Phospholipase D1 corrects impaired βAPP trafficking and neurite outgrowth in familial Alzheimer's disease-linked presenilin-1 mutant neurons

Dongming Cai, Minghao Zhong, Runsheng Wang, William J. Netzer, Dennis Shields, Hui Zheng, Sangram S. Sisodia, David A. Foster, Fred S. Gorelick, Huaxi Xu, Paul Greengard

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

Abstract

Presenilins (PS1/PS2) regulate proteolysis of β-amyloid precursor protein (βAPP) and affect its intracellular trafficking. Here, we demonstrate that a PS1-interacting protein, phospholipase D1 (PLD1), affects intracellular trafficking of βAPP. Overexpression of PLD1 in PS1wt cells promotes generation of βAPP-containing vesicles from the trans-Golgi network. Conversely, inhibition of PLD1 activity by 1-butanol decreases βAPP trafficking in both wt and PS1-deficient cells. The subcellular localization of PLD1 is altered, and PLD enzymatic activity is reduced in cells expressing familial Alzheimer's disease (FAD) PS1 mutations compared with PS1wt cells. Overexpression of wt, but not catalytically inactive, PLD1 increases budding of βAPP-containing vesicles from the trans-Golgi network in FAD mutant cells. Surface delivery of βAPP is also increased by PLD1 in these cells. The impaired neurite outgrowth capacity in FAD mutant neurons was corrected by introducing PLD1 into these cells. The results indicate that PLD1 may represent a therapeutic target for rescuing compromised neuronal function in AD.

Original languageEnglish (US)
Pages (from-to)1936-1940
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number6
DOIs
StatePublished - Feb 15 2006
Externally publishedYes

Keywords

  • Axonal growth
  • Intracellular trafficking
  • Neurite branching
  • Trans-Golgi network
  • β-amyloid precursor protein

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