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

Kazutoshi Nishiyama, Bruce D. Trapp, Tsuneya Ikezu, Richard M. Ransohoff, Taisuke Tomita, Takeshi Iwatsubo, Ichiro Kanazawa, Karen K. Hsiao, Michael P. Lisanti, Takashi Okamoto

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

Abstract

Here, we investigate the involvement of caveolins in the pathophysiology of Alzheimer's disease (AD). We show dramatic upregulation of caveolin-3 immunoreactivity in astroglial cells surrounding senile plaques in brain tissue sections from authentic AD patients and an established transgenic mouse model of AD. In addition, we find that caveolin-3 physically interacts and biochemically colocalizes with amyloid precursor protein (APP) both in vivo and in vitro, interestingly, recombinant overexpression of caveolin-3 in cultured cells stimulated β-secretase-mediated processing of APP. Immunoreactivities of APP and presenilins were concomitantly increased in caveolin-3-positive astrocytes. Because the presenilins also form a physical complex with caveolin-3, caveolin-3 may provide a common platform for APP and the presenilins to associate in astrocytes. In AD, augmented expression of caveolin-3 and presenilins in reactive astrocytes may alter APP processing, leading to the overproduction of its toxic amyloid metabolites.

Original languageEnglish (US)
Pages (from-to)6538-6548
Number of pages11
JournalJournal of Neuroscience
Volume19
Issue number15
DOIs
StatePublished - Aug 1 1999

Keywords

  • Alzheimer's disease
  • Amyloid precursor protein
  • Astrocyte
  • Caveolin
  • Presenilin
  • Secretase

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