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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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
Alzheimer's A beta(1-42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells.
David G. Cook,Mark S. Forman,Jane C. Sung,Susan Leight,Dennis L. Kolson,Takeshi Iwatsubo,Virginia M.-Y. Lee,Robert W. Doms +7 more
TL;DR: Using human NT2N neurons, it is found that retention of APP in the endoplasmic reticulum/intermediate compartment (ER/IC) by three independent approaches eliminated production of intracellular Aβ, but did not alter intrace cellular Aβ(1–42) synthesis.
Journal ArticleDOI
Participation of Presenilin 2 in Apoptosis: Enhanced Basal Activity Conferred by an Alzheimer Mutation
Benjamin Wolozin,Katsunori Iwasaki,Pasquale Vito,J. Kelly Ganjei,Emanuela Lacana,Trey Sunderland,Boyu Zhao,John W. Kusiak,Wilma Wasco,Luciano D'Adamio +9 more
TL;DR: A PS2 mutation associated with familial Alzheimer's disease was found to generate a molecule with enhanced basal apoptotic activity, which might accelerate the process of neurodegeneration that occurs in Alzheimer’s disease, leading to the earlier age of onset characteristic of familial Alzheimers disease.
Journal ArticleDOI
Laying it on thick
TL;DR: Using an electrochemical fabrication technique, the authors claimed to have created the world's thinnest chain from metal layers only micrometres thick, in a simple, automated process.
Journal ArticleDOI
Isolation of low-molecular-weight proteins from amyloid plaque fibers in Alzheimer's disease.
TL;DR: Current evidence suggests that such protein(s) found in PHF‐enriched fractions may derive from copurifying amyloid filament srather than from PHF, and that extraneuronal amyloids plaque filaments in Alzheimer's disease are composed of hydrophobic low‐Mr protein which are also present in vascular amyloidal deposits.
Journal ArticleDOI
Requirements for Presenilin-Dependent Cleavage of Notch and Other Transmembrane Proteins
Gary Struhl,Atsuko Adachi +1 more
TL;DR: It is found that the Presenilin-dependent cleavage does not depend critically on the recognition of particular sequences in these proteins but rather on the size of the extracellular domain: the smaller the size, the greater the efficiency of cleavage.
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