Journal ArticleDOI
Alzheimer's Disease: Genes, Proteins, and Therapy
TLDR
Evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the beta-amyloid precursor protein by the protease called gamma-secretase has spurred progress toward novel therapeutics and provided discrete biochemical targets for drug screening and development.Abstract:
Rapid progress in deciphering the biological mechanism of Alzheimer's disease (AD) has arisen from the application of molecular and cell biology to this complex disorder of the limbic and association cortices. In turn, new insights into fundamental aspects of protein biology have resulted from research on the disease. This beneficial interplay between basic and applied cell biology is well illustrated by advances in understanding the genotype-to-phenotype relationships of familial Alzheimer's disease. All four genes definitively linked to inherited forms of the disease to date have been shown to increase the production and/or deposition of amyloid β-protein in the brain. In particular, evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the β-amyloid precursor protein by the protease called γ-secretase has spurred progress toward novel therapeutics. The finding that presenilin itself may be the long-sought γ-...read more
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Amyloid β-induced changes in nitric oxide production and mitochondrial activity lead to apoptosis
Uta Keil,Astrid Bonert,Celio A. Marques,Isabel Scherping,Jörg Weyermann,Joanna B. Strosznajder,Franz Müller-Spahn,Christian Haass,Christian Czech,Laurent Pradier,Walter E. Müller,Anne Eckert +11 more
TL;DR: A hypothetical sequence of pathogenic steps linking mutant APP expression and amyloid production with enhanced NO production and mitochondrial dysfunction finally leading to cell death is suggested, indicating a direct involvement of Aβ in these processes.
Journal ArticleDOI
Outsourcing in the brain: do neurons depend on cholesterol delivery by astrocytes?
TL;DR: A new kind of job-sharing between neurons and astrocytes is proposed to improve the still insufficient understanding of brain cholesterol metabolism and its role in neurodegeneration.
Journal ArticleDOI
Lipids as Modulators of Proteolytic Activity of BACE: INVOLVEMENT OF CHOLESTEROL, GLYCOSPHINGOLIPIDS, AND ANIONIC PHOSPHOLIPIDS IN VITRO *
Lucie Kalvodova,Nicoletta Kahya,Petra Schwille,Robert Ehehalt,Paul Verkade,David N. Drechsel,Kai Simons +6 more
TL;DR: To examine involvement of individual lipid species in modulating BACE activity, the purified BACE is reconstituted in large (∼100 nm) unilamellar vesicles, and its specific activity in vesicle of various lipid compositions is determined.
Journal ArticleDOI
A ketogenic diet reduces amyloid beta 40 and 42 in a mouse model of Alzheimer's disease.
TL;DR: It is demonstrated that a diet rich in saturated fats and low in carbohydrates can actually reduce levels of Aβ, and dietary strategies aimed at reducing Aβ levels should take into account interactions of dietary components and the metabolic outcomes.
Journal ArticleDOI
Role of cholesterol in synapse formation and function.
TL;DR: The experimental evidence for the hypothesis that the availability of cholesterol in neurons limits the extent of synaptogenesis is summarized and the structural and functional role of cholesterol at synapses is described to discuss how cholesterol may influence synapse development and stability.
References
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Journal ArticleDOI
Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families
Elizabeth H. Corder,Ann M. Saunders,Warren J. Strittmatter,Donald E. Schmechel,P. C. Gaskell,Gary W. Small,A. D. Roses,Jonathan L. Haines,Margaret A. Pericak-Vance +8 more
TL;DR: The APOE-epsilon 4 allele is associated with the common late onset familial and sporadic forms of Alzheimer9s disease (AD) in 42 families with late onset AD.
Journal ArticleDOI
Notch Signaling: Cell Fate Control and Signal Integration in Development
TL;DR: Notch signaling defines an evolutionarily ancient cell interaction mechanism, which plays a fundamental role in metazoan development, providing a general developmental tool to influence organ formation and morphogenesis.
Journal ArticleDOI
Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein
George G. Glenner,Caine W. Wong +1 more
TL;DR: A purified protein derived from the twisted beta-pleated sheet fibrils in cerebrovascular amyloidosis associated with Alzheimer's disease has been isolated and Amino acid sequence analysis and a computer search reveals this protein to have no homology with any protein sequenced thus far.
Journal ArticleDOI
The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor
Jie Kang,H. G. Lemaire,A. Unterbeck,J. M. Salbaum,Colin L. Masters,K.-H. Grzeschik,Gerd Multhaup,Konrad Beyreuther,Benno Müller-Hill +8 more
TL;DR: An apparently full-length complementary DNA clone coding for the A4 polypeptide is isolated and sequenced and suggests that the cerebral amyloid deposited in Alzheimer's disease and aged Down's syndrome is caused by aberrant catabolism of a cell-surface receptor.
Journal ArticleDOI
Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease.
Alison Goate,Marie-Christine Chartier-Harlin,Michael Mullan,Jeremy P Brown,Fiona Crawford,Liana Fidani,L. Giuffra,Andrew Haynes,N.G. Irving,Louise James,R. Mant,Phillippa Newton,Karen Rooke,P Roques,Christopher Talbot,Margaret A. Pericak-Vance,Alien D. Roses,Robert Williamson,Martin N. Rossor,Michael John Owen,John Hardy +20 more
TL;DR: A locus segregating with familial Alzheimer's disease (AD) has been mapped to chromosome 21, close to the amyloid precursor protein (APP) gene as discussed by the authors, which suggests that some cases of AD could be caused by mutations in the APP gene.
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