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Active γ‐secretase is localized to detergent‐resistant membranes in human brain
Author(s) -
Hur JiYeun,
Welander Hedvig,
Behbahani Homira,
Aoki Mikio,
Frånberg Jenny,
Winblad Bengt,
Frykman Susanne,
Tjernberg Lars O.
Publication year - 2008
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2008.06278.x
Subject(s) - gamma secretase , lipid raft , amyloid precursor protein secretase , biochemistry , transmembrane protein , chemistry , amyloid (mycology) , amyloid precursor protein , membrane , microbiology and biotechnology , biology , alzheimer's disease , receptor , medicine , inorganic chemistry , disease
Several lines of evidence suggest that polymerization of the amyloid β‐peptide (Aβ) into amyloid plaques is a pathogenic event in Alzheimer’s disease (AD). Aβ is produced from the amyloid precursor protein as the result of sequential proteolytic cleavages by β‐secretase and γ‐secretase, and it has been suggested that these enzymes could be targets for treatment of AD. γ‐Secretase is an aspartyl protease complex, containing at least four transmembrane proteins. Studies in cell lines have shown that γ‐secretase is partially localized to lipid rafts, which are detergent‐resistant membrane microdomains enriched in cholesterol and sphingolipids. Here, we studied γ‐secretase in detergent‐resistant membranes (DRMs) prepared from human brain. DRMs prepared in the mild detergent CHAPSO and isolated by sucrose gradient centrifugation were enriched in γ‐secretase components and activity. The DRM fraction was subjected to size‐exclusion chromatography in CHAPSO, and all of the γ‐secretase components and a lipid raft marker were found in the void volume (> 2000 kDa). Co‐immunoprecipitation studies further supported the notion that the γ‐secretase components are associated even at high concentrations of CHAPSO. Preparations from rat brain gave similar results and showed a postmortem time‐dependent decline in γ‐secretase activity, suggesting that DRMs from fresh rat brain may be useful for γ‐secretase activity studies. Finally, confocal microscopy showed co‐localization of γ‐secretase components and a lipid raft marker in thin sections of human brain. We conclude that the active γ‐secretase complex is localized to lipid rafts in human brain.