Regulation of gamma-Secretase in Alzheimer's Disease
The {gamma}-secretase complex is an intramembrane aspartyl protease that cleaves its substrates along their transmembrane regions. Sequential proteolytic processing of amyloid precursor protein by {beta}- and {gamma}-secretase produces amyloid {beta}-peptides, which are the major components of amyloid plaques in the brains of Alzheimer's disease patients. The {gamma}-secretase complex is therefore believed to be critical in the pathogenesis of Alzheimer's disease. Here we review the range of factors found to affect the nature and degree of {gamma}-secretase complex activity; these include {gamma}-secretase complex assembly and activation, the integral regulatory subunit CD147, transient or weak binding partners, the levels of cholesterol and sphingolipids in cell membranes, and inflammatory cytokines. Integrated knowledge of the molecular mechanisms supporting the actions of these factors is expected to lead to a comprehensive understanding of the functional regulation of the {gamma}-secretase complex, and this, in turn, should facilitate the development of novel therapeutic strategies for the treatment of Alzheimer's disease.
- Research Organization:
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
- Sponsoring Organization:
- USDOE Director, Office of Science; National Institutes ofHealth
- DOE Contract Number:
- DE-AC02-05CH11231; NIH1R21GM070511,2R01GM054132
- OSTI ID:
- 918642
- Report Number(s):
- LBNL-62789; BICHAW; R&D Project: L0454, L0205; TRN: US200819%%371
- Journal Information:
- Biochemistry, Vol. 46, Issue 10; Related Information: Journal Publication Date: 03/13/2007; ISSN 0006-2960
- Country of Publication:
- United States
- Language:
- English
Similar Records
Cryoelectron Microscopy Structure of Purified gamma-Secretase at 12 angstrom Resolution
Toward structural elucidation of the gamma-secretase complex