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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Journal ArticleDOI
Immunotherapeutic approaches to Alzheimer's disease.
Alon Monsonego,Howard L. Weiner +1 more
TL;DR: These areas provide a new avenue for exploring immune system–based therapy of neurodegenerative diseases and will be discussed here with a primary focus on Alzheimer's disease.
Journal ArticleDOI
Dietary n-3 polyunsaturated fatty acid depletion activates caspases and decreases NMDA receptors in the brain of a transgenic mouse model of Alzheimer's disease.
Frédéric Calon,Giselle P. Lim,Giselle P. Lim,Takashi Morihara,Takashi Morihara,Fusheng Yang,Fusheng Yang,Oliver J. Ubeda,Oliver J. Ubeda,Norman Salem,Sally A. Frautschy,Sally A. Frautschy,Greg M. Cole,Greg M. Cole +13 more
TL;DR: The marked effect of dietary n‐3 PFA on NMDA receptors and caspase/calpain activation in the cortex of an animal model of AD provide new insights into how dietary essential fatty acids may influence cognition and AD risk.
Journal ArticleDOI
Acute γ-Secretase Inhibition Improves Contextual Fear Conditioning in the Tg2576 Mouse Model of Alzheimer's Disease
Thomas A. Comery,Robert Martone,Suzan Aschmies,Kevin Atchison,George Diamantidis,Xiaohai Gong,Hua Zhou,Anthony Kreft,Menelas N. Pangalos,June Sonnenberg-Reines,J. Steven Jacobsen,Karen L. Marquis +11 more
TL;DR: Data are supportive of a role of β-amyloid in the impairment of CFC in Tg2576 mice and suggest that acute treatment with GSI may provide improved cognitive functioning as well as disease-modifying effects in Alzheimer's disease.
Journal ArticleDOI
Increased tau phosphorylation and cleavage in mouse models of type 1 and type 2 diabetes.
TL;DR: The results suggest tau modification caused by insulin dysfunction and hyperglycemia may contribute to the increased incidence of AD in diabetes.
Journal ArticleDOI
Axonal Transport, Amyloid Precursor Protein, Kinesin-1, and the Processing Apparatus: Revisited
Orly Lazarov,Gerardo Morfini,Edward B. Lee,Mohamed H. Farah,Anita Szodorai,Scott R. DeBoer,Vassilis E. Koliatsos,Stefan Kins,Virginia M.-Y. Lee,Philip C. Wong,Donald L. Price,Scott T. Brady,Sangram S. Sisodia +12 more
TL;DR: The hypothesis that APP serves as a kinesin-1 receptor and that the proteolytic processing machinery responsible for generating Aβ is transported in the same vesicular compartment in axons of peripheral nerves requires revision.
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
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Notch Signaling: Cell Fate Control and Signal Integration in Development
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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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