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Proc Natl Acad Sci U S A. 2006 Feb 7;103(6):1941-6. Epub 2006 Jan 31.

Presenilin-1 uses phospholipase D1 as a negative regulator of beta-amyloid formation.

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1
Laboratory of Molecular and Cellular Neuroscience, and Fisher Center for Research on Alzheimer Disease, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.

Abstract

Presenilin (PS1/PS2) is a major component of gamma-secretase, the activity that mediates proteolysis of beta-amyloid precursor protein to generate beta-amyloid (Abeta). Here we demonstrate that PS1, through its loop region, binds to phospholipase D1 (PLD1), thereby recruiting it to the Golgi/trans-Golgi network. Overexpression of wild-type PLD1 reduces Abeta generation. Conversely, down-regulation of endogenous PLD1 by small hairpin RNA elevates Abeta production. The Abeta-lowering effect of PLD1 is independent of its ability to promote vesicular budding of beta-amyloid precursor protein. The data indicate that overexpression of PLD1 decreases, and down-regulation of PLD1 increases, the catalytic activity, and the association of the subunits, of gamma-secretase.

PMID:
16449386
PMCID:
PMC1413665
DOI:
10.1073/pnas.0510708103
[Indexed for MEDLINE]
Free PMC Article
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