Journal of Biological Chemistry
Volume 273, Issue 17, 24 April 1998, Pages 10485-10495
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CELL BIOLOGY AND METABOLISM
Caveolae, Plasma Membrane Microdomains for α-Secretase-mediated Processing of the Amyloid Precursor Protein*

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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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*

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This work was supported in part by United States Public Health Service Grant MH56036 (to T. O.).

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Fellow of Japan Society for the Promotion of Science for Research Abroad.

Supported by National Institutes of Health FIRST Award GM-50443 (to M. P. L.), a grant from the G. Harold and Leila Y. Mathers Charitable Foundation (to M. P. L.), and Scholarship in the Medical Sciences from the Charles E. Culpeper Foundation (to M. P. L.).