Caveolin-1 regulates γ-secretase-mediated AβPP processing by modulating spatial distribution of γ-secretase in membrane.
Amyloidogenic processing of amyloid-β precursor protein (AβPP) 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 γ-secretase-mediated AβPP proteolysis, cellular γ-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 γ-secretase-mediated proteolysis of AβPP, generation of amyloid-β, and cleavage of Notch. Overexpression of caveolin-1 attenuated γ-secretase-mediated proteolysis of AβPP and Notch, substantiating the negative regulation of γ-secretase by caveolin-1. Furthermore, we found that cells deficient in caveolin-1 exhibited significantly increased co-localization of γ-secretase with clathrin-coated non-caveolar endocytic vesicles, demonstrating that the partitioning of γ-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 γ-secretase. Together, our results strongly suggest that caveolin-1 is an important regulator of γ-secretase activity.
Kapoor
Arun
A
Laboratory of Molecular Neurobiology, Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
Hsu
Wen-Ming
WM
Wang
Bo-Jeng
BJ
Wu
Guan-Hsun
GH
Lin
Ti-Yu
TY
Lee
Shyh-Jye
SJ
Yen
Chen-Tung
CT
Liang
Shu-Mei
SM
Liao
Yung-Feng
YF
D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D051242:Caveolin 1 / Q000378:metabolism*; D002461:Cell Line, Transformed; D002462:Cell Membrane / Q000201:enzymology* / Q000648:ultrastructure; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism*; D018613:Microscopy, Confocal / Q000379:methods; D009154:Mutation / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D013347:Subcellular Fractions; D014162:Transfection
D016564:Amyloid beta-Protein Precursor; D051242:Caveolin 1; D034741:RNA, Small Interfering; D051880:Receptors, Notch; D048670:MAP Kinase Kinase 4; D053829:Amyloid Precursor Protein Secretases