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

Dongming Cai, William J. Netzer, Minghao Zhong, Yixin Lin, Guangwei Du, Michael Frohman, David A. Foster, Sangram S. Sisodia, Huaxi Xu, Fred S. Gorelick, Paul Greengard

Research output: Contribution to journalArticlepeer-review

92 Scopus citations

Abstract

Presenilin (PS1/PS2) is a major component of γ-secretase, the activity that mediates proteolysis of β-amyloid precursor protein to generate β-amyloid (Aβ). 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 Aβ generation. Conversely, down-regulation of endogenous PLD1 by small hairpin RNA elevates Aβ production. The Aβ-lowering effect of PLD1 is independent of its ability to promote vesicular budding of β-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 γ-secretase.

Original languageEnglish (US)
Pages (from-to)1941-1946
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number6
DOIs
StatePublished - Feb 15 2006
Externally publishedYes

Keywords

  • Negative regulator
  • Protein interaction
  • Trans-Golgi network
  • β-amyloid precursor protein
  • γ-secretase complex activity

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