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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Journal ArticleDOI
Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts
TL;DR: It is demonstrated that lipid rafts are critically involved in regulating Aβ generation and the existence of two APP pools is suggested, although APP inside raft clusters seems to be cleaved by β-secretase, APP outside rafts undergoes cleavage by α- secretase.
Journal ArticleDOI
Cholesterol, lipid rafts, and disease
Kai Simons,Robert Ehehalt +1 more
TL;DR: The presence of liquid-ordered microdomains in cells transforms the classical membrane fluid mosaic model of Singer and Nicholson into a more complex system, where proteins and lipid rafts diffuse laterally within a two-dimensional liquid.
Journal ArticleDOI
Synaptic Activity Regulates Interstitial Fluid Amyloid-β Levels In Vivo
John R. Cirrito,Kelvin A. Yamada,Mary Beth Finn,Robert S. Sloviter,Kelly R. Bales,Patrick C. May,Darryle D. Schoepp,Steven M. Paul,Steven Mennerick,David M. Holtzman +9 more
TL;DR: It is demonstrated that Aβ levels in the brain interstitial fluid are dynamically and directly influenced by synaptic activity on a timescale of minutes to hours, and it is suggested that synaptic activity may modulate a neurodegenerative disease process, in this case by influencing Aβ metabolism and ultimately region-specific Aβ deposition.
Journal ArticleDOI
Mitochondria are a direct site of Aβ accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression
Maria Manczak,Thimmappa S. Anekonda,Edward Henson,Byung Park,Joseph F. Quinn,P. Hemachandra Reddy +5 more
TL;DR: Findings suggest that early mitochondrially targeted therapeutic interventions may be effective in delaying AD progression in elderly individuals and in treating AD patients.
Journal ArticleDOI
Axonal Pathology in Traumatic Brain Injury
TL;DR: The current understanding of DAI as a uniquely mechanical injury, its histopathological identification, and its acute and chronic pathogenesis following TBI are reviewed.
References
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Journal ArticleDOI
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Journal ArticleDOI
Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease.
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