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
Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo
Gopal Thinakaran,David R. Borchelt,Michael K. Lee,Hilda H. Slunt,Lia Spitzer,Grace Kim,Tamara Ratovitsky,Frances Davenport,Christer Nordstedt,Mary Seeger,John Hardy,Allan I. Levey,Sam Gandy,Nancy A. Jenkins,Neal G. Copeland,Donald L. Price,Sangram S. Sisodia +16 more
TL;DR: It is concluded that PS1 is subject to endoproteolytic processing in vivo, and in brains of transgenic mice expressing human PS1, approximately 17 kDa and approximately 27 kDa PS1 derivatives accumulate to saturable levels, and at approximately 1:1 stoichiometry, independent of transgene-derived mRNA.
Journal ArticleDOI
Neurotoxicity induces cleavage of p35 to p25 by calpain
TL;DR: Observations indicate that cleavage of p35 to p25 by calpain may be involved in the pathogenesis of Alzheimer's disease.
Journal ArticleDOI
Evidence that production and release of amyloid beta-protein involves the endocytic pathway.
Edward H. Koo,Sharon L. Squazzo +1 more
TL;DR: It is hypothesized that the internalization of cell surface amyloid precursor protein (beta PP) via coated pit-mediated endocytosis is one pathway leading to A beta generation and release into medium.
Journal ArticleDOI
Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons.
Dean M. Hartley,Dominic M. Walsh,Chianping P. Ye,Thekla S. Diehl,Sara Vasquez,Peter M. Vassilev,David B. Teplow,Dennis J. Selkoe +7 more
TL;DR: The results raise the possibility that the preclinical and early clinical progression of AD is driven in part by the accumulation of specific Aβ assembly intermediates formed during the process of fibrillogenesis, and suggest that PF have inherent biological activity similar to that of mature fibrils.
Journal ArticleDOI
Skeletal and CNS defects in Presenilin-1-deficient mice.
TL;DR: Results show that PS1 is required for proper formation of the axial skeleton, normal neurogenesis, and neuronal survival.
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