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

J Neurosci. 1999 Aug 1;19(15):6538-48. doi: 10.1523/JNEUROSCI.19-15-06538.1999.

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 beta-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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Protein Precursor / chemistry*
  • Amyloid beta-Protein Precursor / physiology
  • Animals
  • Aspartic Acid Endopeptidases
  • Astrocytes / metabolism
  • Brain / metabolism
  • Brain / pathology
  • Caveolin 3
  • Caveolins*
  • Endopeptidases / metabolism
  • Endopeptidases / physiology*
  • Humans
  • Membrane Proteins / metabolism*
  • Membrane Proteins / physiology
  • Mice
  • Mice, Transgenic
  • Presenilin-1
  • Presenilin-2
  • Recombinant Proteins

Substances

  • Amyloid beta-Protein Precursor
  • Cav3 protein, mouse
  • Caveolin 3
  • Caveolins
  • Membrane Proteins
  • PSEN1 protein, human
  • PSEN2 protein, human
  • Presenilin-1
  • Presenilin-2
  • Recombinant Proteins
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • Bace1 protein, mouse