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PMID: 16449386 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 103 ·No. 6 ·2006-02-07 ·Pages 1941-6

Cai D, Netzer WJ, Zhong M, Lin Y, Du G, Frohman M, Foster DA, Sisodia SS, Xu H, Gorelick FS, Greengard P

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.

MeSH Terms
Amyloid Precursor Protein Secretases Amyloid beta-Peptides/biosynthesis,metabolism Amyloid beta-Protein Precursor/metabolism Animals Aspartic Acid Endopeptidases Cell Line Endopeptidases/metabolism Gene Expression Regulation Humans Membrane Proteins/deficiency,genetics,metabolism Mice Mice, Knockout Phospholipase D/genetics,metabolism Presenilin-1 Protein Binding Protein Processing, Post-Translational Protein Transport trans-Golgi Network/metabolism
Chemicals
Amyloid beta-Peptides Amyloid beta-Protein Precursor Membrane Proteins PSEN1 protein, human Presenilin-1 Phospholipase D phospholipase D1 Amyloid Precursor Protein Secretases Endopeptidases Aspartic Acid Endopeptidases BACE1 protein, human Bace1 protein, mouse
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Cai Dongming
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.
Netzer William J
Zhong Minghao
Lin Yixin
Du Guangwei
Frohman Michael
Foster David A
Sisodia Sangram S
Xu Huaxi
Gorelick Fred S
Greengard Paul
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0510708103
Published
2006-02-07
Epub
2006-00-31
Pages
1941-6
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1413665
Subset
IM
Grants
NCI NIH HHS · CA46677 · United States
NIA NIH HHS · P01 AG009464 · United States
NINDS NIH HHS · NS046673 · United States
NIA NIH HHS · AG09464 · United States
NINDS NIH HHS · R01 NS046673 · United States
NIA NIH HHS · F32 AG023431 · United States
NCI NIH HHS · R01 CA046677 · United States
NIA NIH HHS · 5F32AG023431 · United States
External Links
PubMed source DOI: 10.1073/pnas.0510708103 PMC Full Text View journal details
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