the regulation of viral gene expression within relevant target cell populations. In particular, we have examined the impact of specific viral gene products, particularly Tax, on cellular metabolic function. Tax is a highly promiscuous and pleiotropic viral oncoprotein, and is the most important factor contributing to the initial stages of viral-mediated transformation of T cells after HTLV-I infection. Tax, which weakly binds to Tax response element 1 (TRE-1) in the viral long terminal repeat (LTR), can dramatically trans-activate viral gene expression by interacting with cellular transcription factors, such as activated transcription factors and cyclic AMP response element binding proteins (ATF/CREB), CREB binding protein (CBP/p300), and factors involved with the basic transcription apparatus. At the same time, Tax alters cellular gene expression by directly or indirectly interacting with a variety of cellular transcription factors, cell cycle control elements, and cellular signal transduction molecules ultimately resulting in dysregulated cell proliferation. The mechanisms associated with HTLV-I infection, leading to tropical spastic paraparesis (TSP) are not as clearly resolved. Possible explanations of viral-induced neurologic disease range from central nervous system (CNS) damage caused by direct viral invasion of the CNS to bystander CNS damage caused by the immune response to HTLV-I infection. It is interesting to note that it is very rare for an HTLV-I infected individual to develop both adult T cell leukemia (ATL) and TSP in his/her life time, suggesting that the mechanisms governing development of these

  3. Genetically modified pig models for neurodegenerative disorders.

    Holm, Ida E; Alstrup, Aage Kristian Olsen; Luo, Yonglun

    2016-01-01

    Increasing incidence of neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease has become one of the most challenging health issues in ageing humans. One approach to combat this is to generate genetically modified animal models of neurodegenerative disorders for studying pathogenesis, prognosis, diagnosis, treatment, and prevention. Owing to the genetic, anatomic, physiologic, pathologic, and neurologic similarities between pigs and humans, genetically modified pig models of neurodegenerative disorders have been attractive large animal models to bridge the gap of preclinical investigations between rodents and humans. In this review, we provide a neuroanatomical overview in pigs and summarize and discuss the generation of genetically modified pig models of neurodegenerative disorders including Alzheimer's diseases, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, and ataxia-telangiectasia. We also highlight how non-invasive bioimaging technologies such as positron emission tomography (PET), computer tomography (CT), and magnetic resonance imaging (MRI), and behavioural testing have been applied to characterize neurodegenerative pig models. We further propose a multiplex genome editing and preterm recloning (MAP) approach by using the rapid growth of the ground-breaking precision genome editing technology CRISPR/Cas9 and somatic cell nuclear transfer (SCNT). With this approach, we hope to shorten the temporal requirement in generating multiple transgenic pigs, increase the survival rate of founder pigs, and generate genetically modified pigs that will more closely resemble the disease-causing mutations and recapitulate pathological features of human conditions. PMID:26446984

  4. Estudo por microscopia eletrônica em doenças neurodegenerativas na infância Electron microscopical study in neurodegenerative diseases in infancy

    Luiz Fernando Bleggi Torres

    1997-01-01

    Full Text Available As doenças neuro degenerativas infantis compõem grupo variado de entidades em que os erros inatos do metabolismo induzem a defeitos enzimáticos intrínsecos às células com eventual acúmulo de material intracelular. A microscopia eletrônica (ME pode auxiliar na caracterização do produto acumulado. Os autores relatam a experiência no diagnóstico das doenças neurodegenerativas na infância através da análise por ME de amostras teciduais provenientes de biópsias, principalmente de pele, conjuntiva e reto e em 2 casos material de necrópsia. As amostras teciduais eram de pacientes com quadro de encefalopatia progressiva a esclarecer. As biópsias de 89 pacientes com quadro de encefalopatia progressiva foram estudadas por microscopia eletrônica. A idade dos pacientes variou de 49 dias a 13 anos, com pico de incidência no primeiro ano de vida (n=28, sendo 50 pacientes do sexo feminino e 39 do masculino. Quanto à origem do material, houve predomínio de pele e conjuntiva. Dos 89 pacientes, 15 tiveram diagnóstico de certeza (16,8% sendo 4 casos de gangliosidose, 3 casos de mucopolissacaridose, 1 caso de doença de Gaucher, 1 caso de doença de Niemann-Pick, 3 casos de lipofuscinose ceróide e 3 casos sugestivos de doença de acúmulo não podendo ser especificadas. Os autores analisaram os aspectos clínicos e os achados ultraestruturais e concluem que a ME é um método complementar valioso no diagnóstico de doença hereditária metabólica de acúmulo, porém de baixa acurácia diagnóstica quando feito como único método de "screening" laboratorial em uma população com encefalopatia progressiva a esclarecer.Neurodegenerative diseases are a group of disorders in which there is storage of abnormal material in cells throughout the body due to an enzyme defect. The authors present the experience in the diagnosis of the neurodegenerative diseases in infancy by electron microscopical study of skin, conjunctival and rectum material of

  5. Conformation-Specific IR and UV Spectroscopy of the Amino Acid Glutamine: Amide-Stacking and Hydrogen Bonding in AN Important Residue in Neurodegenerative Diseases

    Walsh, Patrick S.; Dean, Jacob C.; Zwier, Timothy S.

    2014-06-01

    Glutamine plays an important role in several neurodegenerative diseases including Huntington's disease (HD) and Alzheimer's disease (AD). An intriguing aspect of the structure of glutamine is its incorporation of an amide group in its side chain, thereby opening up the possibility of forming amide-amide H-bonds between the peptide backbone and side chain. In this study the conformational preferences of two capped gluatamines Z(carboxybenzyl)-Glutamine-X (X=OH, NHMe) are studied under jet-cooled conditions in the gas phase in order to unlock the intrinsic structural motifs that are favored by this flexible sidechain. Conformational assignments are made by comparing the hydride stretch ( 3100-3700 cm-1) and amide I and II ( 1400-1800 cm-1) resonant ion-dip infrared spectra with predictions from harmonic frequency calculations. Assigned structures will be compared to previously published results on both natural and unnatural residues. Particular emphasis will be placed on the comparison between glutamine and unconstrained γ-peptides due to the similar three-carbon spacing between backbone and side chain in glutamine to the backbone spacing in γ-peptides. The ability of the glutamine side-chain to form amide stacked conformations will be a main focus, along with the prevalence of extended backbone type structures. W. H. James, III, C W. Müller, E. G. Buchanan, M. G. D. Nix, L. Guo, L. Roskop, M. S. Gordon, L. V. Slipchenko, S. H. Gellman, and T. S. Zwier, J. Am. Chem. Soc., 2009, 131(40), 14243-14245.

  6. Viral-toxin interactions and Parkinson’s disease: poly(I:C priming enhanced the neurodegenerative effects of paraquat

    Bobyn Jessica

    2012-05-01

    Full Text Available Abstract Background Parkinson’s disease (PD has been linked with exposure to a variety of environmental and immunological insults (for example, infectious pathogens in which inflammatory and oxidative processes seem to be involved. In particular, epidemiological studies have found that pesticide exposure and infections may be linked with the incidence of PD. The present study sought to determine whether exposure to a viral mimic prior to exposure to pesticides would exacerbate PD-like pathology. Methods Mice received a supra-nigral infusion of 5 μg of the double-stranded RNA viral analog, polyinosinic: polycytidylic acid (poly(I:C, followed 2, 7 or 14 days later by administration of the pesticide, paraquat (nine 10 mg/kg injections over three weeks. Results As hypothesized, poly(I:C pre-treatment enhanced dopamine (DA neuron loss in the substantia nigra pars compacta elicited by subsequent paraquat treatment. The augmented neuronal loss was accompanied by robust signs of microglial activation, and by increased expression of the catalytic subunit (gp91 of the NADPH oxidase oxidative stress enzyme. However, the paraquat and poly(I:C treatments did not appreciably affect home-cage activity, striatal DA terminals, or subventricular neurogenesis. Conclusions These findings suggest that viral agents can sensitize microglial-dependent inflammatory responses, thereby rendering nigral DA neurons vulnerable to further environmental toxin exposure.

  7. Quantification of total apolipoprotein E and its specific isoforms in cerebrospinal fluid and blood in Alzheimer’s disease and other neurodegenerative diseases

    Melinda Rezeli

    2015-09-01

    Full Text Available A targeted mass spectrometric assay was developed for identification and quantification of apoE isoforms (apoE2, E3 and E4, and it was utilized for screening of samples from AD patients (n = 39 and patients with other neurodegenerative disorders (n = 38. The assay showed good linearity with LOQ corresponds to total apoE concentration of 0.8 and 40 ng/mL in CSF and plasma/serum, respectively. We identified apoE phenotypes with 100% accuracy in clinical samples. We found strong association between genotypes of the individuals and their apoE levels in blood; ϵ4 allele carriers had significantly lower apoE levels in blood than non-carriers.

  8. Additional Clues for a Protective Role ofVitamin D in Neurodegenerative Diseases: 1,25-Dihydroxyvitamin D3 Triggers an Anti-Inflammatory Response in BrainPericytes

    Nissou, Marie-France; Guttin, Audrey; Zenga, Cyril; Berger, François; Issartel, Jean-Paul; Wion, Didier

    2014-01-01

    International audience Epidemiological and experimental studies suggest that 1,25-dihydroxyvitamin D3 (1,25D) plays a neuroprotectiverole in neurodegenerative diseases including Alzheimer's disease. Most of the experimental data regarding the genes regulatedby this hormone in brain cells have been obtained with neuron and glial cells. Pericytes play a critical role in brain function thatencompasses their classical function in blood-brain barrier control and maintenance. However, the gene r...

  9. 线粒体铁蛋白与铁相关的神经退行性疾病%Mitochondria Ferritin and Iron-Related Neurodegenerative Diseases

    赵亚硕; 石振华; 常彦忠

    2012-01-01

    In the mammalia, mitochondria ferritin (MtFt) was encoded by intronless genes, it has high homology with cytoplasmic of H-ferritin and has ferrousoxidase activity. The MtFt is specifically targeted to mitochondria. Recent studies found that MtFt overexpression had a role in protecting mitochondria from iron-induced damage. This paper mainly introduces the structure and function of MtFt and the defense of MtFt in some of the iron-related neurodegenerative diseases.%在哺乳动物体内,线粒体铁蛋白(mitochondrial ferritin,MtFt)是一个无内含子的基因编码的蛋白,与胞质中的H-ferritin具有较高的同源性,也具有亚铁氧化酶的活性,特异性地在线粒体中表达.近年来的研究发现,过表达MtFt可以使线粒体免受由铁引起的氧化损伤.本文主要介绍MtFt在结构功能上的特点,及其在与铁相关的一些神经退行性疾病中的保护作用.

  10. Partial volume effect correction in SPECT for striatal uptake measurements in patients with neurodegenerative diseases: impact upon patient classification

    In single-photon emission computed tomography (SPECT) of the dopaminergic system, measurements of striatal uptake are useful for diagnosis and patient follow-up but are strongly biased by the partial volume effect (PVE). We studied whether PVE correction might improve patient classification based on binding potential (BP) measurements. Patients with a probable diagnosis of dementia with Lewy bodies (DLB, 10 patients) or Alzheimer's disease (AD, 13 patients) were studied by 123I-FP-CIT SPECT. SPECT images were reconstructed with and without PVE correction. Each patient SPECT scan was also simulated to obtain SPECT data whose characteristics were fully known. In addition, 17 SPECT scans were simulated with striatal uptake values mimicking pre-symptomatic cases of DLB. Without PVE correction, mean putamen BP values were 2.9±0.4 and 0.9±0.2 for AD and DLB patients respectively, while with PVE correction, they were 8.6±1.5 and 1.9±0.5 respectively. All patients were properly identified as having AD or DLB when considering mean putamen BP measured on their real or simulated SPECT scan, with and without PVE correction. All 30 simulations mimicking pre-symptomatic DLB and AD patients were accurately classified with PVE correction, but without PVE correction 15 mean putamen BP values were in a range where AD and DLB could not be distinguished. We conclude that putamen BP values measured without PVE correction can be used to differentiate probable DLB and AD due to the already severe reduction in dopamine transporter levels. PVE correction appeared useful for accurate differential diagnosis between AD and pre-symptomatic DLB. (orig.)

  11. Role of metabolism in neurodegenerative disorders.

    Procaccini, Claudio; Santopaolo, Marianna; Faicchia, Deriggio; Colamatteo, Alessandra; Formisano, Luigi; de Candia, Paola; Galgani, Mario; De Rosa, Veronica; Matarese, Giuseppe

    2016-09-01

    Along with the increase in life expectancy over the last century, the prevalence of age-related disorders, such as neurodegenerative diseases continues to rise. This is the case of Alzheimer's, Parkinson's, Huntington's diseases and Multiple sclerosis, which are chronic disorders characterized by neuronal loss in motor, sensory or cognitive systems. Accumulating evidence has suggested the presence of a strong correlation between metabolic changes and neurodegeneration. Indeed epidemiologic studies have shown strong associations between obesity, metabolic dysfunction, and neurodegeneration, while animal models have provided insights into the complex relationships between these conditions. In this context, hormones such as leptin, ghrelin, insulin and IGF-1 seem to play a key role in the regulation of neuronal damage, toxic insults and several other neurodegenerative processes. This review aims to presenting the most recent evidence supporting the crosstalk linking energy metabolism and neurodegeneration, and will focus on metabolic manipulation as a possible therapeutic tool in the prevention and treatment of neurodegenerative diseases. PMID:27506744

  12. Sound Naming in Neurodegenerative Disease

    Chow, Maggie L.; Brambati, Simona M.; Gorno-Tempini, Maria Luisa; Miller, Bruce L.; Johnson, Julene K.

    2010-01-01

    Modern cognitive neuroscientific theories and empirical evidence suggest that brain structures involved in movement may be related to action-related semantic knowledge. To test this hypothesis, we examined the naming of environmental sounds in patients with corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), two…

  13. Autonomic Function in Neurodegenerative Diseases

    Sørensen, Gertrud Laura; Jennum, Poul Jørgen

    2013-01-01

    and REM sleep control, indicating that the disorder may serve as a human model for the sleep-wake and REM sleep flip-flop switches. The increased frequency of transitions may cause increased sympathetic activity during sleep and thereby increased heart rate, or the increased heart rate could be caused...... confirm that hypocretin deficiency affects the autonomic nervous system of patients with narcolepsy and that the hypocretin system is important for proper heart rate modulation at rest.Furthermore, it was shown that hypocretin deficiency and cataplexy are associated with signs of destabilized sleep-wake...

  14. Neuroglial Roots of Neurodegenerative Diseases?

    Rodríguez Arellano, Jose Julio; Verkhratsky, Alexei

    2011-01-01

    Roč. 43, č. 2 (2011), s. 87-96. ISSN 0893-7648 R&D Projects: GA ČR GA309/09/1696; GA ČR GA305/08/1384; GA ČR GA309/08/1381 Institutional research plan: CEZ:AV0Z50390703 Keywords : Astrocytes * Oligodendrocytes * Microglia Subject RIV: FH - Neurology Impact factor: 5.735, year: 2011

  15. Nonlinear multi-photon laser wave-mixing optical detection in microarrays and microchips for ultrasensitive detection and separation of biomarkers for cancer and neurodegenerative diseases

    Iwabuchi, Manna; Hetu, Marcel; Maxwell, Eric; Pradel, Jean S.; Ramos, Sashary; Tong, William G.

    2015-09-01

    Multi-photon degenerate four-wave mixing is demonstrated as an ultrasensitive absorption-based optical method for detection, separation and identification of biomarker proteins in the development of early diagnostic methods for HIV- 1, cancer and neurodegenerative diseases using compact, portable microarrays and capillary- or microchip-based chemical separation systems that offer high chemical specificity levels. The wave-mixing signal has a quadratic dependence on concentration, and hence, it allows more reliable monitoring of smaller changes in analyte properties. Our wave-mixing detection sensitivity is comparable or better than those of current methods including enzyme-linked immunoassay for clinical diagnostic and screening. Detection sensitivity is excellent since the wave-mixing signal is a coherent laser-like beam that can be collected with virtually 100% collection efficiency with high S/N. Our analysis time is short (1-15 minutes) for molecular weight-based protein separation as compared to that of a conventional separation technique, e.g., sodium dodecyl sulfate-polyacrylamide gel electrophoresis. When ultrasensitive wavemixing detection is paired with high-resolution capillary- or microchip-based separation systems, biomarkers can be separated and identified at the zepto- and yocto-mole levels for a wide range of analytes. Specific analytes can be captured in a microchannel through the use of antibody-antigen interactions that provide better chemical specificity as compared to size-based separation alone. The technique can also be combined with immune-precipitation and a multichannel capillary array for high-throughput analysis of more complex protein samples. Wave mixing allows the use of chromophores and absorption-modifying tags, in addition to conventional fluorophores, for online detection of immunecomplexes related to cancer.

  16. Differential Impairment of Cognitive and Affective Mentalizing Abilities in Neurodegenerative Dementias: Evidence from Behavioral Variant of Frontotemporal Dementia, Alzheimer's Disease, and Mild Cognitive Impairment.

    Dodich, Alessandra; Cerami, Chiara; Crespi, Chiara; Canessa, Nicola; Lettieri, Giada; Iannaccone, Sandro; Marcone, Alessandra; Cappa, Stefano F; Cacioppo, John T

    2016-01-01

    Cognitive and affective theory of mind (ToM) can be impaired in the course of neurodegenerative dementias. Experimental tests based on different task conditions and/or complexity may fail to capture disease-specific patterns of impairments. In this study, we assessed with a single task both the affective and the cognitive facets of ToM ability in a sample of 47 patients (i.e., 12 AD, 20 bvFTD, and 15 aMCI fulfilling IWG criteria for AD in predementia phase) and 65 healthy controls. Subjects were administered the Story-based Empathy task (SET), a non-verbal task measuring the ability to infer others' intentions (IA) and emotions (EA) compared to a control condition (causal inferences, CI). Global and single sub-condition scores were evaluated with a vectorial method, analyzing the relationship between social abilities and basic cognitive functioning by means of two indices representing the basic ability to perform the task and the balance between basic functions and ToM skills.Dementia (AD and bvFTD) patients showed impaired performances on all SET sub-conditions, whereas aMCI subjects' performance was not different from healthy controls. Vectorial analysis revealed a specific change in the balance between EA and CI conditions only in the bvFTD group, supporting a disproportionate deficit in mental states attribution based on affective cues. The overall deficit in the task in AD appears to be more general and related to the severity of dementia. This latter finding is further supported by the normal performance of the prodromal AD group. PMID:26836153

  17. Interleukin-18 alters protein expressions of neurodegenerative diseases-linked proteins in human SH-SY5Y neuron-like cells

    Elina M Sutinen

    2014-08-01

    Full Text Available Chronic inflammation and oxidative stress (OS are present in Alzheimer´s disease (AD brains in addition to neuronal loss, Amyloid-β (Aβ plaques and hyperphosphorylated tau-protein neurofibrillary tangles. Previously we showed that levels of the pro-inflammatory cytokine, interleukin-18 (IL-18, are elevated in post-mortem AD brains. IL-18 can modulate the tau kinases, Cdk5 and GSK3β, as well as Aβ-production. IL-18 levels are also increased in AD risk diseases, including type-2 diabetes and obesity. Here, we explored other IL-18 regulated proteins in neuron-like SH-SY5Y cells. Differentiated SH-SY5Y cells, incubated with IL-18 for 24, 48 or 72h, were analyzed by two-dimensional gel electrophoresis (2D-DIGE. Specific altered protein spots were chosen and identified with mass spectrometry and verified by western immunoblotting. IL-18 had time-dependent effects on the SH-SY5Y proteome, modulating numerous protein levels/modifications. We concentrated on those related to OS (DDAH2, peroxiredoxins 2, 3 and 6, DJ-1, BLVRA, Aβ-degradation (MMP14, TIMP2, Aβ-aggregation (Septin-2 and modifications of axon growth and guidance associated, collapsing response mediator protein 2 (CRMP2. IL-18 significantly increased antioxidative enzymes, indicative of OS, and altered levels of glycolytic α- and γ-enolase and multifunctional 14-3-3γ and -ε, commonly affected in neurodegenerative diseases. MMP14, TIMP2, α-enolase and 14-3-3ε, indirectly involved in Aβ metabolism, as well as Septin-2 showed changes that increase Aβ levels. Increased 14-3-3γ may contribute to GSK3β driven tau hyperphosphorylation and CRMP2 Thr514 and Ser522 phosphorylation with the Thr555-site, a target for Rho kinase, showing time-dependent changes. IL-18 also increased caspase-1 levels and vacuolization of the cells. Although our SH-SY5Y cells were not aged, as neurons in AD, our work suggests that heightened or prolonged IL-18 levels can drive protein changes of known

  18. Evidence-based therapy for sleep disorders in neurodegenerative diseases%神经变性疾病相关睡眠障碍的循证治疗

    林雪; 李娟; 刘凌

    2013-01-01

    Objective To evaluate the effectiveness of the treatments for sleep disorders in neurodegeuerative diseases so as to provide the best therapeutic regimens for the evidence-based treatment.Methods Search PubMed,MEDLINE,Cochrane Library,Wanfang Data and China National Knowledge Infrastructure (CNKI) databases with "sleep disorder or sleep disturbance","neurodegenerative diseases","Parkinson's disease or PD","Alzheimer's disease or AD","multiple system atrophy or MSA" as retrieval words.The quality of the articles were evaluated with Jadad Scale.Results A total of 35 articles,including 2 systematic reviews,5 randomized controlled trials,13 clinical controlled trials,13 case series and 2 epidemiological investigation studies were included for evaluation,13 of which were high grade and 22 were low grade articles.Clinical evidences showed that:1) advice on sleep hygiene,careful use of dopaminergic drugs and hypnotic sedative agents should be considered for PD.Bright light therapy (BLT)may improve circadian rhythm sleep disorders and clonazepam may be effective for rapid eye movement sleep behavior disorder (RBD).However,to date,very few controlled studies are available to make a recommendation for the management of sleep disorders in PD; 2) treatments for sleep disorders in AD include drug therapy (e.g.melatonin,acetylcholinesterase inhibitors,antipsychotic drugs,antidepressants)and non-drug therapy (e.g.BLT,behavior therapy),but very limited evidence shows the effectiveness of these treatments; 3) the first line treatment for sleep-related breathing disorder in MSA is nasal continuous positive airway pressure (nCPAP),and clonazepam is effective for RBD in MSA; 4) there is rare evidence related to the treatment of sleep disorders in dementia with Lewy body (DLB) and amyotrophic lateral sclerosis (ALS).Conclusion Evidence-based medicine can provide the best clinical evidence on sleep disorders' treatment in neurodegenerative diseases.%目的 评价神经变性疾病相

  19. Oxidative Stress and Neurodegenerative Disorders

    Jie Li

    2013-12-01

    Full Text Available Living cells continually generate reactive oxygen species (ROS through the respiratory chain during energetic metabolism. ROS at low or moderate concentration can play important physiological roles. However, an excessive amount of ROS under oxidative stress would be extremely deleterious. The central nervous system (CNS is particularly vulnerable to oxidative stress due to its high oxygen consumption, weakly antioxidative systems and the terminal-differentiation characteristic of neurons. Thus, oxidative stress elicits various neurodegenerative diseases. In addition, chemotherapy could result in severe side effects on the CNS and peripheral nervous system (PNS of cancer patients, and a growing body of evidence demonstrates the involvement of ROS in drug-induced neurotoxicities as well. Therefore, development of antioxidants as neuroprotective drugs is a potentially beneficial strategy for clinical therapy. In this review, we summarize the source, balance maintenance and physiologic functions of ROS, oxidative stress and its toxic mechanisms underlying a number of neurodegenerative diseases, and the possible involvement of ROS in chemotherapy-induced toxicity to the CNS and PNS. We ultimately assess the value for antioxidants as neuroprotective drugs and provide our comments on the unmet needs.

  20. Cation shifts as markers in neurodegenerative diseases: correlations with transmitter deficts in Alzheimer and Huntington disease and imaging of excitoxic brain damage

    Gramsbergen, Jan Bert Paul

    1988-01-01

    The clinical syndrome of dementia is best defined as an - usually at advanced age - acquired global impairment of intellect, memory and personality, but without impairment of consciousness, prominent causes of dementia are certain intrinsic degenerative diseases of the brain. The most common of these diseases is Alzheimer's disease (AD) . The pathological hallmark of AD is the presence of large amounts of so called plaques extracellular structures which involve processes of different neurons ...

  1. Accelerated infliximab infusions for inflammatory bowel disease improve effectiveness

    John; McConnell; Simona; Parvulescu-Codrea; Brian; Behm; Beth; Hill; Elizabeth; Dunkle; Karen; Finke; Kathryn; Snyder; Anne; Tuskey; Debbie; Cox; Beth; Woodward

    2012-01-01

    AIM:To study the safety and effectiveness associated with accelerated infliximab infusion protocols in patients with inflammatory bowel disease(IBD).METHODS:Original protocols and infusion rates were developed for the administration of infliximab over 90-min and 60-min.Then the IBD patients on stable maintenance infliximab therapy were offered accelerated infusions.To be eligible for the study,patients needed a minimum of four prior infusions.An initial infusion of 90-min was given to each patient;those tolerating the accelerated infusion were transitioned to a 60-min infusion protocol at their next and all subsequent visits.Any patient having significant infusion reactions would be reverted to the standard 120-min protocol.A change in a patient’s dose mandated a single 120-min infusion before accelerated infusions could be administered again.RESULTS:The University of Virginia Medical Center’s Institutional Review Board approved this study.Fifty IBD patients treated with infliximab 5mg/kg,7.5mg/kg and 10mg/kg were offered accelerated infusions.Forty-six patients consented to participate in the study.Nineteen(41.3%) were female,five(10.9%) were African American and nine(19.6%) had ulcerative colitis.The mean age was 42.6 years old.Patients under age 18 were excluded.Ten patients used immunosuppressive drugs concurrently out of which six were taking azathioprine,three were taking 6-mercaptopurine and one was taking methotrexate.One of the 46 study patients used corticosteroid therapy for his IBD.Seventeen of the patients used prophylactic medications prior to receiving infusions;six patients received corticosteroids as pre-medication.Four patients had a history of distant transfusion reactions to infliximab.These reactions included shortness of breath,chest tightness,flushing,pruritus and urticaria.These patients all took prophylactic medications before receiving infusions.46 patients(27 males and 19 females) received a total of fifty 90-min infusions and ninety

  2. 干细胞治疗神经退行性疾病的前景与问题☆◇%Prospects and problems of stem cells in the treatment of neurodegenerative diseases

    熊杰; 宁丽娜; 王再领; 石学敏

    2013-01-01

      背景:虽然各种神经退行性疾病的人群发病率居高不下且有上升趋势,但至今仍无有效治疗方法,因此,寻求有效的治疗神经退行性疾病的途径是科学界面临的挑战。目的:文章分析和综述了对干细胞治疗神经退行性疾病的近年研究进展及热点问题。方法:文章对干细胞移植治疗神经退行性疾病,如阿尔茨海默病、帕金森病、脑卒中、亨廷顿病、视网膜色素变性疾病、肌萎缩性侧索硬化症、癫痫等疾病的基础与临床研究进展进行概述,探讨干细胞治疗神经退行性疾病的可行性、优势及问题。结果与结论:干细胞治疗神经退行性疾病大部分研究还是集中在实验动物模型阶段,还没有支持干细胞临床治疗的有效证据,其安全性和有效性还没有确切临床保证和标准,临床治疗效果及不良反应都有待大宗及长期临床试验研究进一步验证。%BACKGROUND:Although the incidence of neurodegenerative diseases in various populations is high and has an upward trend, so far there is no effective treatment method. So it is a chal enge for scientific community to seek effective treatment method for the treatment of neurodegenerative diseases. OBJECTIVE:To analyze and review the research progress and hot issues of stem cel s for the treatment of neurodegenerative diseases. METHODS:The basic and clinical researches on stem cel s for the treatment of neurodegenerative diseases were overviewed, including Alzheimer’s disease, Parkinson’s disease, stroke, Huntington’s disease, retinitis pigmentosa, amyotrophic lateral sclerosis and epilepsy, in order to investigate the feasibility, advantages and problems of stem cel s in the treatment of neurodegenerative diseases. RESULTS AND CONCLUSION:Most of the studies on stem cel s in the treatment of neurodegenerative diseases are in the stage of experimental animal models, and there is no valid evidence to

  3. Gene Profiling Technique to Accelerate Stem Cell Therapies for Eye Diseases

    ... to accelerate stem cell therapies for eye diseases Gene profiling technique to accelerate stem cell therapies for ... The method simultaneously measures the expression of multiple genes, allowing scientists to quickly characterize cells according to ...

  4. Why industry propaganda and political interference cannot disguise the inevitable role played by human exposure to aluminium in neurodegenerative diseases, including Alzheimer’s disease.

    Chris eExley

    2014-10-01

    Full Text Available In the aluminium age it is clearly unpalatable for aluminium, the globe’s most successful metal, to be implicated in human disease. It is unpalatable because for approximately 100 years humans have reaped the rewards of the most abundant metal of the Earth’s crust without seriously considering the potential consequences for human health. The aluminium industry is a pillar of the developed and developing world and irrespective of the tyranny of human exposure to aluminium it cannot be challenged without significant consequences for businesses, economies and governments. However, no matter how deep the dependency nor unthinkable the withdrawal, science continues to document, if not too slowly, a burgeoning body burden of aluminium in humans. Herein I will make the case that it is inevitable both today and in the future that an individual’s exposure to aluminium is impacting upon their health and is already contributing to, if not causing, chronic diseases such as Alzheimer’s disease. This is the logical, if uncomfortable, consequence of living in the aluminium age.

  5. Environmental Pollutants as Risk Factors for Neurodegenerative Disorders

    Miguel eChin-Chan; Juliana eNavarro-Yepes; Betzabet eQuintanilla-Vega

    2015-01-01

    Neurodegenerative diseases including Alzheimer (AD) and Parkinson (PD) have attracted attention in last decades due to their high incidence worldwide. The etiology of these diseases is still unclear; however the role of the environment, from diet to the new nanomaterials as putative risk factors has gained importance. More worryingly is the evidence that pre- and post-natal exposures to environmental factors predispose to the onset of neurodegenerative diseases in later life. Neurotoxic metal...

  6. Advances in novel anti-neurodegenerative diseases drugs targeting mitochondria%靶向线粒体抗神经退行性疾病新型药物研究进展

    孙竞; 高静

    2016-01-01

    Mitochondria,the major organelle in neurons,which provides energy via oxidative phosphorylation for all kinds of metabolic activities,is involved in many pathophysiological processes,such as calcium homeostasis and apoptosis. Increasing evi⁃dence has indicated that mitochondrial dysfunction displays a significant role in the early stage of neurodegenerative disorders like Par⁃kinson′s disease(PD)and Alzheimer′s disease(AD). Therefore,studies which focus on mitochondrial dysfunction under these patho⁃logical conditions contribute to understanding the pathogenesis of neurodegenerative disorder and discovering new neuroprotective drugs. Actually,various mitochondria-targeting agents have been tried in clinic or under different investigational phases against neuro⁃degenerative disorders. This review discusses the evidence on mitochondrial impairments during neurodegenerative diseases and the advances in mitochondria-targeting agents as a potential alternative drug strategy for effective management of neurodegenerative diseases.%线粒体是广泛存在于神经元细胞中的细胞器,它既能通过氧化磷酸化作用为各种生命活动提供能量,也参与了如钙稳态和细胞凋亡等多种病理生理性活动的调节。大量研究证明线粒体功能障碍在帕金森病、阿尔茨海默病等神经退行性疾病的早期发生过程中发挥重要作用。探索线粒体在该类疾病发生过程中的变化,对认识神经退行性疾病的发病机制,开发新型神经保护药物具有重要意义。事实上,一些线粒体靶向性药物已用于神经退行性疾病的临床治疗或正处于不同研究阶段。本文通过对有关线粒体在神经退行性疾病中相关证据的讨论,综述线粒体靶向性神经保护剂的研究进展,论证其作为神经退行性疾病治疗药物的可行性。

  7. Synthetic prions and other human neurodegenerative proteinopathies.

    Le, Nhat Tran Thanh; Narkiewicz, Joanna; Aulić, Suzana; Salzano, Giulia; Tran, Hoa Thanh; Scaini, Denis; Moda, Fabio; Giachin, Gabriele; Legname, Giuseppe

    2015-09-01

    Transmissible spongiform encephalopathies (TSE) are a heterogeneous group of neurodegenerative disorders. The common feature of these diseases is the pathological conversion of the normal cellular prion protein (PrP(C)) into a β-structure-rich conformer-termed PrP(Sc). The latter can induce a self-perpetuating process leading to amplification and spreading of pathological protein assemblies. Much evidence suggests that PrP(Sc) itself is able to recruit and misfold PrP(C) into the pathological conformation. Recent data have shown that recombinant PrP(C) can be misfolded in vitro and the resulting synthetic conformers are able to induce the conversion of PrP(C) into PrP(Sc)in vivo. In this review we describe the state-of-the-art of the body of literature in this field. In addition, we describe a cell-based assay to test synthetic prions in cells, providing further evidence that synthetic amyloids are able to template conversion of PrP into prion inclusions. Studying prions might help to understand the pathological mechanisms governing other neurodegenerative diseases. Aggregation and deposition of misfolded proteins is a common feature of several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and other disorders. Although the proteins implicated in each of these diseases differ, they share a common prion mechanism. Recombinant proteins are able to aggregate in vitro into β-rich amyloid fibrils, sharing some features of the aggregates found in the brain. Several studies have reported that intracerebral inoculation of synthetic aggregates lead to unique pathology, which spread progressively to distal brain regions and reduced survival time in animals. Here, we review the prion-like features of different proteins involved in neurodegenerative disorders, such as α-synuclein, superoxide dismutase-1, amyloid-β and tau. PMID:25449570

  8. Development of PET tracers for neuro inflammation imaging in neuro degenerative diseases; Developpement de radiotraceurs de la neuroinflammation pour l'imagerie des pathologies neurodegeneratives

    Chauveau, F

    2007-10-15

    Inflammatory processes such as micro-glial or endothelial activation are involved in many neuro-degenerative conditions. Neuro-inflammation imaging is considered an attractive tool for fundamental research, diagnosis and therapeutic evaluation in neuro-pathologies. First, an aptamer was selected against a recombinant fragment of the endothelial target VCAM-1, but proved unable to bind the target protein in native conformation, as expressed by a cell line. Second, five radioligands of the peripheral benzodiazepine receptor (PBR), a marker of micro-glial activation, were evaluated in vivo using PET (Positron Emission Tomography) imaging in a rat model of neuro-inflammation, and were compared to [11C]PK11195. Four radiotracers displayed a better contrast than [11C]PK11195. In a competitive field of research, this work demonstrates the efficiency of in vivo screening of radiotracers for fast selection of clinically relevant molecules. (author)

  9. Accelerator

    The invention claims equipment for stabilizing the position of the front covers of the accelerator chamber in cyclic accelerators which significantly increases accelerator reliability. For stabilizing, it uses hydraulic cushions placed between the electromagnet pole pieces and the front chamber covers. The top and the bottom cushions are hydraulically connected. The cushions are disconnected and removed from the hydraulic line using valves. (J.P.)

  10. Pediatric neurodegenerative white matter processes: leukodystrophies and beyond

    Pediatric neurodegenerative white matter processes are complex, numerous and result from a vast array of causes ranging from white matter injury or inflammation to congenital metabolic disorders. When faced with a neurodegenerative white matter process on neuroimaging, the first step for the radiologist is to determine whether the findings represent a congenital metabolic leukodystrophy or one of various other white matter processes. In this review we first describe a general approach to neurodegenerative white matter disorders. We will briefly describe a few white matter diseases that mimic metabolic leukodystrophies. In the second half of the review we discuss an approach to distinguishing and classifying white matter leukodystrophies. (orig.)

  11. Brain drug delivery systems for neurodegenerative disorders.

    Garbayo, E; Ansorena, E; Blanco-Prieto, M J

    2012-09-01

    Neurodegenerative disorders (NDs) are rapidly increasing as population ages. However, successful treatments for NDs have so far been limited and drug delivery to the brain remains one of the major challenges to overcome. There has recently been growing interest in the development of drug delivery systems (DDS) for local or systemic brain administration. DDS are able to improve the pharmacological and therapeutic properties of conventional drugs and reduce their side effects. The present review provides a concise overview of the recent advances made in the field of brain drug delivery for treating neurodegenerative disorders. Examples include polymeric micro and nanoparticles, lipidic nanoparticles, pegylated liposomes, microemulsions and nanogels that have been tested in experimental models of Parkinson's, Alzheimer's and Huntington's disease. Overall, the results reviewed here show that DDS have great potential for NDs treatment. PMID:23016644

  12. 5,6-Dihydrodibenzo[b,f][1,4,5]thiadiazepine derivatives and the use thereof in the treatment of neurodegenerative diseases

    Conde, Santiago; Rodríguez-Franco, María Isabel; González Muñoz, Gema Cristina; Villarroya Sánchez, Mercedes; García López, Manuela; García García, Antonio

    2008-01-01

    [EN] Chemical compounds derived fkom the 5.6-dihydrodibemo[b;B[l,4,5]thiadiazepine heterocyclic system and the use thereof as pharmaceutical compositions for the treatment of diseases of the central nervous system that are caused by a series of processes included in that which is generally known as neurodegeneration, specifically for the treatment of Alzheimer's disease, Parkinson's disease or Huntington's disease.

  13. Apraxias in neurodegenerative dementias

    Sadanandavalli Retnaswami Chandra

    2015-01-01

    Full Text Available Background: Apraxia is a state of inability to carry out a learned motor act in the absence of motor, sensory or cerebellar defect on command processed through the Praxis circuit. Breakdown in default networking is one of the early dysfunction in cortical dementias and result in perplexity, awkwardness, omission, substitution errors, toying behavior and unrecognizable gestures in response to command with voluntary reflex dissociation where, when unobserved patient will carry out reflex movements normally. Awareness into the organicity of these phenomenas will help in early diagnosis, which will help in initiating appropriate treatment and slowing down the progression of the disease. Aims and Objectives: The aim was to look for the various kinds of apraxias in patients with dementia using appropriate simple tests. Patients and Methods: Three hundred patients satisfying Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for dementia were evaluated in detail with mandatory investigations for dementia followed by testing for ideational, ideomotor, limb-kinetic, buccopharyngeal, dressing apraxia, constructional apraxia and gait apraxias in addition to recording of rare apraxias when present. Results: Alzheimer′s disease showed maximum association with apraxias in all the phases of the disease ideational, ideomotor, dressing and constructional apraxias early and buccopharyngeal and gait apraxia late. Frontotemporal lobe dementia showed buccopharyngeal and gait apraxias late into the disease. Cortical basal ganglionic degeneration showed limb apraxias and diffuse Lewy body disease showed more agnosias and less apraxias common apraxias seen was Ideational and Ideomotor. Conclusion: Recognition of the apraxias help in establishing organicity, categorization, caregiver education, early strategies for treatment, avoiding anti-psychotics and introducing disease modifying pharmacotherapeutic agents and also prognosticating.

  14. 嗅觉障碍与早期神经退行性疾病的研究进展%Advance in Dysosmia and the Early Neurodegenerative Diseases (review)

    石姣姣; 梁珍; 左萍萍

    2014-01-01

    There are a large amount of neural stem cells in the olfactory system which have an active proliferation, ongoing and direc-tional differentiation and migration in order to adapt to the changing environment. The clinical findings showed that the early stages of some neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease all presented dysosmia. In recent years, the relationship be-tween air pollution and dysosmia attracts public concerns. This article introduced some research progresses in this field.%嗅觉系统存在着增殖活跃、持续发生并定向分化及迁移的大量神经干细胞,以适应不断变化的周围环境。而临床发现一些神经退行性疾患如阿尔茨海默病、帕金森病的早期均有明显的嗅觉障碍。近年,空气污染与嗅觉障碍的关系备受关注。本文介绍该领域的部分研究进展。

  15. Vascular health late after Kawasaki disease: implications for accelerated atherosclerosis

    Cheung, Yiu-Fai

    2014-01-01

    Kawasaki disease (KD), an acute vasculitis that primarily affects young children, is the most common acquired paediatric cardiovascular disease in developed countries. While sequelae of arterial inflammation in the acute phase of KD are well documented, its late effects on vascular health are increasingly unveiled. Late vascular dysfunction is characterized by structural alterations and functional impairment in term of arterial stiffening and endothelial dysfunction and shown to involve both ...

  16. Accelerating Next Generation Vaccine Development for Global Disease Prevention

    Koff, Wayne C.; Dennis R Burton; R.Johnson, Philip; Walker, Bruce D; King, Charles R.; Nabel, Gary J.; Ahmed, Rafi; Bhan, Maharaj Kishan; Plotkin, Stanley A.

    2013-01-01

    Vaccines are among the greatest successes in the history of public health. However, past strategies for vaccine development are unlikely to succeed in the future against major global diseases such as AIDS, TB, and malaria. For such diseases, the correlates of protection are poorly defined and the pathogens evade immune detection and/or exhibit extensive genetic variability. Recent advances have heralded in a new era of vaccine discovery. However, translation of these advances into vaccines re...

  17. Ghrelin: a link between ageing, metabolism and neurodegenerative disorders

    Stoyanova, I.I.

    2014-01-01

    Along with the increase in life expectancy over the last century comes the increased risk for development of age-related disorders, including metabolic and neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's diseases. These chronic disorders share two main characteristics: 1

  18. New molecular targets for PET and SPECT imaging in neurodegenerative diseases Novos alvos moleculares para tomografia por emissão de pósitrons (PET) e tomografia computadorizada por emissão de fóton único (SPECT) em doenças neurodegenerativas

    Marcel Benadiba; Gert Luurtsema; Lauro Wichert-Ana; Carlos Alberto Buchpigel; Geraldo Busatto Filho

    2012-01-01

    The pathophysiology of neurodegenerative diseases (ND) such as Alzheimer's disease (AD) and Parkinson's disease (PD) has not yet been completely elucidated. However, in the past few years, there have been great knowledge advances about intra-and extracellular proteins that may display impaired function or expression in AD, PD and other ND, such as amyloid beta (Aβ), α-synuclein, tau protein and neuroinflammatory markers. Recent developments in the imaging techniques of positron emis...

  19. Interaction between -Synuclein and Other Proteins in Neurodegenerative Disorders

    Kurt A. Jellinger

    2011-01-01

    Full Text Available Protein aggregation is a common characteristic of many neurodegenerative disorders, and the interaction between pathological/toxic proteins to cause neurodegeneration is a hot topic of current neuroscience research. Despite clinical, genetic, and experimental differences, evidence increasingly indicates considerable overlap between synucleinopathies and tauopathies or other protein-misfolding diseases. Inclusions, characteristics of these disorders, also occurring in other neurodegenerative diseases, suggest interactions of pathological proteins engaging common downstream pathways. Novel findings that have shifted our understanding in the role of pathologic proteins in the pathogenesis of Parkinson and Alzheimer diseases have confirmed correlations/overlaps between these and other neurodegenerative disorders. The synergistic effects of α-synuclein, hyperphosphorylated tau, amyloid-β, and other pathologic proteins, and the underlying molecular pathogenic mechanisms, including induction and spread of protein aggregates, are critically reviewed, suggesting a dualism or triad of neurodegeneration in protein-misfolding disorders, although the etiology of most of these processes is still mysterious.

  20. Insights on accelerated skeletal repair in Cushing's disease

    So-Young Kim

    2015-06-01

    In this patient, spontaneous recovery of trabecular bone architecture was reflected by the early correction in TBS. Subsequent TPTD treatment was associated with marked improvement in BMD, presumably due to enhanced mineralization. Complete skeletal repair was achieved by this two-step mechanism in a very short time following successful surgical treatment for Cushing's disease.

  1. Chronic traumatic encephalopathy and other neurodegenerative proteinopathies

    Maria Carmela Tartaglia

    2014-01-01

    Full Text Available “Chronic traumatic encephalopathy” (CTE is described as a slowly progressive neurodegenerative disease believed to result from multiple concussions. Traditionally, concussions were considered benign events and although most people recover fully, about 10% develop a post-concussive syndrome with persisting neurological, cognitive and neuropsychiatric symptoms. CTE was once thought to be unique to boxers, but it has now been observed in many different athletes having suffered multiple concussions as well as in military personal after repeated blast injuries. Much remains unknown about the development of CTE but its pathological substrate is usually tau, similar to that seen in Alzheimer’s disease and frontotemporal lobar degeneration. The aim of this “perspective” is to compare and contrast clinical and pathological CTE with the other neurodegenerative proteinopathies and highlight that there is an urgent need for understanding the relationship between concussion and the development of CTE as it may provide a window into the development of a proteinopathy and thus new avenues for treatment.

  2. Establishment of Radiolabelling Method for the Development of Neurodegenerative Disease Imaging Agent Using 5-HT{sub 1A} Subtype of Receptor Anatagonist

    Choi, Sun Ju; Choi, Sang Mu; Kim, On Hee; Hong, Young Don; Park, Kyung Bae [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2005-07-01

    The 5-HT1A subtype of receptors for the neurotransmitter serotonin is predominantly located in the limbic forebrain. And it is involved in the modulation of emotion and the function of the hypothalamus. Since 5-HT1A receptors are implicated in the pathogenesis of anxiety, depression, hallucinogenic behaviour, motion sickness and eating disorders, they are an important target for drug therapy and diagnosis of diseases. Serotonin is synthesized from the amino acid L-tryptophan by sequential hydroxylation and decarboxylation. It is stored in presynaptic vesicles and released from nerve terminals during neuronal firing. One of the best-characterised binding sites for serotonin is the 5-HT1A receptor. This is mainly due to the relatively early discovery of a selective ligand, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) for this subpopulation. Thus, many researchers have tried to develop a radioligand capable of assessing in vivo changes in 5-HT1A receptors in depressed subjects, people with anxiety disorders, patients with Alzheimer's disease and schizophrenics. In present study, we studied the radioligands which would play a role in visualization and quantification of this important neuroreceptor for single-photon emission tomography (SPET)

  3. Establishment of Radiolabelling Method for the Development of Neurodegenerative Disease Imaging Agent Using 5-HT1A Subtype of Receptor Anatagonist

    The 5-HT1A subtype of receptors for the neurotransmitter serotonin is predominantly located in the limbic forebrain. And it is involved in the modulation of emotion and the function of the hypothalamus. Since 5-HT1A receptors are implicated in the pathogenesis of anxiety, depression, hallucinogenic behaviour, motion sickness and eating disorders, they are an important target for drug therapy and diagnosis of diseases. Serotonin is synthesized from the amino acid L-tryptophan by sequential hydroxylation and decarboxylation. It is stored in presynaptic vesicles and released from nerve terminals during neuronal firing. One of the best-characterised binding sites for serotonin is the 5-HT1A receptor. This is mainly due to the relatively early discovery of a selective ligand, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) for this subpopulation. Thus, many researchers have tried to develop a radioligand capable of assessing in vivo changes in 5-HT1A receptors in depressed subjects, people with anxiety disorders, patients with Alzheimer's disease and schizophrenics. In present study, we studied the radioligands which would play a role in visualization and quantification of this important neuroreceptor for single-photon emission tomography (SPET)

  4. The new insight on the regulatory role of the vitamin D3 in metabolic pathways characteristic for cancerogenesis and neurodegenerative diseases.

    Kubis, Adriana Maria; Piwowar, Agnieszka

    2015-11-01

    Apart from the classical function of regulating intestinal, bone and kidney calcium and phosphorus absorption as well as bone mineralization, there is growing evidence for the neuroprotective function of vitamin D3 through neuronal calcium regulation, the antioxidative pathway, immunomodulation and detoxification. Vitamin D3 and its derivates influence directly or indirectly almost all metabolic processes such as proliferation, differentiation, apoptosis, inflammatory processes and mutagenesis. Such multifactorial effects of vitamin D3 can be a profitable source of new therapeutic solutions for two radically divergent diseases, cancer and neurodegeneration. Interestingly, an unusual association seems to exist between the occurrence of these two pathological states, called "inverse comorbidity". Patients with cognitive dysfunctions or dementia have considerably lower risk of cancer, whereas survivors of cancer have lower prevalence of central nervous system (CNS) disorders. To our knowledge, there are few publications analyzing the role of vitamin D3 in biological pathways existing in carcinogenic and neuropathological disorders. PMID:26238411

  5. Gene Mutation of Tau Protein and Neurodegenerative Diseases%Tau蛋白基因突变与神经退行性疾病

    王建枝

    1999-01-01

    @@ Tau蛋白是神经细胞中含量最高的微管相关蛋白,其正常功能是促进微管蛋白(tubulin)组装成微管(microtubule),并维持已形成微管的稳定性.Tau蛋白的翻译后异常修饰与阿尔茨海默病(Alzheimer disease,AD)的神经原纤维退化有关[1].本文综述最近有关Tau蛋白基因突变,Tau mRNA剪接改变导致Tau蛋白组成、结构和功能异常的机制,及其与几种神经退行性疾病的关系的研究.

  6. Anti-VEGF antibody treatment accelerates polycystic kidney disease.

    Raina, Shagun; Honer, Michael; Krämer, Stefanie D; Liu, Yang; Wang, Xueqi; Segerer, Stephan; Wüthrich, Rudolf P; Serra, Andreas L

    2011-10-01

    Polycystic kidney growth implies expansion of the vasculature, suggesting that vascular endothelial growth factor (VEGF)-dependent processes play a critical role and that VEGF is a putative therapeutic target. Whether an anti-VEGF antibody improves renal cystic disease has not been determined. We administrated 5 mg/kg B20.4.1, an anti-VEGF-A antibody, or vehicle intraperitoneally twice weekly to 4-wk-old male normal (+/+) and cystic (Cy/+) Han:SPRD rats for 6 wk. Renal function, urinary protein excretion, organ/body weight ratios, cyst volume, tubular epithelial cell (TEC) proliferation, renal VEGF, hypoxia-inducible factor (HIF)-1α and -2α expression, renal histology, and kidney hypoxia visualized by [(18)F]fluoromisonidazole positron emission tomography were assessed. The treated compared with untreated +/+ rats had lower TEC proliferation rates, whereas Cy/+ rats receiving B20.4.1 displayed an increased proximal TEC proliferation rate, causing enhanced cyst and kidney growth. The +/+ and Cy/+ rats receiving B20.4.1 had severe renal failure and extensive glomerular damage. Proteinuria, which was highest in anti-VEGF-treated Cy/+ and lowest in untreated normal littermates, was positively correlated with renal HIF-1α and negatively correlated with VEGF expression. The untreated Cy/+ vs. +/+ rats had higher overall [(18)F]fluoromisonidazole uptake. The +/+ rats receiving B20.4.1 vs. untreated had increased [(18)F]fluoromisonidazole uptake, whereas the uptake was unchanged among treated vs. untreated Cy/+ animals. In conclusion, B20.4.1 caused an exaggerated cystic response of the proximal tubules in cystic rats and severe kidney injury that was associated with low renal VEGF and high HIF-1α levels. Anti-VEGF drug therapy may therefore not be a treatment option for polycystic kidney disease. PMID:21677148

  7. [18F]desmethoxyfallypride as a novel PET radiotracer for quantitative in vivo dopamine D2/D3 receptor imaging in rat models of neurodegenerative diseases

    Introduction: [18F]desmethoxyfallypride ([18F]DMFP) is a promising tracer for longitudinal assessment of striatal dopamine D2/D3-receptor (D2R) availability by positron emission tomography (PET) in small animal models. We explored the feasibility of [18F]DMFP-PET to image D2R availability in rat models of Huntington's (HD) and Parkinson's disease (PD). Methods: Animals received either unilateral intrastriatal quinolinic acid lesions or medial forebrain bundle injections of 6-OHDA to produce the loss of striatal projection neurones or deplete the striatal dopamine, corresponding to established animal models for HD and PD, respectively. Three weeks after lesioning, PET scans were acquired on a microPET Focus 120 system following the tail vein injection of [18F]DMFP. Results: [18F]DMFP-PET clearly visualized lesion induced decreases and increases of D2R availability. In vivo estimates of D2R binding and changes thereof gained by pharmacokinetic analyses correlated significantly with D2R density and its change provided by in vitro [3H]raclopride-autoradiography. Conclusions: In conclusion, [18F]DMFP-PET is a suitable method for in vivo D2R-assessment in preclinical research, e.g for monitoring cell-based therapies.

  8. Modelling studies on neurodegenerative disease-causing triplet repeat sequences d(GGC/GCC)n and d(CAG/CTG)n

    Shibasish Chowdhury; Manju Bansal

    2001-12-01

    Model building and molecular mechanics studies have been carried out to examine the potential structures for d(GGC/GCC)5 and d(CAG/CTG)5 that might relate to their biological function and association with triplet repeat expansion diseases. Model building studies suggested that hairpin and quadruplex structures could be formed with these repeat sequences. Molecular mechanics studies have demonstrated that the hairpin and hairpin dimer structures of triplet repeat sequences formed by looping out of the two strands are as favourable as the corresponding B-DNA type hetero duplex structures. Further, at high salt condition, Greek key type quadruplex structures are energetically comparable with hairpin dimer and B-DNA type duplex structures. All tetrads in the quadruplex structures are well stacked and provide favourable stacking energy values. Interestingly, in the energy minimized hairpin dimer and Greek key type quadruplex structures, all the bases even in the non-G tetrads are cyclically hydrogen bonded, even though the A, C and T-tetrads were not hydrogen bonded in the starting structures.

  9. Dual activities of the anti-cancer drug candidate PBI-05204 provide neuroprotection in brain slice models for neurodegenerative diseases and stroke.

    Van Kanegan, Michael J; Dunn, Denise E; Kaltenbach, Linda S; Shah, Bijal; He, Dong Ning; McCoy, Daniel D; Yang, Peiying; Peng, Jiangnan; Shen, Li; Du, Lin; Cichewicz, Robert H; Newman, Robert A; Lo, Donald C

    2016-01-01

    We previously reported neuroprotective activity of the botanical anti-cancer drug candidate PBI-05204, a supercritical CO2 extract of Nerium oleander, in brain slice and in vivo models of ischemic stroke. We showed that one component of this neuroprotective activity is mediated through its principal cardiac glycoside constituent, oleandrin, via induction of the potent neurotrophic factor brain-derived neurotrophic factor (BDNF). However, we also noted that the concentration-relation for PBI-05204 in the brain slice oxygen-glucose deprivation (OGD) model is considerably broader than that for oleandrin as a single agent. We thus surmised that PBI-05204 contains an additional neuroprotective component(s), distinct from oleandrin. We report here that neuroprotective activity is also provided by the triterpenoid constituents of PBI-05204, notably oleanolic acid. We demonstrate that a sub-fraction of PBI-05204 (Fraction 0-4) containing oleanolic and other triterpenoids, but without cardiac glycosides, induces the expression of cellular antioxidant gene transcription programs regulated through antioxidant transcriptional response elements (AREs). Finally, we show that Fraction 0-4 provides broad neuroprotection in organotypic brain slice models for neurodegeneration driven by amyloid precursor protein (APP) and tau implicated in Alzheimer's disease and frontotemporal dementias, respectively, in addition to ischemic injury modeled by OGD. PMID:27172999

  10. Discovery of Potent and Selective Inhibitors of Phosphodiesterase 1 for the Treatment of Cognitive Impairment Associated with Neurodegenerative and Neuropsychiatric Diseases.

    Li, Peng; Zheng, Hailin; Zhao, Jun; Zhang, Lei; Yao, Wei; Zhu, Hongwen; Beard, J David; Ida, Koh; Lane, Weston; Snell, Gyorgy; Sogabe, Satoshi; Heyser, Charles J; Snyder, Gretchen L; Hendrick, Joseph P; Vanover, Kimberly E; Davis, Robert E; Wennogle, Lawrence P

    2016-02-11

    A diverse set of 3-aminopyrazolo[3,4-d]pyrimidinones was designed and synthesized. The structure-activity relationships of these polycyclic compounds as phosphodiesterase 1 (PDE1) inhibitors were studied along with their physicochemical and pharmacokinetic properties. Systematic optimizations of this novel scaffold culminated in the identification of a clinical candidate, (6aR,9aS)-2-(4-(6-fluoropyridin-2-yl)benzyl)-5-methyl-3-(phenylamino)-5,6a,7,8,9,9a-hexahydrocyclopenta[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4-(2H)-one phosphate (ITI-214), which exhibited picomolar inhibitory potency for PDE1, demonstrated excellent selectivity against all other PDE families and showed good efficacy in vivo. Currently, this investigational new drug is in Phase I clinical development and being considered for the treatment of several indications including cognitive deficits associated with schizophrenia and Alzheimer's disease, movement disorders, attention deficit and hyperactivity disorders, and other central nervous system (CNS) and non-CNS disorders. PMID:26789933

  11. The stretcher spontaneous neurodegenerative mutation models Charcot-Marie-Tooth disease type 4D [v1; ref status: indexed, http://f1000r.es/8c

    David Chandler

    2013-02-01

    Full Text Available Mice affected by a spontaneous mutation which arose within our colony exhibited a neuromuscular phenotype involving tremor and characteristic stretching of the rear limbs. The mutant, named stretcher, was used to breed a backcross cohort for genetic mapping studies. The gene responsible for the mutant phenotype was mapped to a small region on mouse chromosome 15, with a LOD score above 20. Candidate genes within the region included the Ndrg1 gene. Examination of this gene in the mutant mouse strain revealed that exons 10 to 14 had been deleted. Mutations in the human orthologue are known to result in Charcot-Marie-Tooth disease type 4D (CMT4D a severe early-onset disorder involving Schwann cell dysfunction and extensive demyelination. The stretcher mutant mouse is more severely affected than mice in which the Ndrg1 gene had been knocked out by homologous recombination. Our results demonstrate that the Ndrg1str mutation provides a new model for CMT4D, and demonstrate that exons 10 to 14 of Ndrg1 encode amino acids crucial to the appropriate function of Ndrg1 in the central nervous system.

  12. SÍNDROME DE DISFUNCIÓN COGNITIVA DEL PERRO COMO MODELO DE INVESTIGACIÓN DE LAS ENFERMEDADES NEURODEGENERATIVAS DEL HUMANO Cognitive dysfunction syndrome in dog senior: a suitable model for human neurodegenerative diseases?

    Diana Y. Gallego1

    2010-01-01

    envejecimiento de los humanos.In humans and canines, the aging process increases the risk of neurodegenerative diseases such as Alzheimer’s disease and cognitive dysfunction syndrome in senior dogs. These pathological changes in different brain areas cause dementia syndromes, generating an apparent cognitive deficit characterized by behavioral changes such as alterations in memory and learning processes. The deleterious effects on quality of life in human patient affected by AD, promote the need to find similar pathologies affecting other species, making these, experimental models useful for the investigation of human suffering. Recently it has been suggested a close similarity between several of the clinical, anatomical and physiological characteristic of the Alzheimer’s disease and the cognitive dysfunction syndrome senior dogs, which includes the formation and accumulation of amyloid plaques, apoptosis of cholinergic neurons with a consequent reduction of the neurotransmitter acetyl - hill, progressive type cognitive deficits and alterations in the sleep-wake cycle, among others. Thus, progress in understanding the processes involved in the pathophysiology of cognitive dysfunction syndrome senior dogs, and recognizing their similarities to those that occurred during the Alzheimer’s disease, has facilitated studies aimed at understanding some aspects that have not been well detailed neurodegenrativas disease in humans. Moreover, considering the high probability of getting the cognitive dysfunction syndrome senior dogs, which is identified in several canine populations, allows for the possibility of proposing the dog changes, as an optimal model for research experimentate neurodegenerative processes associated with aging in humans.

  13. Role of brain glutamic acid metabolism changes in neurodegenerative pathologies

    Nina Pavlovna Kanunnikova

    2012-01-01

    Glutamic acid is an essential participant of brain metabolism. It is known that the glutamate is a neurotransmitter in a numerous part of the brain synapses and acts through various ionotropic or metabotropic receptors. Multiple alterations of the brain glutamate system are observed in both acute and chronic brain injures. Glutamate metabolism changes take place in many neurodegenerative pathologies, such as brain ischemia, Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, amyot...

  14. Therapeutic application of neural stem cells and adult neurogenesis for neurodegenerative disorders: regeneration and beyond

    Latchney, Sarah E.; Eisch, Amelia J.

    2012-01-01

    With the growth of the aging population and increasing life expectancy, the diagnosis of age-related neurodegenerative diseases is predicted to increase 12% by 2030. There is urgent need to develop better and novel treatments for disorders like Alzheimer’s, Huntington’s, and Parkinson’s diseases. As these neurodegenerative diseases are customarily defined by the progressive loss of neurons, treatment strategies have traditionally focused on replacing neurons lost during disease progression. T...

  15. Potential role of the interaction between equine estrogens, low-density lipoprotein (LDL and high-density lipoprotein (HDL in the prevention of coronary heart and neurodegenerative diseases in postmenopausal women

    Gerulath Alan

    2003-06-01

    Full Text Available Abstract Background An inverse relationship between the level of high-density lipoprotein (HDL and coronary heart disease (CHD has been reported. In contrast, oxidized HDL (oHDL has been shown to induce neuronal death and may play an important role in the pathogenesis of CHD. In the present study we have investigated a: the effect of various equine estrogens on HDL oxidation, b: the inhibition of LDL oxidation by HDL and c: the effect of these estrogens on LDL oxidation in the presence of HDL. Results All 11 equine estrogens tested protected the HDL from oxidation in a concentration dependant manner. Equilenin, 17β-dihydroequilenin, and 17α-dihydroequilenin (Δ6–8-estrogens were found to be the most potent inhibitors of HDL oxidation. Some of the novel ring B unsaturated estrogens were 2.5 to 4 times more potent inhibitors of HDL oxidation than 17β-estradiol. HDL was found to delay LDL oxidation. The protection of LDL oxidation by HDL is enhanced by the addition of estrogen, with equilenin being again more potent than 17β-estradiol. Conclusions Equine estrogens can differentially inhibit the oxidation of HDL with the Δ6–8-estrogens being the most potent antioxidants. The ability of estrogens to enhance HDL's antioxidant activity is to our knowledge the first report of an interaction of estrogen with HDL that results in the delay or inhibition of LDL oxidation. This may be another mechanism by which estrogens may reduce the risk of CHD and neurodegenerative diseases in healthy and younger postmenopausal women.

  16. Acceleration of pubertal development following pituitary radiotherapy for Cushing's disease

    Nicholl, R.M.; Kirk, J.M.W.; Grossman, A.B.; Plowman, P.N.; Besser, G.M.; Savage, M.O. (Saint Bartholomew' s Hospital, London (United Kingdom))

    1993-01-01

    A 7-year-old boy with pituitary dependent Cushing's disease was treated with pituitary irradiation following unsuccessful microadenomectomy. This led to normalization of the hypercortisolaemia, but was followed by GH deficiency. Two years after radiotherapy he had the onset of pubertal development with testicular enlargement to 8 ml bilaterally. Pubertal regression was induced using the long-acting GnRH analogue goserelin. Acceleration of skeletal maturation was also arrested, resulting in improvement of final height prediction. Irradiation directly to the hypothalamo-pituitary region, as well as whole brain irradiation, may thus be associated with accelerated pubertal development. (author).

  17. Epigenetics and etiology of neurodegenerative diseases

    Beata M. Gruber

    2011-01-01

    Determination of specific gene profile expression is essential for morphological and functional differentiation of cells in the human organism. The human genome consists of 25–30 thousands genes but only some of them are expressed in each cell. Epigenetic modifications such as DNA methylation, histone and chromatin modifications or non-coding RNA functions are also responsible for the unique gene expression patterns. It is suggested that transcriptional gene activation is related to hypomethy...

  18. Stem cell biology and neurodegenerative disease.

    McKay, R D

    2004-01-01

    The fundamental basis of our work is that organs are generated by multipotent stem cells, whose properties we must understand to control tissue assembly or repair. Central nervous system (CNS) stem cells are now recognized as a well-defined population of precursors that differentiate into cells that are indisputably neurons and glial cells. Work from our group played an important role in defining stem cells of the CNS. Embryonic stem (ES) cells also differentiate to specific neuron and glial ...

  19. Need to improve clinical trials in rare neurodegenerative disorders

    Maria Puopolo

    2011-01-01

    Full Text Available Rare neurodegenerative diseases are fatal and no therapy is available to cure or slow down the progression of disease. We report possibly weaknesses in the management of clinical studies in these diseases, ranging from poor preclinical studies, difficulties in the recruitment of patients, delay in the onset of treatment because of lack in early disease-specific biomarkers, and suboptimal design of Phase II clinical trials. The adoption of innovative statistical approaches in early Phase II trials might improve the screening of drugs in rare neurodegenerative disorders, but this implicates efforts from clinical researchers, statisticians, and regulatory people to the development of new strategies that should maintain rigorous scientific integrity together with a more ethical approach to human experimentations.

  20. The Applications of the Induced Pluripotent Stem Cells in Studying the Neurodegenerative Diseases%诱导多能干细胞及其在神经退行性疾病研究中的应用

    韩发彬

    2012-01-01

    It is the prominent breakthrough in stem cell research to generate the induced pluripotent stem cells (iPS cells) through the somatic cell reprogramming of the stem cell transcription factors OCT4, SOX2, c-MYC and KLF4. In recent years, continuous progress has been made in the iPS cell research. Since the iPS cells are generated from the somatic fibroblasts or blood cells, they avoid the concerns on the ethics and immune rejections and open the windows for their clinical applications to study the mechanisms, drug screening and self-transplantation therapy of the human diseases. Here we summarized the recent advances in the methods of iPS cells, the mechanisms of reprogramming by transcription factors and the applications of the iPS cells in research on some neurodegenerative diseases and neurodevelopmental diseases. We also discussed the recent advance in using the iPS cells models from patients with Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease and spinal muscular atrophy to explore the molecular mechanism of the mutations in the genes for these diseases.%用干细胞转录因子OCT4、SOX2、c-MYC和KLF4进行体细胞重编程产生具有胚胎干细胞特性的诱导多能干细胞(iPS细胞)是干细胞研究领域的突破性进展.近年来,iPS细胞的研究从产生方法、重编程机理及实际应用方面不断取得进展.由于iPS细胞的产生可取自体细胞,因而克服了胚胎干细胞应用的伦理学和免疫排斥等缺陷,为iPS细胞的临床应用开辟了广阔的前景.该文将对iPS细胞的产生方法、重编程机理及其在神经性退行性疾病的研究与应用进行文献综述,反映近几年iPS细胞最新研究成果,并阐述了用病人iPS细胞模型探讨帕金森氏病、老年性痴呆症、脊髓侧索硬化症、脊髓肌肉萎缩症及舞蹈症等5种常见神经性退行性疾病发病机理的研究现状.

  1. Cross-pollination of research findings, although uncommon, may accelerate discovery of human disease genes

    Duda Marlena

    2012-11-01

    Full Text Available Abstract Background Technological leaps in genome sequencing have resulted in a surge in discovery of human disease genes. These discoveries have led to increased clarity on the molecular pathology of disease and have also demonstrated considerable overlap in the genetic roots of human diseases. In light of this large genetic overlap, we tested whether cross-disease research approaches lead to faster, more impactful discoveries. Methods We leveraged several gene-disease association databases to calculate a Mutual Citation Score (MCS for 10,853 pairs of genetically related diseases to measure the frequency of cross-citation between research fields. To assess the importance of cooperative research, we computed an Individual Disease Cooperation Score (ICS and the average publication rate for each disease. Results For all disease pairs with one gene in common, we found that the degree of genetic overlap was a poor predictor of cooperation (r2=0.3198 and that the vast majority of disease pairs (89.56% never cited previous discoveries of the same gene in a different disease, irrespective of the level of genetic similarity between the diseases. A fraction (0.25% of the pairs demonstrated cross-citation in greater than 5% of their published genetic discoveries and 0.037% cross-referenced discoveries more than 10% of the time. We found strong positive correlations between ICS and publication rate (r2=0.7931, and an even stronger correlation between the publication rate and the number of cross-referenced diseases (r2=0.8585. These results suggested that cross-disease research may have the potential to yield novel discoveries at a faster pace than singular disease research. Conclusions Our findings suggest that the frequency of cross-disease study is low despite the high level of genetic similarity among many human diseases, and that collaborative methods may accelerate and increase the impact of new genetic discoveries. Until we have a better

  2. Biomarkers of neurodegenerative disorders:How good are they?

    Varun RACHAKONDA; Tian Hong PAN; Wei Dong LE

    2004-01-01

    Biomarkers are very important indicators of normal and abnormal biological processes. Specific changes in pathologies,biochemistries and genetics can give us comprehensive information regarding the nature of any particular disease. A good biomarker should be precise and reliable, distinguishable between normal and interested disease, and differentiable between different diseases. It is believed that biomarkers have great potential in predicting chances for diseases, aiding in early diagnosis, and setting standards for the development of new remedies to treat diseases. New technologies have enabled scientists to identify biomarkers of several different neurodegenerative diseases. The followings, for instance,are only a few of the many new biomarkers that have been recently identified: the phosphorylated tau protein and aggregated β-amyloid peptide for Alzheimer's disease (AD), α-synuclein contained Lewy bodies and altered dopamine transporter (DAT) imaging for Parkinson's disease (PD), SOD mutations for familial amyotrophic lateral sclerosis (ALS), and CAG repeats resulted from Huntington's gene mutations in Huntington's disease (HD). This article will focus on the most-recent findings of biomarkers belonging to the four mentioned neurodegenerative diseases.

  3. Actions of neurosteroids in neurons and the treatment of neurodegenerative disease%神经甾体激素对神经元的影响及在神经退行性疾病治疗中的作用

    杨倩倩; 张鹏; 戴侃纯; 王佳婷; 孙臣友

    2014-01-01

    在中枢神经系统中,神经元和神经胶质细胞能够表达神经甾体激素合成的关键酶。当神经甾体激素产生的浓度足够高时,可行使旁分泌作用。脑内神经甾体激素的合成会随年龄的增长呈现下降的趋势。在应激状态下,神经甾体激素的合成也下降。最近的研究报告显示,脑内神经甾体激素水平的下降与神经元的变性及其功能障碍有关。本文仅就目前研究最多的神经甾体激素(如脱氢表雄酮、孕烯醇酮及其硫酸酯、孕酮和别孕烯醇酮)影响神经元存活,神经突的增长和神经元增生的最新研究成果以及这些神经甾体激素在治疗神经退行性疾病中的潜在性作用进行综述。%Neurons and glia in the central nervous system can express the key enzymes for the synthesis of neurosteroids .Once the concentration of neurosteroids is high enough , they will exert paracrine effects .Synthesis of neurosteroids declines with age in brain .So does it under stressful circumstances .Recent research reports indicate that the decrease of neurosteroids is associated with the neuronal dysfunction and degeneration in the brain .This paper reviews recent research on the most studied neurosteroids ( for example , dehydroepiandrosterone , pregnenolone and their sulphate esters, progesterone and allopregnanolone ) in affecting neuronal survival , neurite outgrowth and neurogenesis , and the potential roles of these neurosteroids in the treatment of neurodegenerative disease as well .

  4. MRI of degenerative lumbar spine disease: comparison of non-accelerated and parallel imaging

    Noelte, Ingo; Gerigk, Lars; Brockmann, Marc A.; Kemmling, Andre; Groden, Christoph [Medical Faculty Mannheim of the University of Heidelberg, Department of Neuroradiology, Mannheim (Germany)

    2008-05-15

    Parallel imaging techniques such as GRAPPA have been introduced to optimize image quality and acquisition time. For spinal imaging in a clinical setting no data exist on the equivalency of conventional and parallel imaging techniques. The purpose of this study was to determine whether T1- and T2-weighted GRAPPA sequences are equivalent to conventional sequences for the evaluation of degenerative lumbar spine disease in terms of image quality and artefacts. In patients with clinically suspected degenerative lumbar spine disease two neuroradiologists independently compared sagittal GRAPPA (acceleration factor 2, time reduction approximately 50%) and non-GRAPPA images (25 patients) and transverse GRAPPA (acceleration factor 2, time reduction approximately 50%) and non-GRAPPA images (23 lumbar segments in six patients). Comparative analyses included the minimal diameter of the spinal canal, disc abnormalities, foraminal stenosis, facet joint degeneration, lateral recess, nerve root compression and osteochondrotic vertebral and endplate changes. Image inhomogeneity was evaluated by comparing the nonuniformity in the two techniques. Image quality was assessed by grading the delineation of pathoanatomical structures. Motion and aliasing artefacts were classified from grade 1 (severe) to grade 5 (absent). There was no significant difference between GRAPPA and non-accelerated MRI in the evaluation of degenerative lumbar spine disease (P > 0.05), and there was no difference in the delineation of pathoanatomical structures. For inhomogeneity there was a trend in favour of the conventional sequences. No significant artefacts were observed with either technique. The GRAPPA technique can be used effectively to reduce scanning time in patients with degenerative lumbar spine disease while preserving image quality. (orig.)

  5. Neurodegenerative changes in patients with clinical history of bipolar disorders.

    Shioya, Ayako; Saito, Yuko; Arima, Kunimasa; Kakuta, Yukio; Yuzuriha, Takefumi; Tanaka, Noriko; Murayama, Shigeo; Tamaoka, Akira

    2015-06-01

    Neurodegeneration in bipolar disorder (BPD) is poorly understood. Therefore, the current study was designed to assess the immunohistochemical changes in neurodegenerative markers in patients with BPD. Eleven consecutive autopsy cases diagnosed with BPD were analyzed. Sections were obtained from archival paraffin blocks of representative areas and stained using conventional methods, as well as immunostained with several antibodies to screen for neurodegenerative diseases. Age- and non-argyrophilic grains (AGs) degeneration matched controls were selected for each case. Clinical information was retrospectively collected from medical charts. All patients were men, and the average age of death was 70 years. Neuropathological diagnoses included dementia with grains (2), argyrophilic grain disease (2), corticobasal degeneration (CBD, 1), Lewy body disease (1), hypoxic encephalopathy (1) and cerebral infarction (1). All cases showed AGs to various degrees. Three patients died in their 50s; one demonstrated dementia with Lewy bodies, while the other two showed abundant AGs in the thalamus and amygdala. Of the three patients who died in their 60s, one showed AGs preferentially in the thalamus and amygdala, while the others demonstrated limbic predominance. The patients who died in/after their 70s demonstrated AGs similar to controls, except for the patient with CBD. Our data provides potentiality that neurodegenerative diseases may be an underlying pathology in certain cases of BPD. PMID:25819679

  6. Genetics Underlying Atypical Parkinsonism and Related Neurodegenerative Disorders.

    Scholz, Sonja W; Bras, Jose

    2015-01-01

    Atypical parkinsonism syndromes, such as dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration, are neurodegenerative diseases with complex clinical and pathological features. Heterogeneity in clinical presentations, possible secondary determinants as well as mimic syndromes pose a major challenge to accurately diagnose patients suffering from these devastating conditions. Over the last two decades, significant advancements in genomic technologies have provided us with increasing insights into the molecular pathogenesis of atypical parkinsonism and their intriguing relationships to related neurodegenerative diseases, fueling new hopes to incorporate molecular knowledge into our diagnostic, prognostic and therapeutic approaches towards managing these conditions. In this review article, we summarize the current understanding of genetic mechanisms implicated in atypical parkinsonism syndromes. We further highlight mimic syndromes relevant to differential considerations and possible future directions. PMID:26501269

  7. Genetics Underlying Atypical Parkinsonism and Related Neurodegenerative Disorders

    Sonja W. Scholz

    2015-10-01

    Full Text Available Atypical parkinsonism syndromes, such as dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration, are neurodegenerative diseases with complex clinical and pathological features. Heterogeneity in clinical presentations, possible secondary determinants as well as mimic syndromes pose a major challenge to accurately diagnose patients suffering from these devastating conditions. Over the last two decades, significant advancements in genomic technologies have provided us with increasing insights into the molecular pathogenesis of atypical parkinsonism and their intriguing relationships to related neurodegenerative diseases, fueling new hopes to incorporate molecular knowledge into our diagnostic, prognostic and therapeutic approaches towards managing these conditions. In this review article, we summarize the current understanding of genetic mechanisms implicated in atypical parkinsonism syndromes. We further highlight mimic syndromes relevant to differential considerations and possible future directions.

  8. The Significance of Small Cerebral Bleeds in Neurodegenerative Dementia Syndromes

    De Reuck, Jacques L.

    2012-01-01

    Small cerebral bleeds are frequently observed in brains of patients with Alzheimer disease (AD) and cerebral amyloid angiopathy (CAA). However, they are also observed in patients with other neurodegenerative dementias and in persons without cognitive impairment. The aim of this survey is to compare the bleeding load in brains with different dementia syndromes and in age-matched controls. Hundred sixty-five brains were examined. The prevalence and the severity of the different cerebrovascular ...

  9. The link between type 2 diabetes and neurodegenerative disorders

    Changqing Liu; Jake Hoekstra; Kangping Xiong; Jing Zhang

    2014-01-01

    Various age-associated diseases are becoming more prominent as a greater percentage of the population reaches old age.Neurodegenerative disorders,e.g.Alzheimer's disease (AD)and Parkinson's disease (PD),and diabetes,in particular type 2 diabetes mellitus (T2DM),are the diseases that represent a large proportion of diagnoses amongst this group.These dis-eases have long been regarded as separate and each has distinct pathologies,symptoms,and treatments.Recent studies in epide-miology and pathology,however,have shown that T2DM may share a common mechanism of disease with AD and PD, which could allow for a therapeutic intervention capable of managing each disease.This review will discuss evidence implicating connections between these diseases,potential shared mechanisms,and possible treatments.

  10. Accelerated microglial pathology is associated with Aβ plaques in mouse models of Alzheimer's disease

    Baron, Rona; Babcock, Alicia A; Nemirovsky, Anna;

    2014-01-01

    earlier in mouse models of Alzheimer's disease (AD), along with a significant increase in brain parenchyma lacking coverage by microglial processes. We further demonstrate that microglia near amyloid plaques acquire unique activated phenotypes with impaired process complexity. We thus show that along with...... a chronic proinflammatory reaction in the brain, aging causes a significant reduction in the capacity of microglia to scan their environment. This type of pathology is markedly accelerated in mouse models of AD, resulting in a severe microglial process deficiency, and possibly contributing to...

  11. Deletion of ErbB4 accelerates polycystic kidney disease progression in cpk mice

    Zeng, Fenghua; Miyazawa, Tomoki; Kloepfer, Lance A.; Harris, Raymond C.

    2014-01-01

    ErbB4 is highly expressed in the cystic kidneys with polycystic kidney diseases. To investigate its potential role in cystogenesis, cpk mice carrying a heart-rescued ErbB4 deletion were generated. Accelerated cyst progression and renal function deterioration were noted as early as 10 days postnatally in cpk mice with ErbB4 deletion compared to cpk mice, as indicated by increased cystic index, higher kidney weight to body weight ratios and elevated BUN levels. No apparent defects in renal deve...

  12. Biochemical, Biomedical and Metabolic Aspects of Imidazole-Containing Dipeptides with the Inherent Complexity to Neurodegenerative Diseases and Various States of Mental Well-Being: A Challenging Correction and Neurotherapeutic Pharmaceutical Biotechnology for Treating Cognitive Deficits, Depression and Intellectual Disabilities.

    Babizhayev, Mark A

    2014-01-01

    , endowed with ferroxidase type activity; possess anti-aging functions, and free-radical scavenging activity, is capable of delaying senescence and extending the life-span of cultured human fibroblasts; is able to kill transformed cells and protect cells against aldehydes and amyloid peptide fragment. Carnosine and carcinine exhibit a well-documented anti-glycating activity against the glycation of proteins, including low-density lipoproteins, glucose degradation products, esterase, histones. A tissue carnosine-degrading enzyme (CN2) colocalized with the activity of histidine decarboxylase to histamine neurons in the hypothalamic tuberomammillary nucleus (TMN) plays a key role in the neuro-transmission and neuroregulation roles of imidazole-containing based dipeptides. Carnosine released from skeletal muscle during exercise may be transported into TMN-histamine neurons and hydrolyzed. Timing of carnosine present in the chicken broth, the specific patented nutraceutical composition (Can-C Plus™), 1% N-acetylcarnosine lubricant eye drops or 1% carcinine lubricant eye drops formulations are important targeting posology vehicles that are involved in many CNS functions through the central brain histamine system including the vision enhancement functions, physiological regulation of cognitive functions, arousal; anxiety; activation of the sympathetic nervous system; the stress-related release of hormones from the pituitary and of central aminergic neurotransmitters; antinociception; water retention and suppression of eating. The roles for the carnosine-stimulated/mediated neuronal histamine system are proposed as a danger and physiological response system active in protection from neurodegenerative diseases and in management of cognitive deficits, depression and intellectual disabilities. PMID:25158972

  13. 疾病特异诱导多能干细胞距离神经退行性疾病的临床治疗还有多远%How long will the disease-specific induced pluripotent stem cells be applied in the clinical treatment of neurodegenerative diseases

    罗虎; 刘渔凯; 李泽桂

    2011-01-01

    BACKGROUND: Both the medical treatments and the surgery can only relieve the symptoms but not prevent the progress of neurodegenerative diseases. Cell replacement therapy proceeds fast but its ethical problem and immune rejection also should be in consideration. However, the production of induced pluripotent stem cells provides us a new way to resolve these problems.OBJECTIVE: To review the basic situations and current treatment of neurodegenerative diseases and the possibility of the induced pluripotent stem (iPS) cells be used in regenerative medicine as a new cell resource.METHODS: The PubMed database (http://www.ncbi.nlm.nih.gov/PubMed) and Wanfang database (http://www.wanfangdata.com.cn) were retrieved for articles published from 1995 to 2010 by computer. The English key words were "induced pluripotent stem cell, PD, ALS, SMA, degenerative disease". The Chinese key words were "stem cells, Parkinson's disease". Totally 374 papers were primarily gotten. Finally, 29 papers were selected according to the inclusion criteria.RERULTS AND CONCLUSION : Patient-specific iPS cells can obtain the same genotype which is beneficial to the elucidation of the molecular mechanism of these diseases. These cells also posses the similar multi-directional differentiation ability as embryonic stem cells, which could be induced to dopamine neurons and relieve the clinical symptoms of Parkinson's disease in animal model in vitro. The iPS cells have broad prospect in the treatment of neurodegenerative diseases.%背景:各种神经退行性疾病传统的内外科治疗只能缓解症状而不能阻止疾病的进一步发展,细胞替代治疗近年进展迅速,但是干细胞存在的伦理问题及免疫排斥等问题不容忽视,而诱导多能干细胞的产生为这些问题提供了新的解决途径.目的:综述神经退行性疾病的治疗现状以及诱导多能干细胞作为新的细胞来源治疗神经退行性疾病的可能性.方法:应用计算机检索1995

  14. Accelerated Vascular Aging as a Paradigm for Hypertensive Vascular Disease: Prevention and Therapy.

    Barton, Matthias; Husmann, Marc; Meyer, Matthias R

    2016-05-01

    Aging is considered the most important nonmodifiable risk factor for cardiovascular disease and death after age 28 years. Because of demographic changes the world population is expected to increase to 9 billion by the year 2050 and up to 12 billion by 2100, with several-fold increases among those 65 years of age and older. Healthy aging and prevention of aging-related diseases and associated health costs have become part of political agendas of governments around the world. Atherosclerotic vascular burden increases with age; accordingly, patients with progeria (premature aging) syndromes die from myocardial infarctions or stroke as teenagers or young adults. The incidence and prevalence of arterial hypertension also increases with age. Arterial hypertension-like diabetes and chronic renal failure-shares numerous pathologies and underlying mechanisms with the vascular aging process. In this article, we review how arterial hypertension resembles premature vascular aging, including the mechanisms by which arterial hypertension (as well as other risk factors such as diabetes mellitus, dyslipidemia, or chronic renal failure) accelerates the vascular aging process. We will also address the importance of cardiovascular risk factor control-including antihypertensive therapy-as a powerful intervention to interfere with premature vascular aging to reduce the age-associated prevalence of diseases such as myocardial infarction, heart failure, hypertensive nephropathy, and vascular dementia due to cerebrovascular disease. Finally, we will discuss the implementation of endothelial therapy, which aims at active patient participation to improve primary and secondary prevention of cardiovascular disease. PMID:27118295

  15. Prions, prion-like prionoids, and neurodegenerative disorders.

    Verma, Ashok

    2016-01-01

    Prion diseases or transmissible spongiform encephalopathies are fatal neurodegenerative diseases characterized by the aggregation and deposition of the misfolded prion protein in the brain. α-synuclein (α-syn)-associated multiple system atrophy has been recently shown to be caused by a bona fide α-syn prion strain. Several other misfolded native proteins such as β-amyloid, tau and TDP-43 share some aspects of prions although none of them is shown to be transmissible in nature or in experimental animals. However, these prion-like "prionoids" are causal to a variety of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The remarkable recent discovery of at least two new α-syn prion strains and their transmissibility in transgenic mice and in vitro cell models raises a distinct question as to whether some specific strain of other prionoids could have the capability of disease transmission in a manner similar to prions. In this overview, we briefly describe human and other mammalian prion diseases and comment on certain similarities between prion and prionoid and the possibility of prion-like transmissibility of some prionoid strains. PMID:27293325

  16. Prions, prion-like prionoids, and neurodegenerative disordersVacancy

    Ashok Verma

    2016-01-01

    Full Text Available Prion diseases or transmissible spongiform encephalopathies are fatal neurodegenerative diseases characterized by the aggregation and deposition of the misfolded prion protein in the brain. α-synuclein (α-syn-associated multiple system atrophy has been recently shown to be caused by a bona fide α-syn prion strain. Several other misfolded native proteins such as β-amyloid, tau and TDP-43 share some aspects of prions although none of them is shown to be transmissible in nature or in experimental animals. However, these prion-like “prionoids” are causal to a variety of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The remarkable recent discovery of at least two new α-syn prion strains and their transmissibility in transgenic mice and in vitro cell models raises a distinct question as to whether some specific strain of other prionoids could have the capability of disease transmission in a manner similar to prions. In this overview, we briefly describe human and other mammalian prion diseases and comment on certain similarities between prion and prionoid and the possibility of prion-like transmissibility of some prionoid strains.

  17. High fat diet accelerates pathogenesis of murine Crohn's disease-like ileitis independently of obesity.

    Lisa Gruber

    Full Text Available BACKGROUND: Obesity has been associated with a more severe disease course in inflammatory bowel disease (IBD and epidemiological data identified dietary fats but not obesity as risk factors for the development of IBD. Crohn's disease is one of the two major IBD phenotypes and mostly affects the terminal ileum. Despite recent observations that high fat diets (HFD impair intestinal barrier functions and drive pathobiont selection relevant for chronic inflammation in the colon, mechanisms of high fat diets in the pathogenesis of Crohn's disease are not known. The aim of this study was to characterize the effect of HFD on the development of chronic ileal inflammation in a murine model of Crohn's disease-like ileitis. METHODS: TNF(ΔARE/WT mice and wildtype C57BL/6 littermates were fed a HFD compared to control diet for different durations. Intestinal pathology and metabolic parameters (glucose tolerance, mesenteric tissue characteristics were assessed. Intestinal barrier integrity was characterized at different levels including polyethylene glycol (PEG translocation, endotoxin in portal vein plasma and cellular markers of barrier function. Inflammatory activation of epithelial cells as well as immune cell infiltration into ileal tissue were determined and related to luminal factors. RESULTS: HFD aggravated ileal inflammation but did not induce significant overweight or typical metabolic disorders in TNF(ΔARE/WT. Expression of the tight junction protein Occludin was markedly reduced in the ileal epithelium of HFD mice independently of inflammation, and translocation of endotoxin was increased. Epithelial cells showed enhanced expression of inflammation-related activation markers, along with enhanced luminal factors-driven recruitment of dendritic cells and Th17-biased lymphocyte infiltration into the lamina propria. CONCLUSIONS: HFD feeding, independently of obesity, accelerated disease onset of small intestinal inflammation in Crohn's disease

  18. Localization of Axonal Motor Molecules Machinery in Neurodegenerative Disorders

    Fulvio Florenzano

    2012-04-01

    Full Text Available Axonal transport and neuronal survival depend critically on active transport and axon integrity both for supplying materials and communication to different domains of the cell body. All these actions are executed through cytoskeleton, transport and regulatory elements that appear to be disrupted in neurodegenerative diseases. Motor-driven transport both supplies and clears distal cellular portions with proteins and organelles. This transport is especially relevant in projection and motor neurons, which have long axons to reach the farthest nerve endings. Thus, any disturbance of axonal transport may have severe consequences for neuronal function and survival. A growing body of literature indicates the presence of alterations to the motor molecules machinery, not only in expression levels and phosphorylation, but also in their subcellular distribution within populations of neurons, which are selectively affected in the course of neurodegenerative diseases. The implications of this altered subcellular localization and how this affects axon survival and neuronal death still remain poorly understood, although several hypotheses have been suggested. Furthermore, cytoskeleton and transport element localization can be selectively disrupted in some disorders suggesting that specific loss of the axonal functionality could be a primary hallmark of the disorder. This can lead to axon degeneration and neuronal death either directly, through the functional absence of essential axonal proteins, or indirectly, through failures in communication among different cellular domains. This review compares the localization of cytoskeleton and transport elements in some neurodegenerative disorders to ask what aspects may be essential for axon survival and neuronal death.

  19. Protective effects of isolecanoric acid on neurodegenerative in vitro models.

    de Pedro, Nuria; Cantizani, Juan; Ortiz-López, Francisco Javier; González-Menéndez, Victor; Cautain, Bastien; Rodríguez, Lorena; Bills, Gerald F; Reyes, Fernando; Genilloud, Olga; Vicente, Francisca

    2016-02-01

    Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS), are neurodegenerative disorders characterized by loss of dopaminergic or motor neurons, respectively. Although understanding of the PD and ALS pathogenesis remains incomplete, increasing evidence from human and animal studies has suggested that aberrant GSK3β, oxidative stress and mitochondrial damage are involved in their pathogenesis. Using two different molecular models, treatment with L-BMAA for ALS and rotenone for PD the effect of isolecanoric acid, a natural product isolated from a fungal culture, was evaluated. Pre-treatment with this molecule caused inhibition of GSK3β and CK1, and a decrease in oxidative stress, mitochondrial damage, apoptosis and cell death. Taken together, these results indicated that isolecanoric acid might have a protective effect against the development of these neurodegenerative disorders. PMID:26455662

  20. Deletion of ErbB4 accelerates polycystic kidney disease progression in cpk mice.

    Zeng, Fenghua; Miyazawa, Tomoki; Kloepfer, Lance A; Harris, Raymond C

    2014-09-01

    ErbB4 is highly expressed in the cystic kidneys with polycystic kidney diseases. To investigate its potential role in cystogenesis, cpk mice carrying a heart-rescued ErbB4 deletion were generated. Accelerated cyst progression and renal function deterioration were noted as early as 10 days postnatally in cpk mice with ErbB4 deletion compared to cpk mice, as indicated by increased cystic index, higher kidney weight to body weight ratios, and elevated BUN levels. No apparent defects in renal development were noted with ErbB4 deletion itself. Increased cell proliferation was predominately seen in the cortex of cystic kidneys with or without ErbB4 deletion. However, there was significantly more cell proliferation in the cyst-lining epithelial cells in cpk mice with ErbB4 deletion. TUNEL staining localized apoptotic cells mainly to the renal medulla. There were significantly more apoptotic cells in the cyst-lining epithelial cells in ErbB4-deleted cpk kidneys, with decreased levels of cyclin D1, increased levels of p21, p27, and cleaved caspase 3. Thus, lack of ErbB4 may contribute to elevated cell proliferation and unbalanced cell apoptosis, resulting in accelerated cyst formation and early renal function deterioration. These studies suggest that the high level of ErbB4 expression seen in cpk mice may exert relative cytoprotective effects in renal epithelia. PMID:24670412

  1. Screening and Mechanism Study of Natural Products and Derivatives for Prevention and Cure of Neurodegenerative Diseases by Taking Microglia Activation as the Target%以抑制小胶质细胞活化为靶标的抗神经退行性疾病的天然产物及衍生物的筛选与机制研究

    杨静玉; 陈国良; 吴春福

    2011-01-01

    Microglia activation is associated with the occurrence and progression of neurodegenerative diseases.Thus, inhibition of microglial activation is generally considered a useful strategy for treatment of many neurodegenerative diseases. This paper reviews our research progress in the inhibitory effects of natural products including resveratrol, curcumin, resveratrol derivatives, curcumin derivatives and ginsenosides on microglia activation. This may provide a reference for the further exploration in this field.%脑内小胶质细胞的活化贯穿了神经退行性疾病的发生、发展全过程.抑制小胶质细胞活化已经成为防治此类疾病的重要策略.本文对近年来本课题组在白藜芦醇及其衍生物、姜黄素及其衍生物、人参皂苷等抑制小胶质细胞活化方面的研究进展进行综述,为防治神经退行性疾病药物的深入研究提供参考.

  2. The cytoskeleton as a novel therapeutic target for old neurodegenerative disorders.

    Eira, Jessica; Silva, Catarina Santos; Sousa, Mónica Mendes; Liz, Márcia Almeida

    2016-06-01

    Cytoskeleton defects, including alterations in microtubule stability, in axonal transport as well as in actin dynamics, have been characterized in several unrelated neurodegenerative conditions. These observations suggest that defects of cytoskeleton organization may be a common feature contributing to neurodegeneration. In line with this hypothesis, drugs targeting the cytoskeleton are currently being tested in animal models and in human clinical trials, showing promising effects. Drugs that modulate microtubule stability, inhibitors of posttranslational modifications of cytoskeletal components, specifically compounds affecting the levels of tubulin acetylation, and compounds targeting signaling molecules which regulate cytoskeleton dynamics, constitute the mostly addressed therapeutic interventions aiming at preventing cytoskeleton damage in neurodegenerative disorders. In this review, we will discuss in a critical perspective the current knowledge on cytoskeleton damage pathways as well as therapeutic strategies designed to revert cytoskeleton-related defects mainly focusing on the following neurodegenerative disorders: Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Amyotrophic Lateral Sclerosis and Charcot-Marie-Tooth Disease. PMID:27095262

  3. Dopamine transporter imaging in neurodegenerative disorders

    The dopamine transporter (DAT) is responsible for the re-uptake of dopamine from the synaptic cleft and is located on dopaminergic nerve terminals only. DAT single photon emission computed tomography (SPECT) and positron emission tomography (PET) imaging, therefore, offer the unique opportunity to study via striatal uptake the integrity of presynaptic dopaminergic nerve terminals in vivo. In recent years SPECT and PET using specific ligands binding to DAT have evolved as an useful tool for diagnosing and monitoring progression of neurodegenerative disorders affecting dopaminergic systems. This article briefly reviews the literature dealing with DTA SPECT and PET imaging in Parkinsonism and other neurodegenerative disorders

  4. Untangling the brain's neuroinflammatory and neurodegenerative transcriptional responses.

    Srinivasan, Karpagam; Friedman, Brad A; Larson, Jessica L; Lauffer, Benjamin E; Goldstein, Leonard D; Appling, Laurie L; Borneo, Jovencio; Poon, Chungkee; Ho, Terence; Cai, Fang; Steiner, Pascal; van der Brug, Marcel P; Modrusan, Zora; Kaminker, Joshua S; Hansen, David V

    2016-01-01

    A common approach to understanding neurodegenerative disease is comparing gene expression in diseased versus healthy tissues. We illustrate that expression profiles derived from whole tissue RNA highly reflect the degenerating tissues' altered cellular composition, not necessarily transcriptional regulation. To accurately understand transcriptional changes that accompany neuropathology, we acutely purify neurons, astrocytes and microglia from single adult mouse brains and analyse their transcriptomes by RNA sequencing. Using peripheral endotoxemia to establish the method, we reveal highly specific transcriptional responses and altered RNA processing in each cell type, with Tnfr1 required for the astrocytic response. Extending the method to an Alzheimer's disease model, we confirm that transcriptomic changes observed in whole tissue are driven primarily by cell type composition, not transcriptional regulation, and identify hundreds of cell type-specific changes undetected in whole tissue RNA. Applying similar methods to additional models and patient tissues will transform our understanding of aberrant gene expression in neurological disease. PMID:27097852

  5. Untangling the brain's neuroinflammatory and neurodegenerative transcriptional responses

    Srinivasan, Karpagam; Friedman, Brad A.; Larson, Jessica L.; Lauffer, Benjamin E.; Goldstein, Leonard D.; Appling, Laurie L.; Borneo, Jovencio; Poon, Chungkee; Ho, Terence; Cai, Fang; Steiner, Pascal; van der Brug, Marcel P.; Modrusan, Zora; Kaminker, Joshua S.; Hansen, David V.

    2016-01-01

    A common approach to understanding neurodegenerative disease is comparing gene expression in diseased versus healthy tissues. We illustrate that expression profiles derived from whole tissue RNA highly reflect the degenerating tissues' altered cellular composition, not necessarily transcriptional regulation. To accurately understand transcriptional changes that accompany neuropathology, we acutely purify neurons, astrocytes and microglia from single adult mouse brains and analyse their transcriptomes by RNA sequencing. Using peripheral endotoxemia to establish the method, we reveal highly specific transcriptional responses and altered RNA processing in each cell type, with Tnfr1 required for the astrocytic response. Extending the method to an Alzheimer's disease model, we confirm that transcriptomic changes observed in whole tissue are driven primarily by cell type composition, not transcriptional regulation, and identify hundreds of cell type-specific changes undetected in whole tissue RNA. Applying similar methods to additional models and patient tissues will transform our understanding of aberrant gene expression in neurological disease. PMID:27097852

  6. Parkinson's disease managing reversible neurodegeneration.

    Hinz, Marty; Stein, Alvin; Cole, Ted; McDougall, Beth; Westaway, Mark

    2016-01-01

    Traditionally, the Parkinson's disease (PD) symptom course has been classified as an irreversible progressive neurodegenerative disease. This paper documents 29 PD and treatment-induced systemic depletion etiologies which cause and/or exacerbate the seven novel primary relative nutritional deficiencies associated with PD. These reversible relative nutritional deficiencies (RNDs) may facilitate and accelerate irreversible progressive neurodegeneration, while other reversible RNDs may induce previously undocumented reversible pseudo-neurodegeneration that is hiding in plain sight since the symptoms are identical to the symptoms being experienced by the PD patient. Documented herein is a novel nutritional approach for reversible processes management which may slow or halt irreversible progressive neurodegenerative disease and correct reversible RNDs whose symptoms are identical to the patient's PD symptoms. PMID:27103805

  7. Linear and nonlinear tremor acceleration characteristics in patients with Parkinson's disease

    The purpose of the study was to evaluate linear and nonlinear tremor characteristics of the hand in patients with Parkinson's disease (PD) and to compare the results with those of healthy old and young control subjects. Furthermore, the aim was to study correlation between tremor characteristics and clinical signs. A variety of nonlinear (sample entropy, cross-sample entropy, recurrence rate, determinism and correlation dimension) and linear (amplitude, spectral peak frequency and total power, and coherence) hand tremor parameters were computed from acceleration measurements for PD patients (n = 30, 68.3 ± 7.8 years), and old (n = 20, 64.2 ± 7.0 years) and young (n = 20, 18.4 ± 1.1 years) control subjects. Nonlinear tremor parameters such as determinism, sample entropy and cross-sample entropy were significantly different between the PD patients and healthy controls. These parameters correlated with the Unified Parkinson's disease rating scale (UPDRS), tremor and finger tapping scores, but not with the rigidity scores. Linear tremor parameters such as the amplitude and the maximum power (power corresponding to peak frequency) also correlated with the clinical findings. No major difference was detected in the tremor characteristics between old and young control subjects. The study revealed that tremor in PD patients is more deterministic and regular when compared to old or young healthy controls. The nonlinear tremor parameters can differentiate patients with PD from healthy control subjects and these parameters may have potential in the assessment of the severity of PD (UPDRS). (paper)

  8. Accelerating regional atrophy rates in the progression from normal aging to Alzheimer's disease

    Sluimer, Jasper D. [VU University Medical Centre, Department of Diagnostic Radiology, Amsterdam (Netherlands); VU University Medical Centre, Alzheimer Centre, Amsterdam (Netherlands); VU University Medical Centre, Image Analysis Centre, Amsterdam (Netherlands); VU University Medical Centre, Department of Diagnostic Radiology and Alzheimer Centre, PO Box 7057, Amsterdam (Netherlands); Flier, Wiesje M. van der; Scheltens, Philip [VU University Medical Centre, Alzheimer Centre, Amsterdam (Netherlands); VU University Medical Centre, Department of Neurology, Amsterdam (Netherlands); Karas, Giorgos B.; Barkhof, Frederik [VU University Medical Centre, Department of Diagnostic Radiology, Amsterdam (Netherlands); VU University Medical Centre, Alzheimer Centre, Amsterdam (Netherlands); VU University Medical Centre, Image Analysis Centre, Amsterdam (Netherlands); Schijndel, Ronald van [VU University Medical Centre, Image Analysis Centre, Amsterdam (Netherlands); VU University Medical Centre, Department of Informatics, Amsterdam (Netherlands); Barnes, Josephine; Boyes, Richard G. [UCL, Institute of Neurology, Dementia Research Centre, London (United Kingdom); Cover, Keith S. [VU University Medical Centre, Department of Physics and Medical Technology, Amsterdam (Netherlands); Olabarriaga, Silvia D. [University of Amsterdam, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Centre, Amsterdam (Netherlands); Fox, Nick C. [VU University Medical Centre, Department of Neurology, Amsterdam (Netherlands); UCL, Institute of Neurology, Dementia Research Centre, London (United Kingdom); Vrenken, Hugo [VU University Medical Centre, Alzheimer Centre, Amsterdam (Netherlands); VU University Medical Centre, Image Analysis Centre, Amsterdam (Netherlands); VU University Medical Centre, Department of Physics and Medical Technology, Amsterdam (Netherlands)

    2009-12-15

    We investigated progression of atrophy in vivo, in Alzheimer's disease (AD), and mild cognitive impairment (MCI). We included 64 patients with AD, 44 with MCI and 34 controls with serial MRI examinations (interval 1.8 {+-} 0.7 years). A nonlinear registration algorithm (fluid) was used to calculate atrophy rates in six regions: frontal, medial temporal, temporal (extramedial), parietal, occipital lobes and insular cortex. In MCI, the highest atrophy rate was observed in the medial temporal lobe, comparable with AD. AD patients showed even higher atrophy rates in the extramedial temporal lobe. Additionally, atrophy rates in frontal, parietal and occipital lobes were increased. Cox proportional hazard models showed that all regional atrophy rates predicted conversion to AD. Hazard ratios varied between 2.6 (95% confidence interval (CI) = 1.1-6.2) for occipital atrophy and 15.8 (95% CI = 3.5-71.8) for medial temporal lobe atrophy. In conclusion, atrophy spreads through the brain with development of AD. MCI is marked by temporal lobe atrophy. In AD, atrophy rate in the extramedial temporal lobe was even higher. Moreover, atrophy rates also accelerated in parietal, frontal, insular and occipital lobes. Finally, in nondemented elderly, medial temporal lobe atrophy was most predictive of progression to AD, demonstrating the involvement of this region in the development of AD. (orig.)

  9. Accelerating regional atrophy rates in the progression from normal aging to Alzheimer's disease

    We investigated progression of atrophy in vivo, in Alzheimer's disease (AD), and mild cognitive impairment (MCI). We included 64 patients with AD, 44 with MCI and 34 controls with serial MRI examinations (interval 1.8 ± 0.7 years). A nonlinear registration algorithm (fluid) was used to calculate atrophy rates in six regions: frontal, medial temporal, temporal (extramedial), parietal, occipital lobes and insular cortex. In MCI, the highest atrophy rate was observed in the medial temporal lobe, comparable with AD. AD patients showed even higher atrophy rates in the extramedial temporal lobe. Additionally, atrophy rates in frontal, parietal and occipital lobes were increased. Cox proportional hazard models showed that all regional atrophy rates predicted conversion to AD. Hazard ratios varied between 2.6 (95% confidence interval (CI) = 1.1-6.2) for occipital atrophy and 15.8 (95% CI = 3.5-71.8) for medial temporal lobe atrophy. In conclusion, atrophy spreads through the brain with development of AD. MCI is marked by temporal lobe atrophy. In AD, atrophy rate in the extramedial temporal lobe was even higher. Moreover, atrophy rates also accelerated in parietal, frontal, insular and occipital lobes. Finally, in nondemented elderly, medial temporal lobe atrophy was most predictive of progression to AD, demonstrating the involvement of this region in the development of AD. (orig.)

  10. Heme-coordinated histidine residues form non-specific functional "ferritin-heme" peroxidase system: Possible and partial mechanistic relevance to oxidative stress-mediated pathology in neurodegenerative diseases.

    Esmaeili, Sajjad; Kooshk, Mohammad Reza Ashrafi; Asghari, Seyyed Mohsen; Khodarahmi, Reza

    2016-10-01

    Ferritin is a giant protein composed of 24 subunits which is able to sequester up to 4500 atoms of iron. We proposed two kinds of heme binding sites in mammalian ferritins and provided direct evidence for peroxidase activity of heme-ferritin, since there is the possibility that "ferritin-heme" systems display unexpected catalytic behavior like heme-containing enzymes. In the current study, peroxidase activity of heme-bound ferritin was studied using TMB(1), l-DOPA, serotonin, and dopamine, in the presence of H2O2, as oxidant substrate. The catalytic oxidation of TMB was consistent with first-order kinetics with respect to ferritin concentration. Perturbation of the binding affinity and catalytic behavior of heme-bound His-modified ferritin were also documented. We also discuss the importance of the peroxidase-/nitrative-mediated oxidation of vital molecules as well as ferritin-induced catalase inhibition using in vitro experimental system. Uncontrollable "heme-ferritin"-based enzyme activity as well as up-regulation of heme and ferritin may inspire that some oxidative stress-mediated cytotoxic effects in AD-affected cells could be correlated to ferritin-heme interaction and/or ferritin-induced catalase inhibition and describe its contribution as an important causative pathogenesis mechanism in some neurodegenerative disorders. PMID:27212214

  11. Acceleration training for managing nonalcoholic fatty liver disease: a pilot study

    Oh S

    2014-11-01

    Full Text Available Sechang Oh,1 Takashi Shida,1 Akemi Sawai,1 Tsuyoshi Maruyama,2 Kiyoshi Eguchi,2 Tomonori Isobe,1 Yoshikazu Okamoto,3 Noriko Someya,4 Kiyoji Tanaka,4 Emi Arai,1 Akiko Tozawa,5 Junichi Shoda1 1Department of Medical Sciences, Faculty of Medicine, University of Tsukuba, 2Department of Rehabilitation, Tsukuba University Hospital, 3Department of Diagnostic Radiology, 4Department of Sports Medicine, Faculty of Health and Sport Sciences, University of Tsukuba, Ibaraki, 5Protea Japan Co Ltd, Chiyoda, Tokyo, Japan Background: While aerobic training is generally recommended as therapeutic exercise in guidelines, the effectiveness of resistance training has recently been reported in the management of nonalcoholic fatty liver disease (NAFLD. Acceleration training (AT is a new training method that provides a physical stimulation effect on skeletal muscles by increasing gravitational acceleration with vibration. AT has recently been indicated as a component of medicine. In this study, we evaluated the effectiveness of AT in the management of NAFLD in obese subjects.Methods: A total of 18 obese patients with NAFLD who had no improvement in liver function test abnormalities and/or steatosis grade after 12 weeks of lifestyle counseling were enrolled in an AT program. These patients attended a 20-minute session of AT twice a week for 12 consecutive weeks.Results: During the AT program, the NAFLD patients showed a modest increase in the strength (+12.6% and cross-sectional area (+3.1% of the quadriceps, coupled with a significant reduction in intramyocellular lipids (−26.4%. Notably, they showed a modest reduction in body weight (−1.9%, abdominal visceral fat area (−3.4%, and hepatic fat content (−8.7%, coupled with a significant reduction in levels of aminotransferase (−15.7%, γ-glutamyltransferase (−14.4%, leptin (−9.7%, interleukin-6 (−26.8%, and tumor necrosis factor-α (−17.9%, and a significant increase of adiponectin (+8.7%. On a health

  12. Lessons Learned From Nocebo Effects in Clinical Trials for Pain Conditions and Neurodegenerative Disorders.

    Amanzio, Martina; Palermo, Sara; Skyt, Ina; Vase, Lene

    2016-10-01

    It has been demonstrated that patients in the placebo arm of a clinical trial may experience adverse events (AEs), which may lead to nonadherence and dropout. However, so far, it is unknown to which extent this phenomenon is observed consistently across different diseases such as pain and neurodegenerative disorders.The current review shows for the first time that different diseases share a common risk for patients in terms of a negative outcome: a large percentage of placebo-treated patients experience AEs in pain conditions (up to 59%) and neurodegenerative disorders (up to 66%). In addition, the rate of patients who discontinue because of AEs is up to 10% and 11% in pain conditions and neurodegenerative disorders, respectively.We highlight methodological shortcomings with the aim of suggesting how the detection and reporting of AEs can be improved in future trials. The insights from the current review should be taken into consideration when designing clinical trials to tailor individualized treatments. PMID:27580494

  13. Chronic traumatic encephalopathy pathology in a neurodegenerative disorders brain bank.

    Bieniek, Kevin F; Ross, Owen A; Cormier, Kerry A; Walton, Ronald L; Soto-Ortolaza, Alexandra; Johnston, Amelia E; DeSaro, Pamela; Boylan, Kevin B; Graff-Radford, Neill R; Wszolek, Zbigniew K; Rademakers, Rosa; Boeve, Bradley F; McKee, Ann C; Dickson, Dennis W

    2015-12-01

    Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder linked to repetitive traumatic brain injury (TBI) and characterized by deposition of hyperphosphorylated tau at the depths of sulci. We sought to determine the presence of CTE pathology in a brain bank for neurodegenerative disorders for individuals with and without a history of contact sports participation. Available medical records of 1721 men were reviewed for evidence of past history of injury or participation in contact sports. Subsequently, cerebral cortical samples were processed for tau immunohistochemistry in cases with a documented history of sports exposure as well as age- and disease-matched men and women without such exposure. For cases with available frozen tissue, genetic analysis was performed for variants in APOE, MAPT, and TMEM106B. Immunohistochemistry revealed 21 of 66 former athletes had cortical tau pathology consistent with CTE. CTE pathology was not detected in 198 individuals without exposure to contact sports, including 33 individuals with documented single-incident TBI sustained from falls, motor vehicle accidents, domestic violence, or assaults. Among those exposed to contact sports, those with CTE pathology did not differ from those without CTE pathology with respect to noted clinicopathologic features. There were no significant differences in genetic variants for those with CTE pathology, but we observed a slight increase in MAPT H1 haplotype, and there tended to be fewer homozygous carriers of the protective TMEM106B rs3173615 minor allele in those with sports exposure and CTE pathology compared to those without CTE pathology. In conclusion, this study has identified a small, yet significant, subset of individuals with neurodegenerative disorders and concomitant CTE pathology. CTE pathology was only detected in individuals with documented participation in contact sports. Exposure to contact sports was the greatest risk factor for CTE pathology. Future

  14. Attenuation of Upper Body Accelerations during Gait: Piloting an Innovative Assessment Tool for Parkinson’s Disease

    2015-01-01

    The objective of the current investigation was to explore whether upper body accelerations obtained during gait provide sensitive measures of postural control in people with Parkinson's disease (PD). Thirteen people with PD (70 ± 11 years) and nineteen age-matched controls (70 ± 7 years) walked continuously for two minutes while wearing three inertial sensors located on their lower back (L5), shoulder level (C7), and head. Magnitude (root mean square (RMS)), attenuation (attenuation coefficie...

  15. The Neuronal Expression of MYC Causes a Neurodegenerative Phenotype in a Novel Transgenic Mouse

    Lee, Hyoung-gon; Casadesus, Gemma; Nunomura, Akihiko; Zhu, Xiongwei; Rudy J. Castellani; Richardson, Sandy L.; Perry, George; Dean W Felsher; Petersen, Robert B.; Smith, Mark A.

    2009-01-01

    Many different proteins associated with the cell cycle, including cyclins, cyclin-dependent kinases, and proto-oncogenes such as c-MYC (MYC), are increased in degenerating neurons. Consequently, an ectopic activation of the cell cycle machinery in neurons has emerged as a potential pathogenic mechanism of neuronal dysfunction and death in many neurodegenerative diseases, including Alzheimer’s disease. However, the exact role of cell cycle re-entry during disease pathogenesis is unclear, prima...

  16. Pharmacological Alternatives for the Treatment of Neurodegenerative Disorders: Wasp and Bee Venoms and Their Components as New Neuroactive Tools

    Juliana Silva

    2015-08-01

    Full Text Available Neurodegenerative diseases are relentlessly progressive, severely impacting affected patients, families and society as a whole. Increased life expectancy has made these diseases more common worldwide. Unfortunately, available drugs have insufficient therapeutic effects on many subtypes of these intractable diseases, and adverse effects hamper continued treatment. Wasp and bee venoms and their components are potential means of managing or reducing these effects and provide new alternatives for the control of neurodegenerative diseases. These venoms and their components are well-known and irrefutable sources of neuroprotectors or neuromodulators. In this respect, the present study reviews our current understanding of the mechanisms of action and future prospects regarding the use of new drugs derived from wasp and bee venom in the treatment of major neurodegenerative disorders, including Alzheimer’s Disease, Parkinson’s Disease, Epilepsy, Multiple Sclerosis and Amyotrophic Lateral Sclerosis.

  17. Pharmacological Alternatives for the Treatment of Neurodegenerative Disorders: Wasp and Bee Venoms and Their Components as New Neuroactive Tools

    Silva, Juliana; Monge-Fuentes, Victoria; Gomes, Flávia; Lopes, Kamila; dos Anjos, Lilian; Campos, Gabriel; Arenas, Claudia; Biolchi, Andréia; Gonçalves, Jacqueline; Galante, Priscilla; Campos, Leandro; Mortari, Márcia

    2015-01-01

    Neurodegenerative diseases are relentlessly progressive, severely impacting affected patients, families and society as a whole. Increased life expectancy has made these diseases more common worldwide. Unfortunately, available drugs have insufficient therapeutic effects on many subtypes of these intractable diseases, and adverse effects hamper continued treatment. Wasp and bee venoms and their components are potential means of managing or reducing these effects and provide new alternatives for the control of neurodegenerative diseases. These venoms and their components are well-known and irrefutable sources of neuroprotectors or neuromodulators. In this respect, the present study reviews our current understanding of the mechanisms of action and future prospects regarding the use of new drugs derived from wasp and bee venom in the treatment of major neurodegenerative disorders, including Alzheimer’s Disease, Parkinson’s Disease, Epilepsy, Multiple Sclerosis and Amyotrophic Lateral Sclerosis. PMID:26295258

  18. Neurodegenerative Disorders with Hair Abnormalities: An Emergency Room Consultation for Dermatologists

    Inamadar, Arun C.; Palit, Aparna

    2009-01-01

    Menke′s syndrome and Elejalde disease are the two neurodegenerative disorders of dermatological interest. These patients present with characteristic hair changes which may be of diagnostic value in resource-poor setup where facilities for specific genetic analysis are not available. Simple light microscopic examination of hair may be a helpful diagnostic tool to pick up such cases.

  19. Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

    Butterfield, D. Allan; Perluigi, Marzia; Reed, Tanea; Muharib, Tasneem; Hughes, Christopher P.; Robinson, Renã A. S.; Sultana, Rukhsana

    2012-01-01

    Several studies demonstrated that oxidative damage is a characteristic feature of many neurodegenerative diseases. The accumulation of oxidatively modified proteins may disrupt cellular functions by affecting protein expression, protein turnover, cell signaling, and induction of apoptosis and necrosis, suggesting that protein oxidation could have both physiological and pathological significance. For nearly two decades, our laboratory focused particular attention on studying oxidative damage o...

  20. Pathological Propagation through Cell-to-Cell Transmission of Non-Prion Protein Aggregates in Neurodegenerative Disorders

    Lee, Seung-Jae; Desplats, Paula; Sigurdson, Christina; Tsigelny, Igor; Masliah, Eliezer

    2016-01-01

    Neurodegenerative disorders such as Alzheimer's Disease, Parkinson's Disease, fronto-temporal dementia, Huntington's Disease and Creutzfeldt-Jakob Disease (CJD) are characterized by progressive accumulation of protein aggregates in selected brain regions. Protein misfolding and templated assembly into aggregates might result from an imbalance between protein synthesis, aggregation and clearance. While protein misfolding and aggregation occur in most neurodegenerative disorders, the concept of spreading and infectivity of aggregates in the CNS has been reserved to prion diseases such as CJD and bovine spongiform encephalopathy. Emerging evidence suggests that prion-like spreading may occur in other neurodegenerative disorders, taking place with secreted proteins, such as amyloid-β,) and cytosolic proteins, such as tau, huntingtin and α-synuclein. Underlying molecular mechanisms and therapeutic implications are discussed. PMID:21045796

  1. 雷帕霉素通过诱导细胞自噬在细胞和动物模型中治疗神经退行性疾病的新思路%A novel way for neurodegenerative diseases within cell and animal model by autophagy induced with rapamycin treatment

    李晓鸣; 张旭东; 梅林; 黄来强

    2014-01-01

    Objective Using rapamycin protecting neurons' mitochondrial within injury model of neurodegenerative disease thus to reduce neuronal damage.Methods Parkinson's disease (PD) injury model of cells and animals were established,then rapamycin was added,and induced autophagy,the polarity changes of mitochondrial membrane potential,intracellular reactive oxygen species (ROS) scavenging and the contents of NF-κB inside the nucleus after dyeing were observed by confocal laser scanning microscopy.Results Rapamycin can induce autophagy and maintain morphology of mitochondria in cells damaged by MPP+.Mitochondrial membrane potential,level of ROS and contents of NF-κB inside the nuclear can be detected obviously reduced in these cells with rapamycin' s function.Furthermore,rapamycin also protects neurons well within PD models of zebrafish and mouse which are damaged by MPTP.Conclusions Rapamycin induces autophagy and protects mitochondria from damage within neurodegenerative disease,and strengthening this kind of protection of mitochondria is a novel way to deal with neurodegenerative diseases.%目的 使用雷帕霉素保护神经退行性疾病损伤模型中神经元的线粒体从而降低神经元的损伤.方法 建立帕金森氏症(PD)细胞和动物的损伤模型,在损伤模型中加入雷帕霉素,经染色后于激光共聚焦显微镜下观察雷帕霉素诱导细胞自噬作用、对线粒体膜极性变化的作用、对细胞内活性氧(ROS)的清除作用以及NF-κB的入核情况.结果 雷帕霉素能诱导细胞自噬在MPP+诱导的细胞损伤中,并能维持线粒体的正常形态、降低线粒体膜电位的变化、降低细胞ROS水平并减少NF-κB的入核.此外,雷帕霉素在MPTP诱发的斑马鱼和小鼠PD模型中对神经元有显著保护作用.结论 雷帕霉素能通过诱导细胞自噬作用于线粒体从而保护神经元免于神经退行性疾病的损伤,加强对线粒体的保护是一种治疗神经退行性疾病的新思路.

  2. MRI features of neurodegenerative Langerhans cell histiocytosis

    CNS complications of LCH include ''space occupying'' lesions corresponding to histiocytic granulomas and ''neurodegenerative'' presentation (ND-LCH) characterized by a progressive cerebellar ataxia. Studies analyzing specifically the MRI presentation of ND-LCH are scarce. We present here the MRIs of 13 patients registered as isolated ND-LCH. Posterior fossa was involved in 12 patients (92%), showing a symmetrical T2 hyperintensity of the cerebellar white matter areas in seven cases with a circumscribed T1 hyperintensity of the dentate nuclei in five cases, definite hyperintense T2 areas in the adjacent pontine tegmentum white matter in nine cases associated with a hyperintensity of the pontine pyramidal tracts in four cases. A cerebellar atrophy was noted in eight cases. The supratentorial region was involved in 11 patients, showing T2 hyperintense lesions in the cerebral white matter in eight cases and a discrete symmetrical T1 hyperintense signal in the globus pallidus in eight patients. A diffuse cortical atrophy was present in three cases and a marked focal atrophy of the corpus callosum in three cases. This series allows us to establish a not previously reported evocative semeiologic MR presentation to precisely orientate to the diagnosis of the pure neurodegenerative form of LCH. (orig.)

  3. MRI features of neurodegenerative Langerhans cell histiocytosis

    Martin-Duverneuil, N.; Guillevin, R.; Chiras, J. [GH Pitie-Salpetriere, 47 Bd de l' Hopital, Department of Neuroradiology, Paris (France); Idbaih, A.; Hoang-Xuan, K. [GH Pitie-Salpetriere, 47 Bd de l' Hopital, Department of Neurology, Paris (France); Donadieu, J. [GH Trousseau, Department of Hematology/Oncology Pediatrics, Paris (France); Genereau, T. [Groupe d' etude des Histiocytoses langerhansiennes, Nantes (France)

    2006-09-15

    CNS complications of LCH include ''space occupying'' lesions corresponding to histiocytic granulomas and ''neurodegenerative'' presentation (ND-LCH) characterized by a progressive cerebellar ataxia. Studies analyzing specifically the MRI presentation of ND-LCH are scarce. We present here the MRIs of 13 patients registered as isolated ND-LCH. Posterior fossa was involved in 12 patients (92%), showing a symmetrical T2 hyperintensity of the cerebellar white matter areas in seven cases with a circumscribed T1 hyperintensity of the dentate nuclei in five cases, definite hyperintense T2 areas in the adjacent pontine tegmentum white matter in nine cases associated with a hyperintensity of the pontine pyramidal tracts in four cases. A cerebellar atrophy was noted in eight cases. The supratentorial region was involved in 11 patients, showing T2 hyperintense lesions in the cerebral white matter in eight cases and a discrete symmetrical T1 hyperintense signal in the globus pallidus in eight patients. A diffuse cortical atrophy was present in three cases and a marked focal atrophy of the corpus callosum in three cases. This series allows us to establish a not previously reported evocative semeiologic MR presentation to precisely orientate to the diagnosis of the pure neurodegenerative form of LCH. (orig.)

  4. Parkinson’s disease managing reversible neurodegeneration

    Hinz, Marty; Stein, Alvin; Cole, Ted; McDougall, Beth; Westaway, Mark

    2016-01-01

    Traditionally, the Parkinson’s disease (PD) symptom course has been classified as an irreversible progressive neurodegenerative disease. This paper documents 29 PD and treatment-induced systemic depletion etiologies which cause and/or exacerbate the seven novel primary relative nutritional deficiencies associated with PD. These reversible relative nutritional deficiencies (RNDs) may facilitate and accelerate irreversible progressive neurodegeneration, while other reversible RNDs may induce previously undocumented reversible pseudo-neurodegeneration that is hiding in plain sight since the symptoms are identical to the symptoms being experienced by the PD patient. Documented herein is a novel nutritional approach for reversible processes management which may slow or halt irreversible progressive neurodegenerative disease and correct reversible RNDs whose symptoms are identical to the patient’s PD symptoms. PMID:27103805

  5. Water, sanitation and hygiene for accelerating and sustaining progress on neglected tropical diseases: a new Global Strategy 2015-20.

    Boisson, Sophie; Engels, Dirk; Gordon, Bruce A; Medlicott, Kate O; Neira, Maria P; Montresor, Antonio; Solomon, Anthony W; Velleman, Yael

    2016-03-01

    Neglected tropical diseases (NTDs) affect over 1 billion people. Safe water, sanitation and hygiene (WASH) contribute to prevention and management of most NTDs. Linking WASH and NTD interventions has potential to impact on multiple NTDs and can help secure sustainable and equitable progress towards universal access to WASH. The need to address the determinants of NTDs has been acknowledged. In response, WHO has published a new Global Strategy: 'Water, Sanitation and Hygiene for accelerating and sustaining progress on Neglected Tropical Diseases'. The Strategy focuses on cross-cutting actions that benefit disease control and care efforts, and strengthen health systems. Implementation of the strategy and the accompanying action plan can help ensure that the health and development agenda leaves no one behind. PMID:26940305

  6. A neurodegenerative vascular burden index and the impact on cognition

    Sebastian Heinzel

    2014-07-01

    Full Text Available A wide range of vascular burden factors have been identified to impact vascular function and structure as indicated by carotid intima-media thickness (IMT. On the basis of their impact on IMT, vascular factors may be selected and clustered in a vascular burden index (VBI. Since many vascular factors increase the risk of Alzheimer's disease (AD, a multifactorial neurodegenerative VBI may be related to early pathological processes in AD and cognitive decline in its preclinical stages.We investigated an elderly cohort at risk for neurodegeneration (TREND study, n = 1102 for the multifactorial influence of vascular burden factors on IMT measured by ultrasound. To create a VBI for this cohort, vascular factors and their definitions (considering medical history, medication and/or blood marker data were selected based on their statistical effects on IMT in multiple regressions including age and sex. The impact of the VBI on cognitive performance was assessed using the Trail-Making Test (TMT and the CERAD neuropsychological battery.IMT was significantly predicted by age (standardized β = .26, sex (.09; males > females and the factors included in the VBI: obesity (.18, hypertension (.14, smoking (.08, diabetes (.07, and atherosclerosis (.05, whereas other cardiovascular diseases or hypercholesterolemia were not significant. Individuals with 2 or more VBI factors compared to individuals without had an odds ratio of 3.17 regarding overly increased IMT (≥1.0 mm. The VBI showed an impact on executive control (log(TMT B-A, p = .047 and a trend towards decreased global cognitive function (CERAD total score, p = .057 independent of age, sex and education.A VBI established on the basis of IMT may help to identify individuals with overly increased vascular burden linked to decreased cognitive function indicating neurodegenerative processes. The longitudinal study of this risk cohort will reveal the value of the VBI as prodromal marker for cognitive decline and

  7. Role of nucleolar dysfunction in neurodegenerative disorders: a game of genes?

    Rosanna Parlato

    2015-05-01

    Full Text Available Within the cell nucleus the nucleolus is the site of rRNA transcription and ribosome biogenesis and its activity is clearly essential for a correct cell function, however its specific role in neuronal homeostasis remains mainly unknown. Here we review recent evidence that impaired nucleolar activity is a common mechanism in different neurodegenerative disorders. We focus on the specific causes and consequences of impaired nucleolar activity to better understand the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease (AD, Parkinson's disease (PD, Huntington's disease (HD and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD. In particular, we discuss the genetic and epigenetic factors that might regulate nucleolar function in these diseases. In addition, we describe novel animal models enabling the dissection of the context-specific series of events triggered by nucleolar disruption, also known as nucleolar stress. Finally, we suggest how this novel mechanism could help to identify strategies to treat these still incurable disorders.

  8. Lesion of the olfactory epithelium accelerates prion neuroinvasion and disease onset when prion replication is restricted to neurons.

    Jenna Crowell

    Full Text Available Natural prion diseases of ruminants are moderately contagious and while the gastrointestinal tract is the primary site of prion agent entry, other mucosae may be entry sites in a subset of infections. In the current study we examined prion neuroinvasion and disease induction following disruption of the olfactory epithelium in the nasal mucosa since this site contains environmentally exposed olfactory sensory neurons that project directly into the central nervous system. Here we provide evidence for accelerated prion neuroinvasion and clinical onset from the olfactory mucosa after disruption and regeneration of the olfactory epithelium and when prion replication is restricted to neurons. In transgenic mice with neuron restricted replication of prions, there was a reduction in survival when the olfactory epithelium was disrupted prior to intranasal inoculation and there was >25% decrease in the prion incubation period. In a second model, the neurotropic DY strain of transmissible mink encephalopathy was not pathogenic in hamsters by the nasal route, but 50% of animals exhibited brain infection and/or disease when the olfactory epithelium was disrupted prior to intranasal inoculation. A time course analysis of prion deposition in the brain following loss of the olfactory epithelium in models of neuron-restricted prion replication suggests that neuroinvasion from the olfactory mucosa is via the olfactory nerve or brain stem associated cranial nerves. We propose that induction of neurogenesis after damage to the olfactory epithelium can lead to prion infection of immature olfactory sensory neurons and accelerate prion spread to the brain.

  9. “Systems-level G protein-coupled receptor therapy across a neurodegenerative continuum by the GLP-1 receptor system”

    StuartMaudsley

    2014-09-01

    Full Text Available With our increasing appreciation of the true complexity of diseases and pathophysiologies it is clear that this knowledge needs to inform the future development of pharmacotherapeutics. For many disorders the disease mechanism itself is a complex process spanning multiple signaling networks, tissues and organ systems. Identifying the precise nature and locations of the pathophysiology is crucial for the creation of systemically-effective drugs. Diseases once considered constrained to a limited range of organ systems, e.g. central neurodegenerative disorders such as Alzheimer’s disease (AD, Parkinson’s disease (PD and Huntington’ disease (HD, the role of multiple central and peripheral organ systems in the etiology of such diseases is now widely accepted. With this knowledge, it is increasingly clear that these seemingly distinct neurodegenerative disorders (AD, PD and HD possess multiple pathophysiological similarities thereby demonstrating an inter-related continuum of disease-related molecular alterations. With this systems-level appreciation of neurodegenerative disease it is now imperative to consider that pharmacotherapeutics should be developed specifically to address the systemic imbalances that create the disorders. Identification of potential systems-level signaling axes may facilitate the generation of therapeutic agents with synergistic remedial activity across multiple tissues, organ systems and even diseases. Here we discuss the potentially therapeutic systems-level interaction of the glucagon-like peptide 1 (GLP-1 ligand-receptor axis with multiple aspects of the AD, PD and HD neurodegenerative continuum.

  10. Antisense Gene Silencing: Therapy for Neurodegenerative Disorders?

    Troels T. Nielsen

    2013-09-01

    Full Text Available Since the first reports that double-stranded RNAs can efficiently silence gene expression in C. elegans, the technology of RNA interference (RNAi has been intensively exploited as an experimental tool to study gene function. With the subsequent discovery that RNAi could also be applied to mammalian cells, the technology of RNAi expanded from being a valuable experimental tool to being an applicable method for gene-specific therapeutic regulation, and much effort has been put into further refinement of the technique. This review will focus on how RNAi has developed over the years and how the technique is exploited in a pre-clinical and clinical perspective in relation to neurodegenerative disorders.

  11. Granulovacuolar degeneration: a neurodegenerative change that accompanies tau pathology.

    Köhler, Christoph

    2016-09-01

    Granule-containing vacuoles in the cytoplasm of hippocampal neurons are a neuropathological feature of Alzheimer's disease. Granulovacuolar degeneration (GVD) is not disease-specific and can be observed in other neurodegenerative disorders and even in the brains of non-demented elderly people. However, several studies have reported much higher numbers of neurons undergoing GVD in the hippocampus of Alzheimer's disease cases. Recently, a neuropathological staging system for GVD has facilitated neuropathological assessment. Data obtained by electron microscopy and immunolabeling suggest that GVD inclusions are a special form of autophagic vacuole. GVD frequently occurs together with pathological changes of the microtubule-associated protein tau, but to date, the relationship between the two lesions remains elusive. Originally identified in hematoxylin- and silver-stained sections, immunolabeling has shown that the granules are composed of a variety of proteins, including those related to tau pathology, autophagy, diverse signal transduction pathways, cell stress and apoptosis. Several of these proteins serve as markers of GVD. Most researchers and authors have interpreted the sequestration of proteins into GVD inclusions as either a cellular defense mechanism or one that leads to the impairment of important cellular functions. This review provides a detailed overview of the various aspects of GVD and focuses on the relationship between tau pathology and GVD. PMID:27062260

  12. Recent Updates in the Treatment of Neurodegenerative Disorders Using Natural Compounds

    Mahmood Rasool

    2014-01-01

    Full Text Available Neurodegenerative diseases are characterized by protein aggregates and inflammation as well as oxidative stress in the central nervous system (CNS. Multiple biological processes are linked to neurodegenerative diseases such as depletion or insufficient synthesis of neurotransmitters, oxidative stress, abnormal ubiquitination. Furthermore, damaging of blood brain barrier (BBB in the CNS also leads to various CNS-related diseases. Even though synthetic drugs are used for the management of Alzheimer’s disease, Parkinson’s disease, autism, and many other chronic illnesses, they are not without side effects. The attentions of researchers have been inclined towards the phytochemicals, many of which have minimal side effects. Phytochemicals are promising therapeutic agents because many phytochemicals have anti-inflammatory, antioxidative as well as anticholinesterase activities. Various drugs of either synthetic or natural origin applied in the treatment of brain disorders need to cross the BBB before they can be used. This paper covers various researches related to phytochemicals used in the management of neurodegenerative disorders.

  13. Geroprotectors as a novel therapeutic strategy for COPD, an accelerating aging disease

    Ito K; Colley T; Mercado N

    2012-01-01

    Kazuhiro Ito, Thomas Colley, Nicolas MercadoAirways Disease Section, National Heart and Lung Institute, Imperial College London, London, United KingdomAbstract: Chronic obstructive pulmonary disease (COPD) progresses very slowly and the majority of patients are therefore elderly. COPD is characterized by an abnormal persistent inflammatory response to noxious environmental stimuli and there are increasing evidences for a close relationship between premature aging and chronic inflammatory dise...

  14. Acceleration in linear growth after splenectomy for hypersplenism in homozygous sickle cell disease.

    Singhal, A.; Thomas, P; Kearney, T; Venugopal, S.; Serjeant, G

    1995-01-01

    Chronic hypersplenism in homozygous sickle cell (SS) disease markedly increases haemolysis and the resulting erythropoietic expansion is likely to have a high metabolic cost. Splenectomy for hypersplenism in SS disease is followed by highly significant changes in haematological indices and an increase in height, but not weight, velocity. This pattern is similar to that observed in the trichuris dysentery syndrome after treatment, and differs from the increases in both height and weight veloci...

  15. Accelerating drug discovery for Alzheimer's disease: best practices for preclinical animal studies

    Shineman, Diana W; Basi, Guriqbal S.; Bizon, Jennifer L.; Colton, Carol A.; Greenberg, Barry D.; Hollister, Beth A; Lincecum, John; Leblanc, Gabrielle G.; Lee, Linda H; Luo, Feng; Morgan, Dave; Morse, Iva; Refolo, Lorenzo M; Riddell, David R; Scearce-Levie, Kimberly

    2011-01-01

    Animal models have contributed significantly to our understanding of the underlying biological mechanisms of Alzheimer's disease (AD). As a result, over 300 interventions have been investigated and reported to mitigate pathological phenotypes or improve behavior in AD animal models or both. To date, however, very few of these findings have resulted in target validation in humans or successful translation to disease-modifying therapies. Challenges in translating preclinical studies to clinical...

  16. How implementation of systems biology into clinical trials accelerates understanding of diseases

    BibianaBielekova

    2014-06-01

    Full Text Available Systems biology comprises a series of concepts and approaches that have been used successfully both to delineate novel biological mechanisms and to drive translational advances. The goal of systems biology is to re-integrate putatively critical elements extracted from multi-modality datasets in order to understand how interactions among multiple components form functional networks at the organism/patient-level, and how dysfunction of these networks underlies a particular disease. Due to the genetic and environmental diversity of human subjects, identification of critical elements related to a particular disease process from cross-sectional studies requires prohibitively large cohorts. Alternatively, implementation of systems biology principles to interventional clinical trials represents a unique opportunity to gain predictive understanding of complex diseases in comparatively small cohorts of patients. This paper reviews systems biology principles applicable to translational research, focusing on lessons from systems approaches to inflammation applied to multiple sclerosis (MS. We suggest that employing systems biology methods in the design and execution of biomarker-supported, proof-of-principle clinical trials provides a singular opportunity to merge therapeutic development with a basic understanding of disease processes. The ultimate goal is to develop predictive computational models of the disease, which will revolutionize diagnostic process and provide mechanistic understanding necessary for personalized therapeutic approaches. Added, biologically-meaningful information can be derived from diagnostic tests, if they are interpreted in functional relationships, rather than as independent measurements. Such systems-biology based diagnostics will transform disease taxonomies from phenotypical to molecular and will allow physicians to select optimal therapeutic regimens for individual patients.

  17. Disease: H00061 [KEGG MEDICUS

    Full Text Available H00061 Prion diseases; Creutzfeldt-Jacob disease (CJD); Gerstmann-Straussler diseas...e (GSD); Gerstmann-Straussler-Scheinker disease (GSSD); Fatal familial insomnia (FFI) Prion diseases, also t...ermed transmissible spongiform encephalopathies (TSEs), are a group of fatal neurodegenerative diseases that... affect humans and a number of other animal species. The etiology of these diseases...vely folded protein, PrPC. Neurodegenerative disease hsa05020 Prion diseases PRNP (mutation) [HSA:5621] [KO:

  18. Low micronutrient intake may accelerate the degenerative diseases of aging through allocation of scarce micronutrients by triage.

    Ames, Bruce N

    2006-11-21

    Inadequate dietary intakes of vitamins and minerals are widespread, most likely due to excessive consumption of energy-rich, micronutrient-poor, refined food. Inadequate intakes may result in chronic metabolic disruption, including mitochondrial decay. Deficiencies in many micronutrients cause DNA damage, such as chromosome breaks, in cultured human cells or in vivo. Some of these deficiencies also cause mitochondrial decay with oxidant leakage and cellular aging and are associated with late onset diseases such as cancer. I propose DNA damage and late onset disease are consequences of a triage allocation response to micronutrient scarcity. Episodic shortages of micronutrients were common during evolution. Natural selection favors short-term survival at the expense of long-term health. I hypothesize that short-term survival was achieved by allocating scarce micronutrients by triage, in part through an adjustment of the binding affinity of proteins for required micronutrients. If this hypothesis is correct, micronutrient deficiencies that trigger the triage response would accelerate cancer, aging, and neural decay but would leave critical metabolic functions, such as ATP production, intact. Evidence that micronutrient malnutrition increases late onset diseases, such as cancer, is discussed. A multivitamin-mineral supplement is one low-cost way to ensure intake of the Recommended Dietary Allowance of micronutrients throughout life. PMID:17101959

  19. Yoga as Therapy for Neurodegenerative Disorders: A Case Report of Therapeutic Yoga for Adrenomyeloneuropathy

    Muhammad, Charlene Marie; Moonaz, Steffany Haaz

    2014-01-01

    Yoga is a promising therapeutic modality for neurodegenerative diseases. This case study presents a therapeutic yoga protocol for adrenomyeloneuropathy (AMN) and its effect on a patient’s quality of life (QOL), agility, balance, and peripheral dexterity. A 61-y-old man diagnosed with AMN who was experiencing (1) peripheral neuropathy in his legs and feet, (2) lower-back pain (LBP), and (3) osteoarthritis received 60-min weekly therapeutic yoga sessions for a 10-mo period. Yoga therapy include...

  20. New molecular targets for PET and SPECT imaging in neurodegenerative diseases Novos alvos moleculares para tomografia por emissão de pósitrons (PET e tomografia computadorizada por emissão de fóton único (SPECT em doenças neurodegenerativas

    Marcel Benadiba

    2012-10-01

    Full Text Available The pathophysiology of neurodegenerative diseases (ND such as Alzheimer's disease (AD and Parkinson's disease (PD has not yet been completely elucidated. However, in the past few years, there have been great knowledge advances about intra-and extracellular proteins that may display impaired function or expression in AD, PD and other ND, such as amyloid beta (Aβ, α-synuclein, tau protein and neuroinflammatory markers. Recent developments in the imaging techniques of positron emission tomography (PET and single photon emission computed tomography (SPECT now allow the non-invasive tracking of such molecular targets of known relevance to ND in vivo. This article summarizes recent findings of PET and SPECT studies using these novel methods, and discusses their potential role in the field of drug development for ND as well as future clinical applications in regard to differential diagnosis of ND and monitoring of disease progression.A fisiopatologia das doenças neurodegenerativas (DN, tais como a doença de Alzheimer (DA e a doença de Parkinson (DP, ainda não é completamente compreendida. No entanto, nos últimos anos, houve grandes avanços em termos do conhecimento sobre proteínas intra e extracelulares, tais como beta-amiloide (Aβ, α-sinucleína, proteína tau e marcadores neuroinflamatórios, que podem ter sua função ou expressão prejudicada na DA, DP ou em outras DN. Progressos recentes nas técnicas de tomografia por emissão de pósitrons (PET e tomografia computadorizada por emissão de fóton único (SPECT permitem hoje em dia a identificação não invasiva de tais alvos moleculares in vivo. Este artigo resume descobertas recentes de estudos de PET e SPECT cerebral usando esses alvos moleculares inovadores e discute o papel potencial dessas técnicas no campo do desenvolvimento de novos medicamentos para as DN, bem como futuras aplicações clínicas em relação ao diagnóstico diferencial e monitoramento da progressão dessas

  1. Conformational properties of trinucleotide repeats associated with human neurodegenerative diseases

    Vorlíčková, Michaela; Renčiuk, Daniel; Fojtík, Petr; Zemánek, Michal; Kejnovská, Iva

    2007-01-01

    Roč. 24, č. 6 (2007), s. 745. ISSN 0739-1102. [The 15th Conversation. 19.06.2007-23.06.2007, Albany] R&D Projects: GA AV ČR(CZ) IAA100040701; GA ČR(CZ) GA204/07/0057 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : DNA conformational properties * trinucleotide repeats * fragile X chromosome Subject RIV: BO - Biophysics

  2. A Chaperome Subnetwork Safeguards Proteostasis in Aging and Neurodegenerative Disease

    Marc Brehme; Cindy Voisine; Thomas Rolland; Shinichiro Wachi; James H. Soper; Yitan Zhu; Kai Orton; Adriana Villella; Dan Garza; Marc Vidal; Hui Ge; Richard I. Morimoto

    2014-01-01

    Chaperones are central to the proteostasis network (PN) and safeguard the proteome from misfolding, aggregation, and proteotoxicity. We categorized the human chaperome of 332 genes into network communities using function, localization, interactome, and expression data sets. During human brain aging, expression of 32% of the chaperome, corresponding to ATP-dependent chaperone machines, is repressed, whereas 19.5%, corresponding to ATP-independent chaperones and co-chaperones, are induced. Thes...

  3. Oxidative stress inhibits axonal transport: implications for neurodegenerative diseases

    Fang Cheng

    2012-06-01

    Full Text Available Abstract Background Reactive oxygen species (ROS released by microglia and other inflammatory cells can cause axonal degeneration. A reduction in axonal transport has also been implicated as a cause of axonal dystrophies and neurodegeneration, but there is a paucity of experimental data concerning the effects of ROS on axonal transport. We used live cell imaging to examine the effects of hydrogen peroxide on the axonal transport of mitochondria and Golgi-derived vesicles in cultured rat hippocampal neurons. Results Hydrogen peroxide rapidly inhibited axonal transport, hours before any detectable changes in mitochondrial morphology or signs of axonal degeneration. Mitochondrial transport was affected earlier and was more severely inhibited than the transport of Golgi-derived vesicles. Anterograde vesicle transport was more susceptible to peroxide inhibition than retrograde transport. Axonal transport partially recovered following removal of hydrogen peroxide and local application of hydrogen peroxide inhibited transport, suggesting that the effects were not simply a result of nerve cell death. Sodium azide, an ATP synthesis blocker, had similar effects on axonal transport, suggesting that ATP depletion may contribute to the transport inhibition due to hydrogen peroxide. Conclusions These results indicate that inhibition of axonal transport is an early consequence of exposure to ROS and may contribute to subsequent axonal degeneration.

  4. Differential diagnosis of neurodegenerative diseases using structural MRI data

    Juha Koikkalainen

    2016-01-01

    The results prove that automatic quantification methods and computerized decision support methods are feasible for clinical practice and provide comprehensive information that may help clinicians in the diagnosis making.

  5. Microtubule-targeting agents: a therapeutic strategy in neurodegenerative diseases

    Apóstolo, Nuno Miguel Ferreira Morais

    2014-01-01

    A presença de microtúbulos instáveis é um fenómeno recorrente em várias doenças neurodegenerativas. Alterações anormais, de origem genética ou ambiental, induzidas na tubulina ou em moléculas relacionadas com os microtúbulos tais como MAPs, proteínas motoras, +TIPs dos microtúbulos ou mesmo enzimas responsáveis por cortar os microtúbulos, estão associadas com a reduzida estabilidade e hiperdinâmica dos microtúbulos em neurónios que degeneram. Os microtúbulos constituem grande parte das estrut...

  6. The basics of preclinical drug development for neurodegenerative disease indications

    Spack Edward G; Steinmetz Karen L

    2009-01-01

    Abstract Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have...

  7. Hyaluronan Synthesis, Catabolism, and Signaling in Neurodegenerative Diseases

    Larry S. Sherman

    2015-01-01

    Full Text Available The glycosaminoglycan hyaluronan (HA, a component of the extracellular matrix, has been implicated in regulating neural differentiation, survival, proliferation, migration, and cell signaling in the mammalian central nervous system (CNS. HA is found throughout the CNS as a constituent of proteoglycans, especially within perineuronal nets that have been implicated in regulating neuronal activity. HA is also found in the white matter where it is diffusely distributed around astrocytes and oligodendrocytes. Insults to the CNS lead to long-term elevation of HA within damaged tissues, which is linked at least in part to increased transcription of HA synthases. HA accumulation is often accompanied by elevated expression of at least some transmembrane HA receptors including CD44. Hyaluronidases that digest high molecular weight HA into smaller fragments are also elevated following CNS insults and can generate HA digestion products that have unique biological activities. A number of studies, for example, suggest that both the removal of high molecular weight HA and the accumulation of hyaluronidase-generated HA digestion products can impact CNS injuries through mechanisms that include the regulation of progenitor cell differentiation and proliferation. These studies, reviewed here, suggest that targeting HA synthesis, catabolism, and signaling are all potential strategies to promote CNS repair.

  8. Decision-making under Ambiguity in Neurodegenerative Disease

    Rogers, Denise

    2011-01-01

    Decision-making is a complex skill that is essential for daily life. Yet the complexities of this process are often overlooked in favour of more obvious cognitive deficits during neuropsychological assessment, such as memory or attention impairments. Decision-making involves affective and motivational aspects of executive functions (Happaney, Zelazo & Stuss, 2004). Executive functions include a range of abilities that can be divided into three categories: 1) goal setting and planning, 2) acti...

  9. Sulfated oligosaccharides for use in treatment of neurodegenerative diseases

    Campion, Colin; Pini, Adrian Peter John; Gilthorpe, Jonathan David

    2012-01-01

    Compounds which interact with HlsTONES Compounds of Formula I : • 4"'-Sulfo-Fucose [alpha]1-3 (4"-sulfo)-Fucose [alpha]1-3 (4'-Sulfo-Fu- cose [alpha]1-4-Glucuronic acid [beta]1-0-Methyl or • 4" "-Sulfo-Fucose [alpha]1-3 (4"-sulfo)-Fucose [alpha]1-3 (4"-sulfo)- Fucose [alpha]1-3 (4'-Sulfo-Fucose [alpha]1-4-Glucuronic acid [be ta]1-0-Methyl. wherein X is sulfate (-SO3H) or phosphate (-PO3H); Su is sulfate and sulfation is most likely at the arrowed positions. The compounds above are useful in t...

  10. [Prion diseases].

    Stoĭda, N I; Zavalishin, I A

    2012-01-01

    Prion diseases are a family of progressive neurodegenerative disorders caused by prions. There are four human prion diseases: Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, fatal insomnia and Kuru. They can arise in three different ways: acquired, familial or sporadic. We review clinical presentations, pathophysiology, morphological picture, diagnostic procedures and available treatment options of prion diseases. PMID:23235426

  11. Anterior Cervical Corpectomy and Fusion Accelerates Degenerative Disease at Adjacent Vertebral Segments

    Pickett, Gwynedd E.; Duggal, Neil; Theodore, Nicholas; Sonntag, Volker K.H.

    2008-01-01

    Background Anterior cervical corpectomy provides the most direct and thorough surgical approach for anterior decompression when spinal cord compression is found directly behind the vertebral body. However, anterior cervical fusion has been shown to be associated with the development of new degenerative changes at levels immediately adjacent to the fused segments. Th e incidence of adjacent segment disease (ASD) following anterior cervical corpectomy has not been widely reported. We set out to...

  12. How Implementation of Systems Biology into Clinical Trials Accelerates Understanding of Diseases

    Bielekova, Bibiana; Vodovotz, Yoram; An, Gary; Hallenbeck, John

    2014-01-01

    Systems biology comprises a series of concepts and approaches that have been used successfully both to delineate novel biological mechanisms and to drive translational advances. The goal of systems biology is to re-integrate putatively critical elements extracted from multi-modality datasets in order to understand how interactions among multiple components form functional networks at the organism/patient-level, and how dysfunction of these networks underlies a particular disease. Due to the g...

  13. How implementation of systems biology into clinical trials accelerates understanding of diseases

    Bibiana eBielekova; Yoram eVodovotz; Gary eAn; John eHallenbeck

    2014-01-01

    Systems biology comprises a series of concepts and approaches that have been used successfully both to delineate novel biological mechanisms and to drive translational advances. The goal of systems biology is to re-integrate putatively critical elements extracted from multi-modality datasets in order to understand how interactions among multiple components form functional networks at the organism/patient-level, and how dysfunction of these networks underlies a particular disease. Due to the...

  14. Antibody response to accelerated Hib immunisation in preterm infants receiving dexamethasone for chronic lung disease

    Robinson, M.; Campbell, F.; Powell, P; Sims, D; Thornton, C

    1999-01-01

    AIM—To study the effect of dexamethasone on the routine immunisation of preterm infants with chronic lung disease.
METHODS—Serum samples were obtained before and after immunisation from an unselected cohort of 59 preterm infants. Haemophilus influenzae antibodies were measured using an ELISA method and differences in the geometric mean values between the two groups of babies analysed.
RESULTS—Sixteen infants received no dexamethasone. Before and after immunisation antibody t...

  15. Early Alzheimer’s Disease Blocks Responses To Accelerating Self-Movement

    Fernandez, Roberto; Duffy, Charles J.

    2012-01-01

    We assessed the cortical processing of self-movement stimuli in aging and Alzheimer’s disease (AD). Our goal was to identify distinguishing effects on neural mechanisms related to driving and navigation. Young (YNC) and older (ONC) normal controls, and early AD patients (EAD) viewed real-world videos and dot motion stimuli simulating self-movement scenes. We recorded visual motion event related potentials (VMERPs) to stimulus motion coherence and speed. Aging delays motion evoked N200s, where...

  16. Cancer and neurodegenerative disorders: pathogenic convergence through microRNA regulation

    Liqin Du; Alexander Pertsemlidis

    2011-01-01

    Although cancer and neurodegenerative disease are two distinct pathological disorders, emerging evidence indicates that these two types of disease share common mechanisms of genetic and molecular abnormalities. Recent studies show that individual microRNAs (miRNAs) could be involved in the pathology of both diseases, indicating that the mechanisms of these two seemingly dichotomous diseases converge in the dysregulation of gene expression at the post-transcriptional level. Given the increasing evidence showing that miRNA-based therapeutic strategies that modulate the activity of one or more miRNAs are potentially effective for a wide range of pathological conditions, the involvement of miRNAs in the common pathways of leading both diseases suggests a bright future for developing common therapeutic approaches for both diseases. Moreover, the miRNAs that are dysregulated in both diseases may hold promise as uniquely informative diagnostic markers. Here, we review recent studies on the miRNAs that have been implicated in both cancer and neurodegenerative diseases.

  17. Pharmacological Alternatives for the Treatment of Neurodegenerative Disorders: Wasp and Bee Venoms and Their Components as New Neuroactive Tools

    Juliana Silva; Victoria Monge-Fuentes; Flávia Gomes; Kamila Lopes; Lilian dos Anjos; Gabriel Campos; Claudia Arenas; Andréia Biolchi; Jacqueline Gonçalves; Priscilla Galante; Leandro Campos; Márcia Mortari

    2015-01-01

    Neurodegenerative diseases are relentlessly progressive, severely impacting affected patients, families and society as a whole. Increased life expectancy has made these diseases more common worldwide. Unfortunately, available drugs have insufficient therapeutic effects on many subtypes of these intractable diseases, and adverse effects hamper continued treatment. Wasp and bee venoms and their components are potential means of managing or reducing these effects and provide new alternatives for...

  18. Disease: H00176 [KEGG MEDICUS

    Full Text Available progressive behavioral, cognitive and neurologic deficit. Inherited metabolic disease; Neurodegenerative dis...ropathy (AMN), Addison-only, and asymptomatic. This disorder is characterized by

  19. Nanoformulated alpha-mangostin ameliorates Alzheimer's disease neuropathology by elevating LDLR expression and accelerating amyloid-beta clearance.

    Yao, Lei; Gu, Xiao; Song, Qingxiang; Wang, Xiaolin; Huang, Meng; Hu, Meng; Hou, Lina; Kang, Ting; Chen, Jun; Chen, Hongzhuan; Gao, Xiaoling

    2016-03-28

    Alzheimer's disease (AD), the most common form of dementia, is now representing one of the largest global healthcare challenges. However, an effective therapy is still lacking. Accumulation of amyloid-beta (Aβ) in the brain is supposed to trigger pathogenic cascades that eventually lead to AD. Therefore, Aβ clearance strategy is being actively pursued as a promising disease modifying therapy. Here, we found that α-mangostin (α-M), a polyphenolic xanthone derivative from mangosteen, up-regulated low density lipoprotein receptor (LDLR) expression in microglia and liver cells, and efficiently facilitated Aβ clearance. However, the in vivo application of α-M is limited due to its hydrophobic nature, poor aqueous solubility and stability, and thus low bioavailability and accumulation in the target organs. To overcome this limitation, α-M was encapsulated into the core of poly(ethylene glycol)-poly(l-lactide) (PEG-PLA) nanoparticles [NP(α-M)]. Such nanoencapsulation improved the biodistribution of α-M in both the brain and liver, enhanced the brain clearance of (125)I-radiolabeled Aβ1-42 in an LDLR-dependent manner, reduced Aβ deposition, attenuated neuroinflammatory responses, ameliorated neurologic changes and reversed behavioral deficits in AD model mice. These findings justified the concept that polyphenol-mediated modulation of LDLR expression might serve as a safe and efficient disease-modifying therapy for AD by accelerating Aβ clearance. It also demonstrated the powerful capacity of nanotechnology in modulating the biodistribution behavior of drug to improve its therapeutic efficacy in AD. PMID:26836197

  20. Accelerated decline in white matter integrity in clinically normal individuals at risk for Alzheimer's disease.

    Rieckmann, Anna; Van Dijk, Koene R A; Sperling, Reisa A; Johnson, Keith A; Buckner, Randy L; Hedden, Trey

    2016-06-01

    Prior studies have identified white matter abnormalities in Alzheimer's disease (AD). Yet, cross-sectional studies in normal older individuals show little evidence for an association between markers of AD risk (APOE4 genotype and amyloid deposition), and white matter integrity. Here, 108 normal older adults (age, 66-87) with assessments of apolipoprotein e4 (APOE4) genotype and assessment of amyloid burden by positron emission tomography underwent diffusion tensor imaging scans for measuring white matter integrity at 2 time points, on average 2.6 years apart. Linear mixed-effects models showed that amyloid burden at baseline was associated with steeper decline in fractional anisotropy in the parahippocampal cingulum (p < 0.05). This association was not significant between baseline measures suggesting that longitudinal analyses can provide novel insights that are not detectable in cross-sectional designs. Amyloid-related changes in hippocampus volume did not explain the association between amyloid burden and change in fractional anisotropy. The results suggest that accumulation of cortical amyloid and white matter changes in parahippocampal cingulum are not independent processes in individuals at increased risk for AD. PMID:27143434

  1. Role of Copper and Cholesterol Association in the Neurodegenerative Process

    Nathalie Arnal

    2013-01-01

    Full Text Available Age is one of the main factors involved in the development of neurological illnesses, in particular, Alzheimer, and it is widely held that the rapid aging of the world population is accompanied by a rise in the prevalence and incidence of Alzheimer disease. However, evidence from recent decades indicates that Cu and Cho overload are emerging causative factors in neurodegeneration, a hypothesis that has been partially investigated in experimental models. The link between these two variables and the onset of Alzheimer disease has opened up interesting new possibilities requiring more in-depth analysis. The aim of the present study was therefore to investigate the effect of the association of Cu + Cho (CuCho as a possible synergistic factor in the development of an Alzheimer-like pathology in Wistar rats. We measured total- and nonceruloplasmin-bound Cu and Cho (free and sterified contents in plasma and brain zones (cortex and hippocampus, markers of oxidative stress damage, inflammation, and programmed cell death (caspase-3 and calpain isoforms. The ratio beta-amyloid (1-42/(1-40 was determined in plasma and brain as neurodegenerative biomarker. An evaluation of visuospatial memory (Barnes maze test was also performed. The results demonstrate the establishment of a prooxidative and proinflammatory environment after CuCho treatment, hallmarked by increased TBARS, protein carbonyls, and nitrite plus nitrate levels in plasma and brain zones (cortex and hippocampus with a consequent increase in the activity of calpains and no significant changes in caspase-3. A simultaneous increase in the plasma Aβ1-42/Aβ1-40 ratio was found. Furthermore, a slight but noticeable change in visuospatial memory was observed in rats treated with CuCho. We conclude that our model could reflect an initial stage of neurodegeneration in which Cu and Cho interact with one another to exacerbate neurological damage.

  2. Differential diagnosis of neurodegenerative dementias with nuclear medicine methods

    Full text: Neurodegenerative dementias (NDD) are characterized by insidious onset and gradual progression of cognitive dysfunction, initially relatively focal with respect to cognitive domains and brain regions involved. Nuclear medicine techniques help to clarify differential diagnoses of syndromes such as Alzheimer’s disease (AD), dementia with Lewy bodies (DlB), posterior cortical atrophy (PCA), logopenic primary progressive aphasia (PPA), agrammatic PPA, semantic dementia (SD), behavioral variant frontotemporal dementia (bvFTD) and progressive supranuclear palsy syndrome (PSPS). The process of pathologic changes in the brain may start decades before first clinical symptoms become evident. An early diagnosis already in the pre-clinical phase of the diseases will be of immense importance when expected effective therapeutic options have been introduced. NDDs are histopathologically characterized by accumulation of pathological proteins in the brain like beta amyloid or protein tau. While radiotracers for labeling of protein tau are in preclinical evaluation, different radiotracers labeling amyloid plaques ([11C]PIB, [18F]Florbetapir (Amyvid, Fa. EliLilly), [18F]Florbetaben (Neuraceq, Fa. Piramal), [18F]Flutemetamol (vVzamyl, Fa. Ge) have already been established in clinical use during the last years. In AD these tracers are intensively accumulated in the whole cortical brain. Even an early disease can be excluded in case of a negative amyloid PET. The method is, however, not highly specific since amyloid plaques may also be present in DlB (70 – 80%), FTD (30%) orlogopenicPPA (100%). Neuronal dysfunction goes along with decreased glucose consumption. Different diseases are characterized by different topographical zones of reduced [18F]FDG uptake. In AD the posterior cingular, temporopariatal and (later) frontal cortex are affected, in DlB the pattern is similar, including the occipital cortex, in FTD the frontal cortex is affected, in nonfluent PPA the

  3. Disease: H00067 [KEGG MEDICUS

    Full Text Available omal recessive ataxia caused by severely reduced levels of frataxin as a result of a large GAA triplet-repea...ion. Neurodegenerative disease FXN; frataxin (GAA repeat expansion) [HSA:2395] Disease class: mitochondrial ...ID:16805775 Kwong JQ, Beal MF, Manfredi G. The role of mitochondria in inherited neurodegenerative diseases.

  4. Development and validation of brain and spinal cord vector and cell-delivery techniques in pre-clinical minipig models of neurodegenerative disorders

    Juhás, Štefan; Juhásová, Jana; Klíma, Jiří; Maršala, M.; Maršala, S.; Atsushi, Y.; Johe, K.; Motlík, Jan

    2015-01-01

    Roč. 78, Suppl 2 (2015), s. 9-10. ISSN 1210-7859. [Conference on Animal Models for neurodegenerative Diseases /3./. 08.11.2015-10.11.2015, Liblice] R&D Projects: GA MŠk ED2.1.00/03.0124; GA MŠk(CZ) 7F14308 Institutional support: RVO:67985904 Keywords : minipig models of neurodegenerative disorders * brin and spinal cord cell delivery techniques Subject RIV: EB - Genetics ; Molecular Biology

  5. The interplay between iron accumulation, mitochondrial dysfunction and inflammation during the execution step of neurodegenerative disorders

    MarcoTulioNunez

    2014-03-01

    Full Text Available A growing set of observations points to mitochondrial dysfunction, iron accumulation, oxidative damage and chronic inflammation as common pathognomonic signs of a number of neurodegenerative diseases that includes Alzheimer's disease, Huntington disease, amyotrophic lateral sclerosis, Friedrich’s ataxia and Parkinson’s disease. Particularly relevant for neurodegenerative processes is the relationship between mitochondria and iron. The mitochondrion upholds the synthesis of iron-sulfur clusters and heme, the most abundant iron-containing prosthetic groups in a large variety of proteins, so a fraction of incoming iron must go through this organelle before reaching its final destination. In turn, the mitochondrial respiratory chain is the source of reactive oxygen species (ROS derived from leaks in the electron transport chain. The co-existence of both iron and ROS in the secluded space of the mitochondrion makes this organelle particularly prone to hydroxyl radical-mediated damage. In addition, a connection between the loss of iron homeostasis and inflammation is starting to emerge; thus, inflammatory cytokines like TNF-alpha and IL-6 induce the synthesis of the divalent metal transporter 1 and promote iron accumulation in neurons and microglia. Here, we review the recent literature on mitochondrial iron homeostasis and the role of inflammation on mitochondria dysfunction and iron accumulation on the neurodegenerative process that lead to cell death in Parkinson’s disease. We also put forward the hypothesis that mitochondrial dysfunction, iron accumulation and inflammation are part of a synergistic self-feeding cycle that ends in apoptotic cell death, once the antioxidant cellular defense systems are finally overwhelmed.

  6. Nonalcoholic fatty liver disease progression in rats is accelerated by splenic regulation of liver PTEN/AKT

    Ziming Wang

    2015-01-01

    Full Text Available Background/Aim: The spleen has been reported to participate in the development of nonalcoholic fatty liver disease (NAFLD, but the mechanism has not been fully characterized. This study aims to elucidate how the spleen affects the development of NAFLD in a rat model. Materials and Methods: Following either splenectomy or sham operation, male Sprague–Dawley (SD rats were fed a high-fat diet to drive the development of NAFLD; animals fed a normal diet were used as controls. Two months after surgery, livers and blood samples were collected. Serum lipids were measured; liver histology, phosphatase and tensin homologue deleted on chromosome 10 (PTEN gene expression, and the ratio of pAkt/Akt were determined. Results: Splenectomy increased serum lipids, except triglyceride (TG and high-density lipoprotein (HDL, in animals fed either a high-fat or normal diet. Furthermore, splenectomy significantly accelerated hepatic steatosis. Western blot analysis and real-time polymerase chain reaction showed splenectomy induced significant downregulation of PTEN expression and a high ratio of pAkt/Akt in the livers. Conclusions: The spleen appears to play a role in the development of NAFLD, via a mechanism involving downregulation of hepatic PTEN expression.

  7. Accelerated senescence and enhanced disease resistance in hybrid chlorosis lines derived from interspecific crosses between tetraploid wheat and Aegilops tauschii.

    Hiroki Nakano

    Full Text Available Hybrid chlorosis, a type of hybrid incompatibility, has frequently been reported in inter- and intraspecific crosses of allopolyploid wheat. In a previous study, we reported some types of growth abnormalities such as hybrid necrosis and observed hybrid chlorosis with mild or severe abnormalities in wheat triploids obtained in crosses between tetraploid wheat cultivar Langdon and four Ae. tauschii accessions and in their derived synthetic hexaploids. However, the molecular mechanisms underlying hybrid chlorosis are not well understood. Here, we compared cytology and gene expression in leaves to characterize the abnormal growth in wheat synthetics showing mild and severe chlorosis. In addition, we compared disease resistance to wheat blast fungus. In total 55 and 105 genes related to carbohydrate metabolism and 53 and 89 genes for defense responses were markedly up-regulated in the mild and severe chlorosis lines, respectively. Abnormal chloroplasts formed in the mesophyll cells before the leaves yellowed in the hybrid chlorosis lines. The plants with mild chlorosis showed increased resistance to wheat blast and powdery mildew fungi, although significant differences only in two, third internode length and maturation time, out of the examined agricultural traits were found between the wild type and plants showing mild chlorosis. These observations suggest that senescence might be accelerated in hybrid chlorosis lines of wheat synthetics. Moreover, in wheat synthetics showing mild chlorosis, the negative effects on biomass can be minimized, and they may show substantial fitness under pathogen-polluted conditions.

  8. Accelerated senescence and enhanced disease resistance in hybrid chlorosis lines derived from interspecific crosses between tetraploid wheat and Aegilops tauschii.

    Nakano, Hiroki; Mizuno, Nobuyuki; Tosa, Yukio; Yoshida, Kentaro; Park, Pyoyun; Takumi, Shigeo

    2015-01-01

    Hybrid chlorosis, a type of hybrid incompatibility, has frequently been reported in inter- and intraspecific crosses of allopolyploid wheat. In a previous study, we reported some types of growth abnormalities such as hybrid necrosis and observed hybrid chlorosis with mild or severe abnormalities in wheat triploids obtained in crosses between tetraploid wheat cultivar Langdon and four Ae. tauschii accessions and in their derived synthetic hexaploids. However, the molecular mechanisms underlying hybrid chlorosis are not well understood. Here, we compared cytology and gene expression in leaves to characterize the abnormal growth in wheat synthetics showing mild and severe chlorosis. In addition, we compared disease resistance to wheat blast fungus. In total 55 and 105 genes related to carbohydrate metabolism and 53 and 89 genes for defense responses were markedly up-regulated in the mild and severe chlorosis lines, respectively. Abnormal chloroplasts formed in the mesophyll cells before the leaves yellowed in the hybrid chlorosis lines. The plants with mild chlorosis showed increased resistance to wheat blast and powdery mildew fungi, although significant differences only in two, third internode length and maturation time, out of the examined agricultural traits were found between the wild type and plants showing mild chlorosis. These observations suggest that senescence might be accelerated in hybrid chlorosis lines of wheat synthetics. Moreover, in wheat synthetics showing mild chlorosis, the negative effects on biomass can be minimized, and they may show substantial fitness under pathogen-polluted conditions. PMID:25806790

  9. Nanowire array chips for molecular typing of rare trafficking leukocytes with application to neurodegenerative pathology

    Kwak, Minsuk; Kim, Dong-Joo; Lee, Mi-Ri; Wu, Yu; Han, Lin; Lee, Sang-Kwon; Fan, Rong

    2014-05-01

    Despite the presence of the blood-brain barrier (BBB) that restricts the entry of immune cells and mediators into the central nervous system (CNS), a small number of peripheral leukocytes can traverse the BBB and infiltrate into the CNS. The cerebrospinal fluid (CSF) is one of the major routes through which trafficking leukocytes migrate into the CNS. Therefore, the number of leukocytes and their phenotypic compositions in the CSF may represent important sources to investigate immune-to-brain interactions or diagnose and monitor neurodegenerative diseases. Due to the paucity of trafficking leucocytes in the CSF, a technology capable of efficient isolation, enumeration, and molecular typing of these cells in the clinical settings has not been achieved. In this study, we report on a biofunctionalized silicon nanowire array chip for highly efficient capture and multiplexed phenotyping of rare trafficking leukocytes in small quantities (50 microliters) of clinical CSF specimens collected from neurodegenerative disease patients. The antibody coated 3D nanostructured materials exhibited vastly improved rare cell capture efficiency due to high-affinity binding and enhanced cell-substrate interactions. Moreover, our platform creates multiple cell capture interfaces, each of which can selectively isolate specific leukocyte phenotypes. A comparison with the traditional immunophenotyping using flow cytometry demonstrated that our novel silicon nanowire-based rare cell analysis platform can perform rapid detection and simultaneous molecular characterization of heterogeneous immune cells. Multiplexed molecular typing of rare leukocytes in CSF samples collected from Alzheimer's disease patients revealed the elevation of white blood cell counts and significant alterations in the distribution of major leukocyte phenotypes. Our technology represents a practical tool for potentially diagnosing and monitoring the pathogenesis of neurodegenerative diseases by allowing an effective

  10. Disease: H01030 [KEGG MEDICUS

    Full Text Available with anterior horn cell disease (LAAHD) is a condition with fetal akinesia deformation sequence (FADS), multiple contract...letal disease; Neurodegenerative disease GLE1 [HSA:2733] Lethal congenital contract

  11. Neurodegenerative Erkrankungen (ZNS) - Eine aktuelle Übersicht

    Jellinger KA

    2005-01-01

    Neurodegenerative Erkrankungen, die, mit Ausnahme seltener, genetisch bedingter Formen, vorwiegend im vorgerückten Lebensalter auftreten, zeigen langsam fortschreitenden Verlauf und komplexe klinische und morphologische Phänotypen, bedingt durch progredienten Funktionsverlust und Ausfall spezifischer sensibler Neuronenpopulationen im Zentralnervensystem. Da ihnen meist Störungen von Proteinverarbeitung und -abbau mit Aggregation fehlgefalteter Proteinpartikel in Nervenzellen und Glia zugrunde...

  12. The senescence-accelerated mouse (SAM): a higher oxidative stress and age-dependent degenerative diseases model.

    Chiba, Yoichi; Shimada, Atsuyoshi; Kumagai, Naoko; Yoshikawa, Keisuke; Ishii, Sanae; Furukawa, Ayako; Takei, Shiro; Sakura, Masaaki; Kawamura, Noriko; Hosokawa, Masanori

    2009-04-01

    The SAM strain of mice is actually a group of related inbred strains consisting of a series of SAMP (accelerated senescence-prone) and SAMR (accelerated senescence-resistant) strains. Compared with the SAMR strains, the SAMP strains show a more accelerated senescence process, a shorter lifespan, and an earlier onset and more rapid progress of age-associated pathological phenotypes similar to human geriatric disorders. The higher oxidative stress status observed in SAMP mice is partly caused by mitochondrial dysfunction, and may be a cause of this senescence acceleration and age-dependent alterations in cell structure and function. Based on our recent observations, we discuss a possible mechanism for mitochondrial dysfunction resulting in the excessive production of reactive oxygen species, and a role for the hyperoxidative stress status in neurodegeneration in SAMP mice. These SAM strains can serve as a useful tool to understand the cellular mechanisms of age-dependent degeneration, and to develop clinical interventions. PMID:18688709

  13. MicroRNAs in Human Diseases: From Autoimmune Diseases to Skin, Psychiatric and Neurodegenerative Diseases

    Ha, Tai-You

    2011-01-01

    MicroRNAs (miRNAs) are small noncoding RNA molecules that negatively regulate gene expression via degradation or translational repression of their target messenger RNAs (mRNAs). Recent studies have clearly demonstrated that miRNAs play critical roles in several biologic processes, including cell cycle, differentiation, cell development, cell growth, and apoptosis and that miRNAs are highly expressed in regulatory T (Treg) cells and a wide range of miRNAs are involved in the regulation of immu...

  14. Alpha fucosidase and beta galactosidase in serum of a Lyme disease patients as a possible marker of accelerated senescence — a preliminary study

    Anna Wasiluk

    2012-07-01

    Full Text Available Lyme disease (LD is the most prevalent tick-borne disease in Europe. LD is caused by the spirochete Borrelia burgdorferi. LD is a chronic disease which can attack a number of organs: skin, heart, brain, joints. Chronic, low-grade inflammation involves general production of pro-inflammatory cytokines and inflammatory markers and is a typical feature of aging. So far, the best method of diagnosing LD is a time-consuming and expensive two-stage serological method. The aim of our study was to evaluate the activity of two lysosomal exoglycosidases: α-fucosidase (FUC and β-galactosidase (GAL in the serum of patients with Lyme disease, as potential markers of LD. Due to the increasing number of patients with Lyme disease and a number of false results, new ways to diagnose this disease are still being sought. As elevated level of β-galactosidase is a manifestation of residual lysosomal activity in senescent cells, the increase in its activity in serum during chronic Lyme disease might be a marker of a potentially accelerated senescence process. The study was performed on serum taken from cubital veins of 15 patients with Lyme disease and eight healthy subjects (control group. FUC and GAL activity was measured by the method of Chatterjee et al. as modified by Zwierz et al. In the serum of patients with Lyme disease, GAL activity significantly increased (p = 0.029, and the activity of FUC had a tendency to increase (p = 0.153, compared to the control group. A significant increase in GAL activity in the serum of patients with Lyme disease indicates an increased catabolism of glycoconjugates (glycoproteins, glycolipids, proteoglycans and could be helpful in the diagnosis of Lyme disease, although this requires confirmation in a larger group of patients. As GAL is the most widely used assay for detection of senescent cells, an elevated level of β-galactosidase might be a manifestation of accelerated senescence process in the course of Lyme

  15. Hippocampal-Prefrontal Circuit and Disrupted Functional Connectivity in Psychiatric and Neurodegenerative Disorders

    Ming Li

    2015-01-01

    Full Text Available In rodents, the hippocampus has been studied extensively as part of a brain system responsible for learning and memory, and the prefrontal cortex (PFC participates in numerous cognitive functions including working memory, flexibility, decision making, and rewarding learning. The neuronal projections from the hippocampus, either directly or indirectly, to the PFC, referred to as the hippocampal-prefrontal cortex (Hip-PFC circuit, play a critical role in cognitive and emotional regulation and memory consolidation. Although in certain psychiatric and neurodegenerative diseases, structural connectivity viewed by imaging techniques has been consistently found to be associated with clinical phenotype and disease severity, the focus has moved towards the investigation of connectivity correlates of molecular pathology and coupling of oscillation. Moreover, functional and structural connectivity measures have been emerging as potential intermediate biomarkers for neuronal disorders. In this review, we summarize progress on the anatomic, molecular, and electrophysiological characters of the Hip-PFC circuit in cognition and emotion processes with an emphasis on oscillation and functional connectivity, revealing a disrupted Hip-PFC connectivity and electrical activity in psychiatric and neurodegenerative disorders as a promising candidate of neural marker for neuronal disorders.

  16. Modifiers and mechanisms of multi-system polyglutamine neurodegenerative disorders: lessons from fly models

    Moushami Mallik; Subhash C. Lokhotia

    2010-12-01

    Polyglutamine (polyQ) diseases, resulting from a dynamic expansion of glutamine repeats in a polypeptide, are a class of genetically inherited late onset neurodegenerative disorders which, despite expression of the mutated gene widely in brain and other tissues, affect defined subpopulations of neurons in a disease-specific manner. We briefly review the different poly Q-expansion-induced neurodegenerative disorders and the advantages of modelling them in Drosophila. Studies using the fly models have successfully identified a variety of genetic modifiers and have helped in understanding some of the molecular events that follow expression of the abnormal polyQ proteins. Expression of the mutant polyQ proteins causes, as a consequence of intra-cellular and inter-cellular networking, mis-regulation at multiple steps like transcriptional and post-transcriptional regulations, cell signalling, protein quality control systems (protein folding and degradation networks), axonal transport machinery etc., in the sensitive neurons, resulting ultimately in their death. The diversity of genetic modifiers of polyQ toxicity identified through extensive genetic screens in fly and other models clearly reflects a complex network effect of the presence of the mutated protein. Such network effects pose a major challenge for therapeutic applications.

  17. High power accelerator-based boron neutron capture with a liquid lithium target and new applications to treatment of infectious diseases

    Halfon, S. [Soreq NRC, Yavne 81800 (Israel); Racah Institute of Physics, Hebrew University, Jerusalem 91904 (Israel)], E-mail: halfon@phys.huji.ac.il; Paul, M. [Racah Institute of Physics, Hebrew University, Jerusalem 91904 (Israel); Steinberg, D. [Biofilm Laboratory, Institute of Dental Sciences, Faculty of Dentistry, Hebrew University-Hadassah (Israel); Nagler, A.; Arenshtam, A.; Kijel, D. [Soreq NRC, Yavne 81800 (Israel); Polacheck, I. [Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University Medical Center (Israel); Srebnik, M. [Department of Medicinal Chemistry and Natural Products, School of Pharmacy, Hebrew University, Jerusalem 91120 (Israel)

    2009-07-15

    A new conceptual design for an accelerator-based boron neutron capture therapy (ABNCT) facility based on the high-current low-energy proton beam driven by the linear accelerator at SARAF (Soreq Applied Research Accelerator Facility) incident on a windowless forced-flow liquid-lithium target, is described. The liquid-lithium target, currently in construction at Soreq NRC, will produce a neutron field suitable for the BNCT treatment of deep-seated tumor tissues, through the reaction {sup 7}Li(p,n){sup 7}Be. The liquid-lithium target is designed to overcome the major problem of solid lithium targets, namely to sustain and dissipate the power deposited by the high-intensity proton beam. Together with diseases conventionally targeted by BNCT, we propose to study the application of our setup to a novel approach in treatment of diseases associated with bacterial infections and biofilms, e.g. inflammations on implants and prosthetic devices, cystic fibrosis, infectious kidney stones. Feasibility experiments evaluating the boron neutron capture effectiveness on bacteria annihilation are taking place at the Soreq nuclear reactor.

  18. High power accelerator-based boron neutron capture with a liquid lithium target and new applications to treatment of infectious diseases

    A new conceptual design for an accelerator-based boron neutron capture therapy (ABNCT) facility based on the high-current low-energy proton beam driven by the linear accelerator at SARAF (Soreq Applied Research Accelerator Facility) incident on a windowless forced-flow liquid-lithium target, is described. The liquid-lithium target, currently in construction at Soreq NRC, will produce a neutron field suitable for the BNCT treatment of deep-seated tumor tissues, through the reaction 7Li(p,n)7Be. The liquid-lithium target is designed to overcome the major problem of solid lithium targets, namely to sustain and dissipate the power deposited by the high-intensity proton beam. Together with diseases conventionally targeted by BNCT, we propose to study the application of our setup to a novel approach in treatment of diseases associated with bacterial infections and biofilms, e.g. inflammations on implants and prosthetic devices, cystic fibrosis, infectious kidney stones. Feasibility experiments evaluating the boron neutron capture effectiveness on bacteria annihilation are taking place at the Soreq nuclear reactor.

  19. Lipoprotein-based nanoparticles rescue the memory loss of mice with Alzheimer's disease by accelerating the clearance of amyloid-beta.

    Song, Qingxiang; Huang, Meng; Yao, Lei; Wang, Xiaolin; Gu, Xiao; Chen, Juan; Chen, Jun; Huang, Jialin; Hu, Quanyin; Kang, Ting; Rong, Zhengxing; Qi, Hong; Zheng, Gang; Chen, Hongzhuan; Gao, Xiaoling

    2014-03-25

    Amyloid-beta (Aβ) accumulation in the brain is believed to play a central role in Alzheimer's disease (AD) pathogenesis, and the common late-onset form of AD is characterized by an overall impairment in Aβ clearance. Therefore, development of nanomedicine that can facilitate Aβ clearance represents a promising strategy for AD intervention. However, previous work of this kind was concentrated at the molecular level, and the disease-modifying effectiveness of such nanomedicine has not been investigated in clinically relevant biological systems. Here, we hypothesized that a biologically inspired nanostructure, apolipoprotein E3-reconstituted high density lipoprotein (ApoE3-rHDL), which presents high binding affinity to Aβ, might serve as a novel nanomedicine for disease modification in AD by accelerating Aβ clearance. Surface plasmon resonance, transmission electron microscopy, and co-immunoprecipitation analysis showed that ApoE3-rHDL demonstrated high binding affinity to both Aβ monomer and oligomer. It also accelerated the microglial, astroglial, and liver cell degradation of Aβ by facilitating the lysosomal transport. One hour after intravenous administration, about 0.4% ID/g of ApoE3-rHDL gained access to the brain. Four-week daily treatment with ApoE3-rHDL decreased Aβ deposition, attenuated microgliosis, ameliorated neurologic changes, and rescued memory deficits in an AD animal model. The findings here provided the direct evidence of a biomimetic nanostructure crossing the blood-brain barrier, capturing Aβ and facilitating its degradation by glial cells, indicating that ApoE3-rHDL might serve as a novel nanomedicine for disease modification in AD by accelerating Aβ clearance, which also justified the concept that nanostructures with Aβ-binding affinity might provide a novel nanoplatform for AD therapy. PMID:24527692

  20. Prions and Prion-Like Pathogens in Neurodegenerative Disorders

    Caterina Peggion; Maria Catia Sorgato; Alessandro Bertoli

    2014-01-01

    Prions are unique elements in biology, being able to transmit biological information from one organism to another in the absence of nucleic acids. They have been identified as self-replicating proteinaceous agents responsible for the onset of rare and fatal neurodegenerative disorders—known as transmissible spongiform encephalopathies, or prion diseases—which affect humans and other animal species. More recently, it has been proposed that other proteins associated with common neurodegenerati...

  1. Clinicopathologic assessment and imaging of tauopathies in neurodegenerative dementias

    Murray, Melissa E.; Kouri, Naomi; Lin, Wen-Lang; Jack, Clifford R.; Dickson, Dennis W.; Vemuri, Prashanthi

    2014-01-01

    Microtubule-associated protein tau encoded by the MAPT gene binds to microtubules and is important for maintaining neuronal morphology and function. Alternative splicing of MAPT pre-mRNA generates six major tau isoforms in the adult central nervous system resulting in tau proteins with three or four microtubule-binding repeat domains. In a group of neurodegenerative disorders called tauopathies, tau becomes aberrantly hyperphosphorylated and dissociates from microtubules, resulting in a progr...

  2. Mucolipidosis Type IV: A Subtle Pediatric Neurodegenerative Disorder

    Geer, Joseph S.; Skinner, Steve A.; Goldin, Ehud; Holden, Kenton R.

    2010-01-01

    The mucolipidoses are a heterogenous group of autosomal recessive neurodegenerative lysosomal storage disorders. Mucolipidosis type IV is rare, is seen predominantly in the Ashkenazi Jewish population, and usually presents with global neurodevelopmental delays in infancy, subtle corneal opacifications or clouding, and very slowly progressive neurodegeneration over many years. Elevation of serum gastrin is reported while x-rays of bone and joints and lysosomal studies are normal. We report two...

  3. Global warming and neurodegenerative disorders: speculations on their linkage

    Laleh Habibi; George Perry; Morteza Mahmoudi

    2014-01-01

    Climate change is having considerable impact on biological systems. Eras of ice ages and warming shaped the contemporary earth and origin of creatures including humans. Warming forces stress conditions on cells. Therefore, cells evolved elaborate defense mechanisms, such as creation of heat shock proteins, to combat heat stress. Global warming is becoming a crisis and this process would yield an undefined increasing rate of neurodegenerative disorders in future decades. S...

  4. Automatic evaluation of speech rhythm instability and acceleration in dysarthrias associated with basal ganglia dysfunction

    Jan eRusz

    2015-07-01

    Full Text Available Speech rhythm abnormalities are commonly present in patients with different neurodegenerative disorders. These alterations are hypothesized to be a consequence of disruption to the basal ganglia circuitry involving dysfunction of motor planning, programming and execution, which can be detected by a syllable repetition paradigm. Therefore, the aim of the present study was to design a robust signal processing technique that allows the automatic detection of spectrally-distinctive nuclei of syllable vocalizations and to determine speech features that represent rhythm instability and acceleration. A further aim was to elucidate specific patterns of dysrhythmia across various neurodegenerative disorders that share disruption of basal ganglia function. Speech samples based on repetition of the syllable /pa/ at a self-determined steady pace were acquired from 109 subjects, including 22 with Parkinson's disease (PD, 11 progressive supranuclear palsy (PSP, 9 multiple system atrophy (MSA, 24 ephedrone-induced parkinsonism (EP, 20 Huntington's disease (HD, and 23 healthy controls. Subsequently, an algorithm for the automatic detection of syllables as well as features representing rhythm instability and rhythm acceleration were designed. The proposed detection algorithm was able to correctly identify syllables and remove erroneous detections due to excessive inspiration and nonspeech sounds with a very high accuracy of 99.6%. Instability of vocal pace performance was observed in PSP, MSA, EP and HD groups. Significantly increased pace acceleration was observed only in the PD group. Although not significant, a tendency for pace acceleration was observed also in the PSP and MSA groups. Our findings underline the crucial role of the basal ganglia in the execution and maintenance of automatic speech motor sequences. We envisage the current approach to become the first step towards the development of acoustic technologies allowing automated assessment of rhythm

  5. Can Accelerators Accelerate Learning?

    The 'Young Talented' education program developed by the Brazilian State Funding Agency (FAPERJ)[1] makes it possible for high-schools students from public high schools to perform activities in scientific laboratories. In the Atomic and Molecular Physics Laboratory at Federal University of Rio de Janeiro (UFRJ), the students are confronted with modern research tools like the 1.7 MV ion accelerator. Being a user-friendly machine, the accelerator is easily manageable by the students, who can perform simple hands-on activities, stimulating interest in physics, and getting the students close to modern laboratory techniques.

  6. Localization of A11-reactive oligomeric species in prion diseases

    Aidt, Frederik H; Hasholt, Lis F; Christiansen, Michael;

    2013-01-01

    To investigate in prion diseases the in-situ localization of prion protein oligomers sharing a common epitope with amyloid oligomers involved in a range of neurodegenerative diseases.......To investigate in prion diseases the in-situ localization of prion protein oligomers sharing a common epitope with amyloid oligomers involved in a range of neurodegenerative diseases....

  7. Plasma accelerators

    Recently attention has focused on charged particle acceleration in a plasma by a fast, large amplitude, longitudinal electron plasma wave. The plasma beat wave and plasma wakefield accelerators are two efficient ways of producing ultra-high accelerating gradients. Starting with the plasma beat wave accelerator (PBWA) and laser wakefield accelerator (LWFA) schemes and the plasma wakefield accelerator (PWFA) steady progress has been made in theory, simulations and experiments. Computations are presented for the study of LWFA. (author)

  8. Parkinson’s disease managing reversible neurodegeneration

    Hinz M

    2016-04-01

    Full Text Available Marty Hinz,1 Alvin Stein,2 Ted Cole,3 Beth McDougall,4 Mark Westaway5 1Clinical Research, NeuroResearch Clinics, Inc., Cape Coral, FL, 2Stein Orthopedic Associates, Plantation, FL, 3Cole Center for Healing, Cincinnati, OH, 4CLEARCenter of Health, Mill Valley, CA, USA; 5Four Pillars Health, Brendale, QLD, Australia Abstract: Traditionally, the Parkinson’s disease (PD symptom course has been classified as an irreversible progressive neurodegenerative disease. This paper documents 29 PD and treatment-induced systemic depletion etiologies which cause and/or exacerbate the seven novel primary relative nutritional deficiencies associated with PD. These reversible relative nutritional deficiencies (RNDs may facilitate and accelerate irreversible progressive neurodegeneration, while other reversible RNDs may induce previously undocumented reversible pseudo-neurodegeneration that is hiding in plain sight since the symptoms are identical to the symptoms being experienced by the PD patient. Documented herein is a novel nutritional approach for reversible processes management which may slow or halt irreversible progressive neurodegenerative disease and correct reversible RNDs whose symptoms are identical to the patient’s PD symptoms. Keywords: Parkinson’s disease, L-dopa, carbidopa, B6, neurodegeneration

  9. Early lens aging is accelerated in subjects with a high risk of ischemic heart disease: an epidemiologic study

    Glümer Charlotte; Jørgensen Torben; Kessel Line; Larsen Michael

    2006-01-01

    Abstract Background Ischemic heart disease (IHD) is one of the most important causes of mortality and morbidity in the Western world. There is a relationship between aging of the lens of the human eye and cardiovascular disease. The present study was conducted to examine if the risk of ischemic heart disease could be estimated by fluorophotometric assessment of lens aging. Methods A total of 421 subjects were included. Risk of IHD was estimated from non-ocular data using the Precard ® softwar...

  10. Linear Accelerators

    Vretenar, M

    2014-01-01

    The main features of radio-frequency linear accelerators are introduced, reviewing the different types of accelerating structures and presenting the main characteristics aspects of linac beam dynamics.

  11. Diseases leading to accelerated decline of reef corals in the largest South Atlantic reef complex (Abrolhos Bank, eastern Brazil).

    Francini-Filho, Ronaldo B; Moura, Rodrigo L; Thompson, Fabiano L; Reis, Rodrigo M; Kaufman, Les; Kikuchi, Ruy K P; Leão, Zelinda M A N

    2008-05-01

    Although reef corals worldwide have sustained epizootics in recent years, no coral diseases have been observed in the southwestern Atlantic Ocean until now. Here we present an overview of the main types of diseases and their incidence in the largest and richest coral reefs in the South Atlantic (Abrolhos Bank, eastern Brazil). Qualitative observations since the 1980s and regular monitoring since 2001 indicate that coral diseases intensified only recently (2005-2007). Based on estimates of disease prevalence and progression rate, as well as on the growth rate of a major reef-building coral species (the Brazilian-endemic Mussismilia braziliensis), we predict that eastern Brazilian reefs will suffer a massive coral cover decline in the next 50 years, and that M. braziliensis will be nearly extinct in less than a century if the current rate of mortality due to disease is not reversed. PMID:18348890

  12. Neurodegenerative changes in the brainstem and olfactory bulb in people older than 50 years old: a descriptive study

    Francine Hehn de Oliveira

    2015-07-01

    Full Text Available With the increase in life expectancy in Brazil, concerns have grown about the most prevalent diseases in elderly people. Among these diseases are neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases. Protein deposits related to the development of these diseases can pre-date the symptomatic phases by years. The tau protein is particularly interesting: it might be found in the brainstem and olfactory bulb long before it reaches the limbic cortex, at which point symptoms occur. Of the 14 brains collected in this study, the tau protein was found in the brainstems of 10 (71.42% and in olfactory bulbs of 3 out 11. Of the 7 individuals who had a final diagnosis of Alzheimer’s disease (AD, 6 presented tau deposits in some region of the brainstem. Our data support the idea of the presence of tau protein in the brainstem and olfactory bulb in the earliest stages of AD.

  13. Mutant SOD1 in cell types other than motor neurons and oligodendrocytes accelerates onset of disease in ALS mice

    Yamanaka, Koji; Boillee, Severine; Roberts, Elizabeth A.; Garcia, Michael L.; McAlonis-Downes, Melissa; Mikse, Oliver R.; Cleveland, Don W.; Lawrence S B Goldstein

    2008-01-01

    Dominant mutations in ubiquitously expressed superoxide dismutase (SOD1) cause familial ALS by provoking premature death of adult motor neurons. To test whether mutant damage to cell types beyond motor neurons is required for the onset of motor neuron disease, we generated chimeric mice in which all motor neurons and oligodendrocytes expressed mutant SOD1 at a level sufficient to cause fatal, early-onset motor neuron disease when expressed ubiquitously, but did so in a cellular environment co...

  14. Adult Bone Marrow: Which Stem Cells for Cellular Therapy Protocols in Neurodegenerative Disorders?

    Sabine Wislet-Gendebien

    2012-01-01

    Full Text Available The generation of neuronal cells from stem cells obtained from adult bone marrow is of significant clinical interest in order to design new cell therapy protocols for several neurological disorders. The recent identification in adult bone marrow of stem cells derived from the neural crests (NCSCs might explain the neuronal phenotypic plasticity shown by bone marrow cells. However, little information is available about the nature of these cells compared to mesenchymal stem cells (MSCs. In this paper, we will review all information available concerning NCSC from adult tissues and their possible use in regenerative medicine. Moreover, as multiple recent studies showed the beneficial effect of bone marrow stromal cells in neurodegenerative diseases, we will discuss which stem cells isolated from adult bone marrow should be more suitable for cell replacement therapy.

  15. Adult bone marrow: which stem cells for cellular therapy protocols in neurodegenerative disorders?

    Wislet-Gendebien, Sabine; Laudet, Emerence; Neirinckx, Virginie; Rogister, Bernard

    2012-01-01

    The generation of neuronal cells from stem cells obtained from adult bone marrow is of significant clinical interest in order to design new cell therapy protocols for several neurological disorders. The recent identification in adult bone marrow of stem cells derived from the neural crests (NCSCs) might explain the neuronal phenotypic plasticity shown by bone marrow cells. However, little information is available about the nature of these cells compared to mesenchymal stem cells (MSCs). In this paper, we will review all information available concerning NCSC from adult tissues and their possible use in regenerative medicine. Moreover, as multiple recent studies showed the beneficial effect of bone marrow stromal cells in neurodegenerative diseases, we will discuss which stem cells isolated from adult bone marrow should be more suitable for cell replacement therapy. PMID:22319243

  16. [Signaling molecules in the brain and epigenetic factors in neurodegenerative and mental disorders].

    Gomazkov, O A

    2015-01-01

    The literature on a role of signaling molecules in the organization of memory and cognitive functions is analyzed basing on mechanisms of memory physiology determined by a complex of biochemical processes initiated by the transmission of the signal to the synapse and completed by the synthesis of functionally significant molecules in the neuronal genetic apparatus. The center of these processes is a coordinated system of signal transduction, transcription, epigenetic and neurotrophic molecules. The dissonance of signal mechanisms is a prime cause of memory impairment and cognitive dysfunction as social maladaptation factors. The results of experimental and clinical studies of a role of the multilevel signaling system in age-related, neurodegenerative (Alzheimer’s disease) and mental (depression) disorders are discussed. At the same time, signaling molecules may be considered as particular targets for new therapeutic approaches. PMID:26649375

  17. Alterations of Eye Movement Control in Neurodegenerative Movement Disorders

    Martin Gorges

    2014-01-01

    Full Text Available The evolution of the fovea centralis, the most central part of the retina and the area of the highest visual accuracy, requires humans to shift their gaze rapidly (saccades to bring some object of interest within the visual field onto the fovea. In addition, humans are equipped with the ability to rotate the eye ball continuously in a highly predicting manner (smooth pursuit to hold a moving target steadily upon the retina. The functional deficits in neurodegenerative movement disorders (e.g., Parkinsonian syndromes involve the basal ganglia that are critical in all aspects of movement control. Moreover, neocortical structures, the cerebellum, and the midbrain may become affected by the pathological process. A broad spectrum of eye movement alterations may result, comprising smooth pursuit disturbance (e.g., interrupting saccades, saccadic dysfunction (e.g., hypometric saccades, and abnormal attempted fixation (e.g., pathological nystagmus and square wave jerks. On clinical grounds, videooculography is a sensitive noninvasive in vivo technique to classify oculomotion function alterations. Eye movements are a valuable window into the integrity of central nervous system structures and their changes in defined neurodegenerative conditions, that is, the oculomotor nuclei in the brainstem together with their directly activating supranuclear centers and the basal ganglia as well as cortical areas of higher cognitive control of attention.

  18. Testosterone treatment fails to accelerate disease in a transgenic mouse model of spinal and bulbar muscular atrophy

    Erica S. Chevalier-Larsen

    2012-01-01

    Evidence from multiple animal models demonstrates that testosterone plays a crucial role in the progression of symptoms in spinal and bulbar muscular atrophy (SBMA, a condition that results in neurodegeneration and muscle atrophy in affected men. Mice bearing a transgene encoding a human androgen receptor (AR that contains a stretch of 112 glutamines (expanded polyglutamine tract; AR112Q mice reproduce several aspects of the human disease. We treated transgenic male AR112Q mice with testosterone for 6 months. Surprisingly, testosterone treatment of AR112Q males did not exacerbate the disease. Although transgenic AR112Q males exhibited functional deficits when compared with non-transgenics, long-term testosterone treatment had no effect on motor function. Testosterone treatment also failed to affect cellular markers of disease, including inclusion formation (the accumulation of large nuclear aggregates of mutant AR protein and levels of unphosphorylated neurofilament heavy chain. These data suggest that the mechanism of disease in SBMA saturates at close to endogenous hormone levels and that individuals with SBMA who take, or have taken, testosterone for its putative therapeutic properties are unlikely to suffer adverse effects.

  19. Future accelerators (?)

    I describe the future accelerator facilities that are currently foreseen for electroweak scale physics, neutrino physics, and nuclear structure. I will explore the physics justification for these machines, and suggest how the case for future accelerators can be made

  20. Future accelerators (?)

    John Womersley

    2003-08-21

    I describe the future accelerator facilities that are currently foreseen for electroweak scale physics, neutrino physics, and nuclear structure. I will explore the physics justification for these machines, and suggest how the case for future accelerators can be made.