Caveolin-1 Regulates γ-Secretase-Mediated AβPP Processing by Modulating Spatial Distribution of γ-Secretase in Membrane

Article type: Research Article

Authors: Kapoor, Arun^{a; b; c} | Hsu, Wen-Ming^d | Wang, Bo-Jeng^{a; e} | Wu, Guan-Hsun^{a; e} | Lin, Ti-Yu^{a; e} | Lee, Shyh-Jye^e | Yen, Chen-Tung^e | Liang, Shu-Mei^{b; c; f; *} | Liao, Yung-Feng^{a; *}

Affiliations: [a] Laboratory of Molecular Neurobiology, Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan | [b] Molecular and Biological Agricultural Sciences Program, Taiwan International Graduate Program, National Chung-Hsing University and Academia Sinica, Taipei, Taiwan | [c] Graduate Institute of Biotechnology and Department of Life Sciences, National Chung-Hsing University, Taichung, Taiwan | [d] Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taiwan | [e] Institute of Zoology, National Taiwan University, Taiwan | [f] Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan

Correspondence: [*] Correspondence to: Yung-Feng Liao, Ph.D., Rm. 238, Institute of Cellular and Organismic Biology, Academia Sinica, 128 Sec. 2 Academia Rd., Taipei 11529, Taiwan. Tel./Fax: +886 2 27871514; E-mail: [email protected]. Shu-Mei Liang, Ph.D., Agricultural Biotechnology Research Center, Academia Sinica, 128 Sec. 2 Academia Rd., Taipei 11529, Taiwan. Tel.: +886 2 26522870; Fax: +886 2 26515120; E-mail: [email protected].

Abstract: 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.

Keywords: Amyloid-β, amyloid-β precursor protein, caveolin-1, clathrin, γ-secretase, lipid raft

DOI: 10.3233/JAD-2010-100531

Journal: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 423-442, 2010