Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/69666
標題: Caveolin-1 Regulates gamma-Secretase-Mediated A beta PP Processing by Modulating Spatial Distribution of gamma-Secretase in Membrane
作者: Kapoor, A.
Hsu, W.M.
Wang, B.J.
Wu, G.H.
Lin, T.Y.
Lee, S.J.
Yen, C.T.
Liang, S.M.
Liao, Y.F.
關鍵字: Amyloid-beta
amyloid-beta precursor protein
caveolin-1
clathrin
gamma-secretase
lipid raft
amyloid precursor protein
necrosis-factor-alpha
alzheimers-disease
lipid rafts
plasma-membrane
cell-surface
in-vivo
cholesterol
endocytosis
activation
期刊/報告no:: Journal of Alzheimers Disease, Volume 22, Issue 2, Page(s) 423-442.
摘要: Amyloidogenic processing of amyloid-beta protein precursor protein (A beta PP) is associated with cholesterol- and sphingolipid-rich lipid rafts. Caveolin-1, a raft-residing protein, has been implicated in the pathogenesis of Alzheimer's disease. To determine the role of caveolin-1 in governing gamma-secretase-mediated A beta PP proteolysis, cellular gamma-secretase activity was assessed in response to alteration in caveolin-1 expression. We demonstrated that suppression of caveolin-1 expression by RNA interference resulted in a significant increase in gamma-secretase-mediated proteolysis of A beta PP, generation of amyloid-beta, and cleavage of Notch. Overexpression of caveolin-1 attenuated gamma-secretase-mediated proteolysis of A beta PP and Notch, substantiating the negative regulation of gamma-secretase by caveolin-1. Furthermore, we found that cells deficient in caveolin-1 exhibited significantly increased co-localization of gamma-secretase with clathrin-coated non-caveolar endocytic vesicles, demonstrating that the partitioning of gamma-secretase between caveolar and non-caveolar membranes can be modulated by caveolin-1. Our data also showed that JNK activation is essential for caveolin-1-mediated regulation of gamma-secretase. Together, our results strongly suggest that caveolin-1 is an important regulator of gamma-secretase activity.
URI: http://hdl.handle.net/11455/69666
ISSN: 1387-2877
文章連結: http://dx.doi.org/10.3233/jad-2010-100531
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