Caveolin-3 upregulation activates beta-secretase-mediated cleavage of the amyloid precursor protein in Alzheimer's disease

Here, we investigate the involvement of caveolins in the pathophysiology of Alzheimer's disease(AD). We show dramatic upregulation of caveolin-3 immun oreactivity in astroglial cells surrounding senile plaques in brain tissue sections from authentic AD patients and an established transgenic mouse mod el of AD. In addition, we find that caveolin-3 physically interacts and bio chemically colocalizes with amyloid precursor protein (APP) both in vivo an d in vitro. Interestingly, recombinant overexpression of caveolin-3 in cult ured cells stimulated beta-secretase-mediated processing of APP. Immunoreac tivities of APP and presenilins were concomitantly increased in caveolin-3- positive astrocytes. Because the presenilins also form a physical complex w ith caveolin-3, caveolin-3 may provide a common platform for APP and the pr esenilins to associate in astrocytes. In AD, augmented expression of caveol in-3 and presenilins in reactive astrocytes may alter APP processing, leadi ng to the overproduction of its toxic amyloid metabolites.