Elucidating Amyloid Precursor Protein Function in Human Astrocytes Derived from Pluripotent Stem Cells PDF Download
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Author: Lauren Kristen Fong
Publisher:
ISBN:
Category :
Languages : en
Pages : 138
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Book Description
Successful development of effective therapeutics for Alzheimer's disease (AD) requires a deep understanding of the mechanisms of disease pathogenesis. Recent human induced pluripotent stem cell (hiPSC)-derived models have shown it is possible to recapitulate the complex genetic diversity of a patient and more completely model AD pathology. While most work has focused on neuronal AD phenotypes, there is mounting evidence that failure to regulate cholesterol homeostasis by neighboring nonneuronal support cells may be involved in AD pathogenesis. Amyloid precursor protein (APP) or multiple fragments generated by APP proteolytic processing have previously been implicated in the regulation of cholesterol metabolism. However, the physiological function of APP in regulating lipoprotein homeostasis in astrocytes, which are responsible for the brain's de novo cholesterol biosynthesis and regulation, remains unclear. To address this, we independently validated and characterized a novel in vitro differentiation protocol to generate human astrocytes from hiPSC. We found that cells derived by this method recapitulated native astrocytes in their form and function. We also utilized CRISPR/Cas9 genome editing to generate isogenic APP knockout (KO) hiPSCs. We found that APP KO astrocytes have reduced cholesterol, elevated levels of sterol regulatory element-binding protein (SREBP)-target gene transcripts, and increased low-density lipoprotein (LDL) receptor protein, all downstream consequences of reduced lipoprotein endocytosis. To elucidate which APP fragments regulate cholesterol homeostasis and examine whether familial AD mutations in APP affect lipoprotein metabolism, we analyzed an isogenic allelic series using the APP Swedish and APP V717F mutations. Only astrocytes homozygous for the APP Swedish (APPSwe/Swe) mutation, which had reduced full-length APP (FL APP) due to aggressive beta-secretase cleavage, recapitulated the APP KO phenotypes. Further, astrocytic internalization of amyloid-beta (A-beta), another ligand of LDL receptors, was impaired in APP KO and APPSwe/Swe astrocytes. Given that FL APP is known to bind to multiple LDL receptors, we propose that FL APP acts as a co-receptor for known LDL receptor ligands and is required for proper cholesterol homeostasis and A-beta clearance in human astrocytes.
Author: Lauren Kristen Fong
Publisher:
ISBN:
Category :
Languages : en
Pages : 138
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Book Description
Successful development of effective therapeutics for Alzheimer's disease (AD) requires a deep understanding of the mechanisms of disease pathogenesis. Recent human induced pluripotent stem cell (hiPSC)-derived models have shown it is possible to recapitulate the complex genetic diversity of a patient and more completely model AD pathology. While most work has focused on neuronal AD phenotypes, there is mounting evidence that failure to regulate cholesterol homeostasis by neighboring nonneuronal support cells may be involved in AD pathogenesis. Amyloid precursor protein (APP) or multiple fragments generated by APP proteolytic processing have previously been implicated in the regulation of cholesterol metabolism. However, the physiological function of APP in regulating lipoprotein homeostasis in astrocytes, which are responsible for the brain's de novo cholesterol biosynthesis and regulation, remains unclear. To address this, we independently validated and characterized a novel in vitro differentiation protocol to generate human astrocytes from hiPSC. We found that cells derived by this method recapitulated native astrocytes in their form and function. We also utilized CRISPR/Cas9 genome editing to generate isogenic APP knockout (KO) hiPSCs. We found that APP KO astrocytes have reduced cholesterol, elevated levels of sterol regulatory element-binding protein (SREBP)-target gene transcripts, and increased low-density lipoprotein (LDL) receptor protein, all downstream consequences of reduced lipoprotein endocytosis. To elucidate which APP fragments regulate cholesterol homeostasis and examine whether familial AD mutations in APP affect lipoprotein metabolism, we analyzed an isogenic allelic series using the APP Swedish and APP V717F mutations. Only astrocytes homozygous for the APP Swedish (APPSwe/Swe) mutation, which had reduced full-length APP (FL APP) due to aggressive beta-secretase cleavage, recapitulated the APP KO phenotypes. Further, astrocytic internalization of amyloid-beta (A-beta), another ligand of LDL receptors, was impaired in APP KO and APPSwe/Swe astrocytes. Given that FL APP is known to bind to multiple LDL receptors, we propose that FL APP acts as a co-receptor for known LDL receptor ligands and is required for proper cholesterol homeostasis and A-beta clearance in human astrocytes.
Author: Douglas W. DeSimone
Publisher: Springer Science & Business Media
ISBN: 3642359353
Category : Science
Languages : en
Pages : 260
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Book Description
Cells in the developing embryo depend on signals from the extracellular environment to help guide their differentiation. An important mediator in this process is the extracellular matrix – secreted macromolecules that interact to form large protein networks outside the cell. During development, the extracellular matrix serves to separate adjacent cell groups, participates in establishing morphogenic gradients, and, through its ability to interact directly will cell-surface receptors, provides developmental clocks and positional information. This volume discusses how the extracellular matrix influences fundamental developmental processes and how model systems can be used to elucidate ECM function. The topics addressed range from how ECM influences early development as well as repair processes in the adult that recapitulate developmental pathways.
Author: Donald W. Pfaff
Publisher: Springer
ISBN: 9781493934737
Category : Medical
Languages : en
Pages : 0
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Book Description
Edited and authored by a wealth of international experts in neuroscience and related disciplines, this key new resource aims to offer medical students and graduate researchers around the world a comprehensive introduction and overview of modern neuroscience. Neuroscience research is certain to prove a vital element in combating mental illness in its various incarnations, a strategic battleground in the future of medicine, as the prevalence of mental disorders is becoming better understood each year. Hundreds of millions of people worldwide are affected by mental, behavioral, neurological and substance use disorders. The World Health Organization estimated in 2002 that 154 million people globally suffer from depression and 25 million people from schizophrenia; 91 million people are affected by alcohol use disorders and 15 million by drug use disorders. A more recent WHO report shows that 50 million people suffer from epilepsy and 24 million from Alzheimer’s and other dementias. Because neuroscience takes the etiology of disease—the complex interplay between biological, psychological, and sociocultural factors—as its object of inquiry, it is increasingly valuable in understanding an array of medical conditions. A recent report by the United States’ Surgeon General cites several such diseases: schizophrenia, bipolar disorder, early-onset depression, autism, attention deficit/ hyperactivity disorder, anorexia nervosa, and panic disorder, among many others. Not only is this volume a boon to those wishing to understand the future of neuroscience, it also aims to encourage the initiation of neuroscience programs in developing countries, featuring as it does an appendix full of advice on how to develop such programs. With broad coverage of both basic science and clinical issues, comprising around 150 chapters from a diversity of international authors and including complementary video components, Neuroscience in the 21st Century in its second edition serves as a comprehensive resource to students and researchers alike.
Author: Philip Beart
Publisher: Springer
ISBN: 3319571931
Category : Medical
Languages : en
Pages : 546
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Book Description
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.
Author: Jesus Avila
Publisher: Frontiers E-books
ISBN: 288919261X
Category : Medicine (General)
Languages : en
Pages : 114
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Book Description
Neurofibrillary tangles (NFTs) composed of intracellular aggregates of tau protein are a key neuropathological feature of Alzheimer’s Disease (AD) and other neurodegenerative diseases, collectively termed tauopathies. The abundance of NFTs has been reported to correlate positively with the severity of cognitive impairment in AD. However, accumulating evidences derived from studies of experimental models have identified that NFTs themselves may not be neurotoxic. Now, many of tau researchers are seeking a “toxic” form of tau protein. Moreover, it was suggested that a “toxic” tau was capable to seed aggregation of native tau protein and to propagate in a prion-like manner. However, the exact neurotoxic tau species remain unclear. Because mature tangles seem to be non-toxic component, “tau oligomers” as the candidate of “toxic” tau have been investigated for more than one decade. In this topic, we will discuss our consensus of “tau oligomers” because the term of “tau oligomers” [e.g. dimer (disulfide bond-dependent or independent), multimer (more than dimer), granular (definition by EM or AFM) and maybe small filamentous aggregates] has been used by each researchers definition. From a biochemical point of view, tau protein has several unique characteristics such as natively unfolded conformation, thermo-stability, acid-stability, and capability of post-translational modifications. Although tau protein research has been continued for a long time, we are still missing the mechanisms of NFT formation. It is unclear how the conversion is occurred from natively unfolded protein to abnormally mis-folded protein. It remains unknown how tau protein can be formed filaments [e.g. paired helical filament (PHF), straight filament and twisted filament] in cells albeit in vitro studies confirmed tau self-assembly by several inducing factors. Researchers are still debating whether tau oligomerization is primary event rather than tau phosphorylation in the tau pathogenesis. Inhibition of either tau phosphorylation or aggregation has been investigated for the prevention of tauopathies, however, it will make an irrelevant result if we don’t know an exact target of neurotoxicity. It is a time to have a consensus of definition, terminology and methodology for the identification of “tau oligomers”.
Author: George Comninel
Publisher: Routledge
ISBN: 1317487966
Category : Political Science
Languages : en
Pages : 311
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Book Description
The International Workingmen’s Association was the prototype of all organizations of the Labour movement and the 150th anniversary of its birth (1864-2014) offers an important opportunity to rediscover its history and learn from its legacy. The International helped workers to grasp that the emancipation of labour could not be won in a single country but was a global objective. It also spread an awareness in their ranks that they had to achieve the goal themselves, through their own capacity for organization, rather than by delegating it to some other force; and that it was essential to overcome the capitalist system itself, since improvements within it, though necessary to pursue, would not eliminate exploitation and social injustice. This book reconsider the main issues broached or advanced by the International – such as labor rights, critiques of capitalism and the search for international solidarity – in light of present-day concerns. With the recent crisis of capitalism, that has sharpened more than before the division between capital and labour, the political legacy of the organization founded in London in 1864 has regained profound relevance, and its lessons are today more timely than ever. This book was published as a special issue of Socialism and Democracy.
Author: Artemissia-Phoebe Nifli
Publisher: Frontiers Media SA
ISBN: 2889665720
Category : Science
Languages : en
Pages : 66
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Book Description
Author: Lauri Saxén
Publisher:
ISBN:
Category : Science
Languages : en
Pages : 316
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Book Description
Author: Trygve O. Tollefsbol
Publisher: Springer Science & Business Media
ISBN: 1441906398
Category : Medical
Languages : en
Pages : 462
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Book Description
Recent studies have indicated that epigenetic processes may play a major role in both cellular and organismal aging. These epigenetic processes include not only DNA methylation and histone modifications, but also extend to many other epigenetic mediators such as the polycomb group proteins, chromosomal position effects, and noncoding RNA. The topics of this book range from fundamental changes in DNA methylation in aging to the most recent research on intervention into epigenetic modifications to modulate the aging process. The major topics of epigenetics and aging covered in this book are: 1) DNA methylation and histone modifications in aging; 2) Other epigenetic processes and aging; 3) Impact of epigenetics on aging; 4) Epigenetics of age-related diseases; 5) Epigenetic interventions and aging: and 6) Future directions in epigenetic aging research. The most studied of epigenetic processes, DNA methylation, has been associated with cellular aging and aging of organisms for many years. It is now apparent that both global and gene-specific alterations occur not only in DNA methylation during aging, but also in several histone alterations. Many epigenetic alterations can have an impact on aging processes such as stem cell aging, control of telomerase, modifications of telomeres, and epigenetic drift can impact the aging process as evident in the recent studies of aging monozygotic twins. Numerous age-related diseases are affected by epigenetic mechanisms. For example, recent studies have shown that DNA methylation is altered in Alzheimer’s disease and autoimmunity. Other prevalent diseases that have been associated with age-related epigenetic changes include cancer and diabetes. Paternal age and epigenetic changes appear to have an effect on schizophrenia and epigenetic silencing has been associated with several of the progeroid syndromes of premature aging. Moreover, the impact of dietary or drug intervention into epigenetic processes as they affect normal aging or age-related diseases is becoming increasingly feasible.
Author: Masaki Ieda
Publisher: Springer
ISBN: 3319561065
Category : Medical
Languages : en
Pages : 274
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Book Description
This Volume of the series Cardiac and Vascular Biology offers a comprehensive and exciting, state-of-the-art work on the current options and potentials of cardiac regeneration and repair. Several techniques and approaches have been developed for heart failure repair: direct injection of cells, programming of scar tissue into functional myocardium, and tissue-engineered heart muscle support. The book introduces the rationale for these different approaches in cell-based heart regeneration and discusses the most important considerations for clinical translation. Expert authors discuss when, why, and how heart muscle can be salvaged. The book represents a valuable resource for stem cell researchers, cardiologists, bioengineers, and biomedical scientists studying cardiac function and regeneration.
