Protein phosphorylation regulates secretion of Alzheimer β/A4 amyloid precursor protein

Gregg L. Caporaso, Samuel E. Gandy, Joseph D. Buxbaum, Triprayar V. Ramabhadran, Paul Greengard

Research output: Contribution to journalArticlepeer-review

344 Scopus citations

Abstract

Extracellular deposition of the β/ A4 amyloid peptide is a characteristic feature of the brain in patients with Alzheimer disease. β/A4 amyloid is derived from the amyloid precurrsor protein (APP), an integral membrane protein that exists as three major isoforms (APP695, APP751, and APP770). Serreted forms of APP found in blood plasma and cerebrospinal fluid arise by proteolytic cleavage of APP within the β/A4 amyloid domain, precluding the possibility of amyloidogenesis for that population of molecules. In the present study, we have demonstrated that treatment of PC12 cells with phorbol ester produces a severalfold increase in secretion of APP695, APP751, and APP770. This increase is augmented by simultaneous treatment with the protein phosphatase inhibitor okadaic acid. These data indicate that protein phosphorylation regulates intra-β amyloid cleavage and APP secretion. These and other results suggest that APP molecules can normally follow either of two processing pathways: regulated secretion or proteolytic degradation unassociated with secretion.

Original languageEnglish
Pages (from-to)3055-3059
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume89
Issue number7
DOIs
StatePublished - 1992
Externally publishedYes

Keywords

  • Okadaic acid
  • Phorbol ester
  • Protein kinase
  • Protein phosphatase
  • Proteolytic processing

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