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- Title
Active γ-secretase is localized to detergent-resistant membranes in human brain.
- Authors
Ji-Yeun Hur; Welander, Hedvig; Behbahani, Homira; Aoki, Mikio; Frånberg, Jenny; Winblad, Bengt; Frykman, Susanne; Tjernberg, Lars O.
- Abstract
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.
- Subjects
BRAIN; POLYMERIZATION; AMYLOID; ALZHEIMER'S disease; SPHINGOLIPIDS
- Publication
FEBS Journal, 2008, Vol 275, Issue 6, p1174
- ISSN
1742-464X
- Publication type
Article
- DOI
10.1111/j.1742-4658.2008.06278.x