Download or read book The Contribution of Oligodendrocytes to Amyloid and Tau Pathologies in Mouse Models of Alzheimer s Disease written by Andrew Octavian Sasmita and published by . This book was released on 2024 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Oligodendrocytes (OLs) are the myelinating glia of the CNS and are capable of metabolically supporting long axonal projections by providing local fuel production. OL and myelin health, however, start degrading around the second half of human life, which coincides with the predicted age at which Alzheimer's disease (AD), a debilitating neurodegenerative disease, may begin to develop. Although AD is often considered a disease of the gray matter, or neurons to be exact, recent evidence has indicated the involvement of glial cells in its pathophysiology. Earlier work has shown that dysfunctiona...

Download or read book The Role of Glia in Alzheimer s Disease written by Beatriz G. Perez-Nievas and published by Frontiers Media SA. This book was released on 2019-03-20 with total page 128 pages. Available in PDF, EPUB and Kindle. Book excerpt: We believe that the role of glia is the next frontier to be explored in Alzheimer’s disease research. This eBook is an update on both the current knowledge of astrocytes and microglia involvement in Alzheimer’s disease pathophysiology, and some of the techniques available to study them.

Download or read book Tau Pathology in Neurological Disorders written by Sonia Do Carmo and published by Frontiers Media SA. This book was released on 2021-11-12 with total page 268 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book The Contribution of Amyloid Vs Tau to Alzheimer s like Phenotypes in Transgenic Mouse Models written by Jie Yeap and published by . This book was released on 2019 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Both APP- and Tau specific early EEG alterations were detected in the double transgenic mice and could be easily segregated, which was not possible by solely assessing their cognitive and molecular profiles. This indicates that EEG-based differential diagnoses may offer greater sensitivity and specificity than cognitive assessments and other biomarkers.

Download or read book Neurodegenerative Diseases written by Philip Beart and published by Springer. This book was released on 2017-07-03 with total page 546 pages. Available in PDF, EPUB and Kindle. Book excerpt: Provides a timely overview of critical advances in molecular and cellular neurobiology, covers key methodologies driving progress, and highlights key future directions for research on neuronal injury and neurodegeneration relevant to neuronal brain pathologies. The editors bring together contributions from internationally recognized workers in the field to provide an up to date account of how and why molecular and cellular neurobiology is such an important area for clinical neuroscience. Understanding the molecular aspects of a number of neurodegenerative conditions such as Parkinson's or Alzheimer's disease for the purpose of improving patient management remains a major challenge of neurobiology be it from the basic or clinical perspective. A strategic evaluation of research contributions and the power of modern methods will help advance knowledge over the next years.

Download or read book Neurodegenerative Diseases written by Uday Kishore and published by BoD – Books on Demand. This book was released on 2013-05-15 with total page 642 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book highlights the pathophysiological complexities of the mechanisms and factors that are likely to be involved in a range of neuroinflammatory and neurodegenerative diseases including Alzheimer's disease, other Dementia, Parkinson Diseases and Multiple Sclerosis. The spectrum of diverse factors involved in neurodegeneration, such as protein aggregation, oxidative stress, caspases and secretase, regulators, cholesterol, zinc, microglia, astrocytes, oligodendrocytes, etc, have been discussed in the context of disease progression. In addition, novel approaches to therapeutic interventions have also been presented. It is hoped that students, scientists and clinicians shall find this very informative book immensely useful and thought-provoking.

Download or read book The Contribution of Amyloid Vs Tau to Alzheimer s like Phenotypes in Transgenic Mouse Models written by Jie Yeap and published by . This book was released on 2019 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Alzheimer s Disease Research Guide written by Takaomi C. Saido and published by Elsevier. This book was released on 2024-07-25 with total page 284 pages. Available in PDF, EPUB and Kindle. Book excerpt: Alzheimer's Disease Research Guide: Animal Models for Understanding Mechanisms and Medications provides researchers with a comprehensive guide, detailing every aspect of Alzheimer's Disease research, including chapters on neuroinflammation, immunotherapy, biomarkers, and animal modeling. This book begins with historical perspectives of both pathological chronology and pathological biochemistry in relation to Alzheimer’s disease. Other chapters review Amyloidogenic AB and Non-Amyloidogenic tau and Metabolism of AB major components to the research and understanding of Alzheimer’s research. The book concludes with specific treatment chapters including how to develop safe, effective, and inexpensive medications and the application of genome editing to the treatment of Familial Alzheimer's Disease. Written by world renowned expert in Alzheimer’s research, this book is a valuable resource for all researchers. Reviews why familial Alzheimer’s disease is vital to understanding sporadic Alzheimer’s disease Describes the latest “game changer” animal models of Alzheimer's disease and frontotemporal dementia in detail Explains how various Alzheimer’s disease medications have failed clinical trials Discusses pros and cons of therapeutic antibodies, lecanemab and donanemab, that were recently found to be effective in recent clinical trials Details the application of genome editing as a treatment for familial Alzheimer’s disease Proposes publishing “Journal of Negative Data” for the days of generative AI-assisted publication, AI being unable to distinguish between reproducible and unreproducible data, particularly important in Alzheimer’s research

Download or read book Loss of TREM2 dependent Microgliosis in Mouse Models of Amyloid beta and Tau Pathologies Reveal Juxtaposed Roles for Reactive Microglia in Alzheimer s Disease written by Cheryl E. G. Leyns and published by . This book was released on 2018 with total page 215 pages. Available in PDF, EPUB and Kindle. Book excerpt: Alzheimer's (AD) disease is the most common cause of dementia and is a major public health problem for which there is currently no disease modifying therapy. Two types of protein aggregates characterize AD pathology, extracellular amyloid-[beta] (A[beta]) plaques and intraneuronal tau tangles. They are accompanied by wide-spread gliosis, neuroinflammation, synaptic and neuronal loss. While these defining characteristics were described over 115 years ago, there is still a need for greater understanding of the mechanisms connecting these pathologies and how they lead to the brain atrophy and cognitive decline observed in patients. Recently, genetic studies uncovered novel sporadic AD risk variants in the microglial receptor, TREM2, which indicated the innate immune system may have a more active role in disease pathogenesis. Early studies have suggested that TREM2 facilitates microglial clustering around A[beta] plaques that limits surrounding neurite damage while TREM2 AD risk variants lead to a loss or reduction of function that impairs microglial signaling and is deleterious. However, the role of TREM2 in the setting of tau pathology had not yet been reported. Here, I describe how TREM2 deficiency reduced the microglial response to tau pathology, without increasing the amount of tau inclusions, which protected against neuroinflammation and brain atrophy in a mouse model of tangle deposition. Despite TREM2 function not overtly altering the amount of late-stage tau pathology, I hypothesized that plaque-associated microglia may be critical to mitigating early tau aggregation surrounding neuritic amyloid plaques. Using a newly developed paradigm for inciting the aggregation of mouse tau in mice transgenic for A[beta] plaque deposition, I found that less plaque-associated microglia in mice with impaired or null TREM2 function allowed for increased peri-plaque axonal dystrophy and neuritic plaque tau deposits. This novel discovery places TREM2-mediated microgliosis at the intersection of A[beta] and tau pathologies and, considered alongside previous studies, suggest that microglial TREM2 function is critical for preventing amyloid-dependent toxicity which may agonize initial tau pathogenesis early in AD. Yet subsequently, TREM2 enables detrimental microgliosis following the accumulation of tau pathology that can promote neurodegeneration. These findings imply dual roles for microglia in AD that are important to consider in developing potential therapies, such as antibody-directed clearance of protein aggregates. Early immunotherapeutic attempts to treat AD used monoclonal antibodies (mAbs) to reduce A[beta] and plaque deposition. While several A[beta] mAbs are still in phase 3 clinical trials for asymptomatic and prodromal patient populations, it has become clear that A[beta] mAbs will not provide clinically meaningful benefits for mild to moderate stage AD patients. Inability to rescue cognitive deficits in these patients is hypothesized to be because by the time individuals are in the symptomatic phase of disease, A[beta]-related effects have peaked and tau-related pathologies are driving disease progression. The presence of tau in specific brain regions strongly correlates with cognitive decline in AD and other neurodegenerative disorders, termed tauopathies, where tau inclusions alone are linked with neurodegeneration. Thus, immunotherapeutic approaches to reduce tau aggregation are now being investigated. Previously, an anti-tau mAb, HJ8.5, was reported to reduce tau-associated pathologies in a mouse model of tauopathy, yet the mechanism of action for the mAb was still unclear. The immunoglobulin Fc domain of mAbs can bind to Fc[gamma] receptors primarily expressed on microglia in the brain and mediates phagocytosis and clearance of the antibody-antigen complex. This binding, depending on its nature and the target, can theoretically lead to adverse effects like complement activation and the release of inflammatory cytokines that may exacerbate tau pathology and neurodegeneration. I investigated the necessity of Fc effector function for tau immunotherapy by generating full-length and truncated anti-tau HJ8.5-based constructs with differential and selective binding to Fc[gamma] receptors. In addition, I engineered a gene therapy-based system to optimize delivery of mAbs by expressing them directly in the brain using adeno-associated virus (AAV). Using this new immunization paradigm, I saw certain anti-tau constructs without Fc effector function were still efficacious, suggesting that microglial-mediated tau clearance may not be required for anti-tau mAbs to protect against tau accumulation. However, some of my studies did not fully recapitulate the published protective effects of HJ8.5 treatment. Further optimization of technical barriers may allow for better interpretation of this data. Regardless, this AAV expression system has been successfully applied to other immunotherapy paradigms. In summary, I have demonstrated that microglia play a critical role in preventing early tau aggregation around A[beta] plaques, yet can promote neuroinflammation and exacerbate neurodegeneration incited by accumulating tau pathology. Anti-tau mAbs offer a way to reduce tau aggregation and this may be achieved independent of Fc effector function, though additional work is needed to better interpret collective data. Lastly, my gene therapy approach represents a plausible, long-term method for optimized delivery of full-length and truncated mAb constructs to the brain for the treatment of AD, related tauopathies, and other diseases.

Download or read book The Role of Glial Glutamate Transporter and Its Impact on Amyloid beta and Tau Pathology in Alzheimer s Disease written by and published by . This book was released on 2017 with total page 178 pages. Available in PDF, EPUB and Kindle. Book excerpt: Alzheimer's disease (AD) is the leading cause of dementia among elderly in the United States. There is no effective treatment available, in part due to lack of understanding of the full spectrum of the disease mechanisms. Brain is structured in highly heterogeneous and complex way, and the number of different cell lineages, such as neurons, astrocytes, microglia, oligodendrocytes, perivascular macrophages, and capillary endothelial cells, interact with each other and functionally integrate into one highly hierarchical and organized unit. Traditionally, neurodegeneration has been centered for investigation on neurodegenerative diseases like AD. However, recent rapidly growing evidence strongly implicates the pathogenic involvement of non-neuronal cell lineages, such as astrocytes and microglia, and this work may uncover key disease mechanisms. The purpose of this dissertation is to elucidate the role of glutamate transporter 1 (GLT-1) primarily expressed in astrocytes in the progression or initiation of AD pathology. In humans, its loss is evident even in early or prodromal stages of AD and correlates well with cognitive impairment. The loss of GLT-1 causes glutamate dyshomeostasis in the synaptic cleft, which eventually leads to glutamate-induced excitotoxicity and neurodegeneration. While glutamate excitotoxicity has long been a suspected cause of progressive neurodegeneration in AD, it remains unclear whether the loss of the glutamate transporter directly contributes to the pathological buildup of amyloid ß (Aß) and neurofibrillary tau tangles (NFTs) - two key pathological hallmarks of AD. Thus, we hypothesize that the Aß-induced GLT-1 downregulation links Aß pathology to tau pathology, synaptic loss, and cognitive decline. To test this hypothesis, we utilized both in vitro and in vivo models of AD and thoroughly performed biochemical and histopathological examinations. We show an age-dependent decrease of GLT-1 in animal models and GLT-1 decrease in human hippocampal samples. In addition, pharmacological restoration of GLT-1 can ameliorate AD-like pathology in an animal model of AD. We also present a possible molecular mechanism that regulates GLT-1 independent of Aß. The contribution of this research includes a better understanding on the role of astrocyte dysfunction in the early stages of AD and its consequences on the progression of the disease.

Download or read book Apolipoprotein E and Alzheimer s Disease written by A.D. Roses and published by Springer Science & Business Media. This book was released on 2012-12-06 with total page 208 pages. Available in PDF, EPUB and Kindle. Book excerpt: There is now considerable genetic evidence that the type 4 allele of the apolipoprotein E gene is a major susceptibility factor associated with late-onset Alzheimer's disease, the common form of the disease defined as starting after sixty years of age. The role of apolipoprotein E in normal brain metabolism and in the pathogenesis of Alzheimer's disease are new and exciting avenues of research. This book, written by the most outstanding scientists in this new filed, is the first presentation of results concerning the implications of apolipoprotein E on the genetics, cell biology, neuropathology, biochemistry, and therapeutic management of Alzheimer's disease.

Download or read book Studying the Interactions Between Tau Amyloid and Alpha Synuclein in Alzheimer s Disease Animal and Human Cell Models written by Wesley W. L. Chen and published by . This book was released on 2016 with total page 210 pages. Available in PDF, EPUB and Kindle. Book excerpt: Alzheimer's disease (AD) is the leading cause of age related dementia and involves a progressive loss of neurons and synapses, leading to anxiety, cognitive impairment and a diminished quality of life. Pathologically, AD is characterized by extracellular amyloid beta (Abeta) plaque accumulation and the intraneuronal formation of tau-laden neurofibrillary tangles. In up to 70% of AD patients, these two hallmark pathologies are accompanied by a third proteinopathy; the aggregation of ??synuclein into intraneuronal Lewy bodies. The aggregate stress caused by these proteinopathies interacts with the immune system to produce a chronic neuroinflammatory condition that can further exacerbate disease progression.The goal of my dissertation is investigate how beta-amyloid, tau and alpha-synuclein pathologies interact with each other and to examine the role of the immune system in these interactions. To study how these proteinapathies interact in later stages of AD, I developed a new mouse model of AD termed 'T5x' mice, by crossing two existing transgenic lines; 5xFAD and Tau22 mice---aggressive lines that exhibit robust amyloidosis and tauopathy respectively. During my studies I found that T5x mice exhibit dramatically increased tau hyperphosphorylation, neuroinflammatory response, and microgliosis. However, quite surprisingly I also found that T5x mice exhibit increased microglial Abeta phagocytosis leading to decreased amyloid plaque burden and insoluble Abeta. In subsequent studies I further determine that T5x mice also develop inclusions composed of murine alpha-synuclein (alpha-syn) and form Lewy-body like pathologies---the first transgenic AD model to our knowledge to be found to develop Lewy body-like inclusions without an alpha-synuclein transgene.To further study the specific effects that the immune system has on the development of tau pathology, I also developed a mouse model of tau pathology lacking the adaptive immune. Thy1-Tau22 mice were crossed with Rag2 -/-/Il2rgamma-/- double knockout mice over multiple generations to create 'RagTau' mice. RagTau mice lack T-, B- and NK-cells, yet exhibit significant accumulation and hyperphosphorylation of human tau. Although RagTau mice exhibit increases microglial activation relative to immune-intact Tau22 transgenics, no significant increases in tau pathology were detected in RagTau mice. To further validate the minimal influence of the adaptive immune system on the development of tau pathology, I performed adoptive transfer experiments, transplanting bone marrow cells from strain-matched GFP donors into RagTau mice. Using this approach I examined the potential effects of bone marrow reconstitution on tau pathology and the infiltration of GFP-labeled cells into the brain of tau mice. Unlike recent equivalent studies performed in our lab with Abeta-producing mice, I detected no changes in tau pathology in response to bone marrow transplantation. However, I did find that tau pathology induces a significant increase in T-cell infiltration into the brain parenchyma in comparison to Rag-wild type recipients. Lastly, I was the first in our lab to establish the paradigm of generating human induced pluripotent stem cells (iPSCs). Using this approach I differentiated iPSCs into neural stem cells (NSCs) and transplanted into RagTau mice to examine potential questions about tau propagation. Interestingly, while iPSC-derived NSCs survived for at least 3 months post-transplantation I found no evidence that tau pathology could spread to these transplanted human cells. Taken together, my thesis research has helped to improve our understanding of the interactions between AD pathologies and the immune system.

Download or read book Oligodendrocytes From Their Development to Function and Dysfunction written by Hiroaki Wake and published by Frontiers Media SA. This book was released on 2024-03-12 with total page 118 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Alzheimer s Disease From Basic Research to Clinical Applications written by Hermann J. Gertz and published by Springer Science & Business Media. This book was released on 2013-06-29 with total page 313 pages. Available in PDF, EPUB and Kindle. Book excerpt: As human longevity continues to be extended, so will the impact of age-associated dementia on individual lives and society. Alzheimer’s disease as the most common cause of dementia in the elderly remains a sentinal problem and its underlying pathology is still poorly understood. Available therapeutic strategies require considerable refinement and the development of new therapeutic strategies need input from basic research. Thus continued efforts are necessary both to understand basic mechanisms of the condition and to achieve more powerfull therapies. This volume brings together the reports of basic scientists and clinical investigators. The chapters provide a spectrum of information valuable for clinicians and scientists. This issue bridges the gap between laboratory work in basic science and the development of urgently needed therapeutic strategies. Areas presented are the molecular and cellular biology of the disease, pathogenetic mechanisms and potential therapeutic targets, genetics, risk factors, strategies of prevention and treatment as well as practical aspects of medical and social care for patients with Alzheimer’s disease.

Download or read book The Contribution of the Complement System in the Development of Alzheimer s Disease Pathology and Cognitive Dysfunction written by Rahasson Roland Ager and published by . This book was released on 2009 with total page 194 pages. Available in PDF, EPUB and Kindle. Book excerpt: Alzheimer's Disease (AD), a progressive neurodegenerative disorder characterized by amyloid-[beta]; and hyperphosphorylated tau accumulation, and neuronal loss, is associated with aging. Genetic studies have contributed to the development of the amyloid cascade hypothesis, as a cause of disease development. An immune presence, including activated glia and complement deposition, in reaction to amyloid buildup, has produced the hypothesis that complement activation is a substantial component in AD progression. Most AD mouse models lack substantial neuronal degeneration or loss, which could impact their learning impairment and thus their usefulness as a model for human AD. Previous experiments, demonstrated weaker mouse complement activation, in response to fibrillar A[beta]; (fA[beta]) compared with human complement, possibly due to differences in human vs. mouse C1q A chain. It was hypothesized that weaker complement activation could result in lower neuronal loss. Thus, the A chain of mouse complement component C1q, was altered to mimic human C1q. However, increased fA[beta]-C1q interaction was not observed after the modification. The subsequently published crystal structure of C1q globular head domains, suggested that a similar 3-dimensional arrangement of amino acids on the B chain subunit provides sufficient interaction between mouse C1q and fA[beta] without the A chain contribution. One complement activation product, C5a, is an initiator of inflammation. Analysis of AD model mice revealed that CNS expression of CD88, a cellular receptor for C5a, increases with age and is localized around A[beta] plaques. Targeting C5a activity, with a CD88 antagonist (PMX205) for 12 weeks, resulted in a significant reduction in thoiflavine positive A[beta] plaques and activated glia. Additionally, reductions in hyperphosphorylated tau (in 3xTg mice) and neuronal damage in the hippocampus (in Tg2576 mice) were observed. Reductions in pathology were correlated with improved contextual memory in Tg2576 mice. Treatment with PMX205, demonstrated that CD88 in microglia surrounding plaques was reduced in parallel with reduced plaque load. Importantly, the treatment does not negatively interfere with complement components which have been suggested to be protective in other AD models. These results suggest, inhibition of CD88 may serve as a therapy towards AD.

Download or read book Amyloid beta clearance in Alzheimer s disease written by Robert Marr and published by Frontiers Media SA. This book was released on 2015-03-24 with total page 112 pages. Available in PDF, EPUB and Kindle. Book excerpt: Strong evidence continues to accumulate indicating that amyloid-beta (Aß) is a central part of Alzheimer’s disease (AD) pathogenesis in spite of the negative evidence coming from failed clinical trials. Therefore, mechanisms of clearance of Aß are of great interest in understanding AD pathogenesis and the development of effective treatments. This topic focuses on the issues related to Aß clearance in AD. The topics covered include proteases that degrade Aß and their localization, regulation, and functions. This topic also covers issues related to clearance through uptake by glia and through low-density lipoprotein (LDL) receptor mediated mechanisms. Signal transduction related to AD pathology and clearance is also addressed. Finally, immunotherapy and other novel therapeutic approaches are discussed.

Download or read book Analysis of the Role of the Microtubule Associated Protein Tau and the Amyloid Precursor Protein APP in Transgenic Mouse Models of Alzheimer s Disease written by Karolin Selle and published by . This book was released on 2012 with total page 117 pages. Available in PDF, EPUB and Kindle. Book excerpt: