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 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.
Department of Neurosciences, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
K
K
Nishiyama
B D
BD
Trapp
T
T
Ikezu
R M
RM
Ransohoff
T
T
Tomita
T
T
Iwatsubo
I
I
Kanazawa
K K
KK
Hsiao
M P
MP
Lisanti
T
T
Okamoto
D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000502:physiology; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D051244:Caveolin 3; D022461:Caveolins; D010450:Endopeptidases / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D053764:Presenilin-1; D053766:Presenilin-2; D011994:Recombinant Proteins
D016564:Amyloid beta-Protein Precursor; C495548:Cav3 protein, mouse; D051244:Caveolin 3; D022461:Caveolins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D011994:Recombinant Proteins; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse