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
Citations
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Journal ArticleDOI
Aggregation-Induced Emission: Together We Shine, United We Soar!
TL;DR: This paper presents a meta-analysis of the chiral stationary phase transition of Na6(CO3)(SO4)2, a major component of the response of the immune system to Na2CO3.
Journal ArticleDOI
Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
Dominic M. Walsh,Igor Klyubin,Julia V. Fadeeva,William K. Cullen,Roger Anwyl,Michael S. Wolfe,Michael J. Rowan,Dennis J. Selkoe +7 more
TL;DR: It is reported that natural oligomers of human Aβ are formed soon after generation of the peptide within specific intracellular vesicles and are subsequently secreted from the cell, indicating that synaptotoxic Aβ oligomers can be targeted therapeutically.
Journal ArticleDOI
Alzheimer's Disease Is a Synaptic Failure
TL;DR: Mounting evidence suggests that this syndrome begins with subtle alterations of hippocampal synaptic efficacy prior to frank neuronal degeneration, and that the synaptic dysfunction is caused by diffusible oligomeric assemblies of the amyloid β protein.
Journal ArticleDOI
Triple-Transgenic Model of Alzheimer's Disease with Plaques and Tangles: Intracellular Aβ and Synaptic Dysfunction
Salvatore Oddo,Antonella Caccamo,Jason D. Shepherd,M. Paul Murphy,Todd E. Golde,Rakez Kayed,Raju Metherate,Mark P. Mattson,Yama Akbari,Frank M. LaFerla +9 more
TL;DR: The recapitulation of salient features of AD in these mice clarifies the relationships between Abeta, synaptic dysfunction, and tangles and provides a valuable model for evaluating potential AD therapeutics as the impact on both lesions can be assessed.
Journal ArticleDOI
The Calpain System
TL;DR: How calpain activity is regulated in cells is still unclear, but the calpains ostensibly participate in a variety of cellular processes including remodeling of cytoskeletal/membrane attachments, different signal transduction pathways, and apoptosis.
References
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Journal ArticleDOI
Effects of PS1 Deficiency on Membrane Protein Trafficking in Neurons
Satoshi Naruse,Gopal Thinakaran,Jin Jun Luo,John W. Kusiak,Taisuke Tomita,Takeshi Iwatsubo,Xiaozhong Qian,David D. Ginty,Donald L. Price,David R. Borchelt,Philip C. Wong,Sangram S. Sisodia +11 more
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Journal ArticleDOI
The presenilin 2 mutation (N141I) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid β protein ending at the 42nd (or 43rd) residue
Taisuke Tomita,Kei Maruyama,Takaomi C. Saido,Hideaki Kume,Kohki Shinozaki,Shinya Tokuhiro,Anja Capell,Jochen Walter,Jürgen Grünberg,Christian Haass,Takeshi Iwatsubo,Kunihiko Obata +11 more
TL;DR: Results strongly suggest that the PS2 mutation (N141I) linked to FAD alters the metabolism of A beta/betaAPP to foster the production of the form of Abeta that most readily deposits in amyloid plaques.
Journal ArticleDOI
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Hilda H. Slunt,Gopal Thinakaran,C. S. Von Koch,Amy C. Y. Lo,Rudolph E. Tanzi,Sangram S. Sisodia +5 more
TL;DR: Although APLP2 cannot give rise to A beta, its near identity to APP outside the A beta domain confounds the interpretation of previous immunocytochemical and biochemical characterizations of APP biosynthesis and metabolism.
Journal ArticleDOI
Molecular mapping of alzheimer-type dementia in Down's syndrome
V. P. Prasher,Matthew J. Farrer,Anna M. Kessling,Elizabeth M. C. Fisher,R. J. West,P. C. Barber,A. C. Butler +6 more
TL;DR: The case of a 78‐year‐old woman with Down's syndrome with partial trisomy 21 with no evidence of Alzheimer's disease and the gene sequence for APP was present in only two copies supports the hypothesis that Alzheimer’s disease is associated withtrisomy for proximal chromosome 21q, including the APP gene.
Journal ArticleDOI
Amyloid β protein (Aβ) deposition: Aβ42(43) precedes Aβ40 in down Syndrome
TL;DR: The chronological relationship regarding deposition of amyloid beta protein (A beta) species, A beta 40 and A beta 42(43), was investigated in 16 brains from Down syndrome patients aged 31 to 64 years.
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