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Journal ArticleDOI

Alzheimer's Disease: Genes, Proteins, and Therapy

Dennis J. Selkoe
- 01 Apr 2001 - 
- Vol. 81, Iss: 2, pp 741-766
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-...

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Citations
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Tumor Necrosis Factor-α, Interleukin-1β, and Interferon-γ Stimulate γ-Secretase-mediated Cleavage of Amyloid Precursor Protein through a JNK-dependent MAPK Pathway

TL;DR: It is demonstrated that interferon-γ, interleukin-1β, and tumor necrosis factor-α can specifically stimulate γ-secretase activity, concomitant with increased production of Aβ and the intracellular domain of APP
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Transthyretin aggregation under partially denaturing conditions is a downhill polymerization.

TL;DR: It is suggested that amyloid formation by M-TTR under partially denaturing conditions is a downhill polymerization, in which the highest energy species is the native monomer.
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Beta-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress-activated protein kinases pathways.

TL;DR: HNE, an oxidative stress mediator detected in vivo in the brains of Alzheimer's disease patients, may play a pathogenetic role in Alzheimer’s disease by selectively activating SAPK pathways and BACE‐1 that regulate the proteolytic processing of AβPP.
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The molecular and cellular biology of enhanced cognition

TL;DR: Surprising results point to key synaptic and nuclear signalling events that can be manipulated to facilitate the induction or increase the stability of synaptic plasticity, and therefore enhance the acquisition or retention of information.
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Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer's disease

TL;DR: It is demonstrated that clusterin markedly influences Aβ structure and neuritic toxicity in vivo and is likely to play an important role in Alzheimer's disease pathogenesis.
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

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

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

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.

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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