TY - JOUR
T1 - Caveolae, plasma membrane microdomains for α-secretase-mediated processing of the amyloid precursor protein
AU - Ikezu, Tsuneya
AU - Trapp, Bruce D.
AU - Song, Kenneth S.
AU - Schlegel, Amnon
AU - Lisanti, Michael P.
AU - Okamoto, Takashi
PY - 1998/4/24
Y1 - 1998/4/24
N2 - Caveolae are plasma membrane invaginations where key signaling elements are concentrated. In this report, both biochemical and histochemical analyses demonstrate that the amyloid precursor protein (APP), a source of Aβ amyloid peptide, is enriched within caveolae. Caveolin-1, a principal component of caveolae, is physically associated with APP, and the cytoplasmic domain of APP directly participates in this binding. The characteristic C-terminal fragment that results from APP processing by α-secretase, an as yet unidentified enzyme that cleaves APP within the Aβ amyloid sequence, was also localized within these caveolae-enriched fractions. Further analysis by cell surface biotinylation revealed that this cleavage event occurs at the cell surface. Importantly, α-secretase processing was significantly promoted by recombinant overexpression of caveolin in intact cells, resulting in increased secretion of the soluble extracellular domain of APP. Conversely, caveolin depletion using antisense oligonucletotides prevented this cleavage event. Our current results indicate that caveolae and caveolins may play a pivotal role in the α-secretase-mediated proteolysis of APP in vivo.
AB - Caveolae are plasma membrane invaginations where key signaling elements are concentrated. In this report, both biochemical and histochemical analyses demonstrate that the amyloid precursor protein (APP), a source of Aβ amyloid peptide, is enriched within caveolae. Caveolin-1, a principal component of caveolae, is physically associated with APP, and the cytoplasmic domain of APP directly participates in this binding. The characteristic C-terminal fragment that results from APP processing by α-secretase, an as yet unidentified enzyme that cleaves APP within the Aβ amyloid sequence, was also localized within these caveolae-enriched fractions. Further analysis by cell surface biotinylation revealed that this cleavage event occurs at the cell surface. Importantly, α-secretase processing was significantly promoted by recombinant overexpression of caveolin in intact cells, resulting in increased secretion of the soluble extracellular domain of APP. Conversely, caveolin depletion using antisense oligonucletotides prevented this cleavage event. Our current results indicate that caveolae and caveolins may play a pivotal role in the α-secretase-mediated proteolysis of APP in vivo.
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U2 - 10.1074/jbc.273.17.10485
DO - 10.1074/jbc.273.17.10485
M3 - Article
C2 - 9553108
AN - SCOPUS:0032562615
SN - 0021-9258
VL - 273
SP - 10485
EP - 10495
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 17
ER -