[PDF] The Role Of Lipid Rafts On The Trafficking And Processing Of The Amyloid Precursor Protein eBook

Author : Christopher Towlson
Publisher :
Page : 496 pages
File Size : 38,29 MB
Release : 2010
Category : Alzheimer's disease
ISBN :

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Alzheimer's disease (AD) brain pathology is characterised by the presence of senile plaques containing insoluble aggregates of the amyloid beta peptide (A[beta]). The mechanisms of A[beta] generation are not well understood but previous work has shown that amyloid precursor protein (APP) internalization from the cell surface may be an important step in this process. APP and the amyloidogenic enzymes involved in its processing have been shown to reside in cholesterol rich membrane micro-domains called lipid rafts. Lipid rafts are important cell signalling centres on the plasma membrane and may be involved in certain types of endocytosis. APP processing, including endocytosis, is also modulated by insulin signalling pathways. This thesis describes the generation and expression of APP endocytosis deficient mutants to study the role of APP intemalisation, insulin signalling and lipid rafts in A[beta] generation. -- Subcellular fractionation of cultured cells expressing human APP reveals that [beta]CTF, the direct precursor to A[beta], is found almost exclusively in lipid raft fractions. Furthermore, [beta]CTF is reduced in lipid rafts from cells expressing endocytosis deficient APP mutants. By contrast, APP endocytosis mutations have no effect on the localization of full-length APP or [beta]- and [gamma]-secretases. We also show that insulin treatment increases non-amyloidogenic processing of APP in neuroblastoma cells and primary mouse neurons, possibly by a mechanism involving decreased APP endocytosis. - Taken together, my results are consistent with the notion that plasma membrane bound APP and the [beta]-secretase BACE reside in distinct lipid raft species that merge upon endocytosis, resulting in enzyme and substrate converging in endosomes where APP is cleaved to generate A[beta]. Furthermore, altered APP endocytosis due to insulin resistance may increase the generation of A[beta] in AD.

Author :
Publisher :
Page : pages
File Size : 30,87 MB
Release : 2013
Category :
ISBN :

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Additionally, removing PLD1 from primary neurons causes a redistribution of APP from endosomes, a primary station for amyloidogenesis, to the Golgi complex, while PLD1 overexpression produces the converse phenotype. Pld1 null mice harboring familial AD-linked (FAD) APP mutations exhibited decreased brain amyloid and an accumulation of APP COOH-terminal fragments. This finding was particularly evident in Pld1 null membrane rafts, whose lipidome was profoundly altered. Acute inhibition of PLD1 reduced APP processing by gamma secretase, consistent with a regulatory role of the lipid raft environment on gamma secretase, a complex highly active in membrane rafts. Finally, Pld1 nullizygosity rescued cognitive deficits in the transgenic model. Thus, PLD1 and its product PA control the metabolism of APP and emerge as potential drug targets for Alzheimer's disease therapy.

Author : Christopher J. Fielding
Publisher : John Wiley & Sons
Page : 294 pages
File Size : 46,41 MB
Release : 2006-12-13
Category : Science
ISBN : 3527607501

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This keenly awaited first overview of the field represents a complete guide to the structure and function of the most important mammalian cell membrane organelles. Filling a huge gap in the primary literature, this book is the first to cover the subject in detail. Following an introduction by Kai Simons, the discoverer of lipid rafts and the most prominent scientist in the field, chapters include: Historical background Distinct structures and functions Structural basis Signaling Viral entry and virion budding Cholesterol transport Caveolins Lipid shells Cell polarity and intracellular trafficking Cancer cells Of prime importance to molecular and cell biologists, biochemists, membrane scientists, cancer researchers, and virologists.

Author : Stavros J. Baloyannis
Publisher :
Page : 0 pages
File Size : 15,17 MB
Release : 2021
Category : Brain
ISBN : 9781839680984

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Cerebral and Cerebellar Cortex - Interaction and Dynamics in Health and Disease discusses several important issues of cerebro-cerebellar collaboration and interactions. The morphological and functional study of the cerebral and cerebellar cortices and their interaction has considerable value for interpreting the clinical phenomenology of cortical degenerations in the initial stage of the disease. In addition, the analysis of cerebro-cerebellar interactions strongly supports the concept of the close functional unity and harmonization of the brain and the cerebellum, underlining the important role that the cerebellar cortex plays in the performance of higher mental faculties, creativity, emotional processes, and homeostatic equilibrium of the human body.

Author : Steve P. Watson
Publisher : Academic Press
Page : 452 pages
File Size : 10,84 MB
Release : 1994-02-28
Category : Medical
ISBN :

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Catalogues major facts about receptors, G-proteins and effector molecules. Each entry has a common format, using a minimum amount of text, and contains information on the sequence, gene structure, distribution, agonists/antagonists and physiochemical properties of these proteins.

Author : Raz Jelinek
Publisher : John Wiley & Sons
Page : 431 pages
File Size : 46,6 MB
Release : 2011-04-27
Category : Science
ISBN : 3527634339

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Addressing one of the biggest riddles in current molecular cell biology, this ground-breaking monograph builds the case for the crucial involvement of lipids and membranes in the formation of amyloid deposits. Tying together recent knowledge from in vitro and in vivo studes, and built on a sound biophysical and biochemical foundation, this overview brings the reader up to date with current models of the interplay between membranes and amyloid formation. Required reading for any researcher interested in amyloid formation and amyloid toxicity, and possible avenues for the prevention or treatment of neurodegenerative disorders. From the contents: * Interactions of Alpha-Synuclein with Lipids * Interaction of hIAPP and its Precursors with Membranes * Amyloid Polymorphisms: Structural Basis and Significance in Biology and Molecular Medicine * The Role of Lipid Rafts in Alzheimer's Disease * Alzheimer's Disease as a Membrane-Associated Enzymopathy of Beta-Amyloid Precursor Protein (APP) Secretases * Impaired Regulation of Glutamate Receptor Channels and Signaling Molecules by Beta-Amyloid in Alzheimer's Disease * Membrane Changes in BSE and Scrapie * Experimental Approaches and Technical Challenges for Studying Amyloid-Membrane Interactions and more

Author : Eunice Chungyu Chen
Publisher :
Page : 46 pages
File Size : 12,25 MB
Release : 2008
Category :
ISBN :

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Alzheimer's disease (AD) is the most common form of neurodegenerative disorder affecting the elderly, presenting symptoms such as memory impairment and dementia. AD is pathologically characterized by the development of extracellular senile plaques and intracellular neurofibrillary tangles (NFT). The plaques are composed of amyloid-[Beta] peptide (A[Beta]) and the NFTs are composed of a hyperphosphorylated form of the tau protein. A[Beta] is formed by sequential proteolytic processing of the amyloid precursor protein (APP) by [Beta]-, and [Gamma]-secretase. Accordingly, alterations in APP processing result in increased A[Beta] generation. The low-density lipoprotein receptor-related protein (LRP) is a large endocytic protein involved in diverse biological functions. It has been hypothesized that LRP plays a dual role in AD, playing a role in both the clearance and the production of A[Beta]. Previous studies have shown that the cytoplasmic tail alone is able to promote A[Beta] generation and promote APP processing. This study seeks to determine the area of the cytoplasmic tail responsible for pro-amyloidogenic activity and how it occurs. Our findings indicate that the last 37 amino acids of the tail, containing a dileucine motif, are sufficient. Additionally, LRP facilitates the generation of A[Beta] by trafficking APP and BACE1 to the lipid raft domains. This function of LRP may be altered due to the presence of a Kunitz protease inhibitor (KPI) domain on APP. The results of our study have therapeutic potential to reduce [Beta]-amyloid by understanding the function of LRP in the amyloidogenic processing of APP.

Author : Jorg Tatzelt
Publisher :
Page : 80 pages
File Size : 34,66 MB
Release : 2010
Category : Prions
ISBN : 9780954333522

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A conformational transition of the cellular prion protein (PrPC) into an aberrantly folded isoform designated scrapie prion protein (PrPSc) is the hallmark of a variety of neurodegenerative disorders collectively called prion diseases. They include Creutzfeldt-Jakob disease and Gerstmann-Stäussler-Scheinker syndrome in humans, scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle and chronic wasting disease (CWD) in free-ranging deer. In contrast to the deadly properties of misfolded PrP, PrPC seems to possess a neuroprotective activity. More-over, animal models indicated that the stress-protective activity of PrPC and the neurotoxic effects of PrPSc are somehow interconnected. In this timely book, leading scientists in the field have come together to highlight the apparently incongruous activities of different PrP conformers. The articles outline current research on celluar pathways implicated in the formation and signaling of neurotoxic and physiological PrP isoforms and delineate future research direction. Topics covered include the physiologcial activity of PrPC and its possible role as a neurotrophic factor, the finding that aberrant PrP conformers can cause neurodegeneration in the absence of infectious prion propagation, the requirement of the GPI anchor of PrPC for the neurotoxic effects of scrapie prions, the pathways implicated in the formation and neurotoxic properties of cytosolically localized PrP, the impact of metal ions on the processing of PrP, and the role of autophagy in the propagation and clearance of PrPSc. The book is fully illustrated and chapters include comprehensive reference sections. Essential reading for scientists involved in prion research.

Author : Mario Díaz
Publisher :
Page : 0 pages
File Size : 41,78 MB
Release : 2022
Category : Medical
ISBN :

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A wealth of evidence accumulated over the last two decades has unambiguously linked lipid rafts to neurodegenerative diseases, in particular to Alzheimer,Äôs disease (AD). These microdomains are highly dynamic membrane platforms with differentiated physicochemical and molecular properties compared to the surrounding membrane microenvironment, and are the locus for a number of central processes¬†in neuronal physiology. Most recent evidence pinpoint to lipid rafts as main players in AD neuropathology. It is now widely accepted that lipid rafts actively participate in the processing of amyloid precursor protein to generate amyloid beta peptides, a main component of amyloid plaques. Current evidence have highlighted the existence of severe alterations in the molecular structure and functionality of lipid rafts in the frontal cortex of human brains affected by Alzheimer,Äôs disease. An exceptionally interesting observation is that lipid raft destabilization can be demonstrated even at the earliest stages of AD neuropathology. In the present review, we will first elaborate on the structure and function of these multifaceted subcellular structures and second to focus on the impact of their alterations in neuronal pathophysiology along the onset and progression of AD continuum.