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
More filters
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
More filters
Journal ArticleDOI
Preamyloid deposits in the cerebral cortex of patients with Alzheimer's disease and nondemented individuals
TL;DR: A polyclonal antibody to a 28 residue synthetic peptide, homologous to the NH2 terminal region of amyloid beta-protein, was employed in a study of the frontal and temporal cortex of 8 Alzheimer patients and 13 non-demented individuals to define the relationship of immunolabelled to argyrophilic, congophilic and thioflavine S-positive cortical lesions.
Journal ArticleDOI
Interaction between amyloid precursor protein and presenilins in mammalian cells: Implications for the pathogenesis of Alzheimer disease
TL;DR: It is demonstrated that wt and mutant PS1 and PS2 proteins form complexes with APP in living cells, strongly supporting the hypothesis that mutant PS interacts withAPP in a way that enhances the intramembranous proteolysis of the latter by a gamma-secretase cleaving at Abeta42.
Journal ArticleDOI
Processing of beta-amyloid precursor protein in microglia and astrocytes favors an internal localization over constitutive secretion.
TL;DR: The findings indicate that both astrocytes and microglia strongly express all three major forms of beta APP but apparently process these molecules by an alternative pathway that generates very small amounts of soluble beta APP.
Journal ArticleDOI
A Substrate-Based Difluoro Ketone Selectively Inhibits Alzheimer's γ-Secretase Activity
Journal ArticleDOI
Endoproteolytic cleavage and proteasomal degradation of presenilin 2 in transfected cells.
Tae-Wan Kim,Warren H. Pettingell,Olivia G. Hallmark,Robert D. Moir,Wilma Wasco,Rudolph E. Tanzi +5 more
TL;DR: Using a stably transfected, inducible cell system, it is found that PS2 is proteolytically cleaved into two stable cellular polypeptides including an ∼20-kDa C-terminal fragment and an ∼34-k da N-terminals fragment.
Related Papers (5)
The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics
John Hardy,Dennis J. Selkoe +1 more