Caveolin-1 regulates γ-secretase-mediated AβPP processing by modulating spatial distribution of γ-secretase in membrane.

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.