| Summary: | 碩士 === 國立臺灣大學 === 動物學研究研究所 === 94 === Accumulated evidence has suggested that β- and γ-cleavage of amyloid precursor protein (APP) may take place in specialized membrane microdomains called lipid
rafts. Caveolin-1 is an important structure protein of this membrane domain, and its expression in the hippocampus region of Alzheimer’s disease patients’ brains is upregulated. These data all imply that caveoiln-1 could play a role in modulating the proteolytic processing of APP and the pathogenesis of Alzheimer’s disease. We thus seek to determine whether caveolin-1 can actively involve in the regulation of γ-secretase-mediated proteolysis. In this study, we observe that overexpression of caveolin-1 promotes the formation of raft-membranes in HEK293 cells and concomitantly stimulates γ-secretase-mediated cleavage of APP. However, the γ-secretase-mediated S3 cleavage of Notch, another substrate of γ-secretase, is not affected by the overexpression of caveolin-1, suggesting that substrate selectivity of
γ-secretase can be modulated by caveolin-1. Consistently, the caveolin-1-enhanced γ-secretase activity can be completely abolished by a cholesterol-depleting drug called
MβCD that also destabilizes the raft membranes. This strengthen the notion that caveolin-1 can promote the formation of raft membrane. We further confirm that APP,
nicastrin, and ERK are co-localized with caveolin-1 in raft membranes. Caveolin-1 is also known to be a scaffold protein that can suppress ERK activation. In caveolin-1-overexpressed cells, the evidence that the suppression of ERK activation is prominent in accordance to our previous findings that down-regulation of ERK can promote γ-secretase activity. And then, the down-regulation of dynamin-2, a critical component of endocytosis, results in a significant decrease in caveolin-1-enhanced γ-secretase activity. Finally, we discover that overexpression of caveolin-1 also can increases Aβ production, and inhibition of endocytosis blocks this effect. Together,
the present study strongly suggests that caveolin-1 plays an important role in the regulation of γ-secretase-catalyzed proteolysis of APP and may exacerbate the
pathogenesis of Alzheimer’s disease.
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