Phospholipase D1 corrects impaired betaAPP trafficking and neurite outgrowth in familial Alzheimer's disease-linked presenilin-1 mutant neurons.
Presenilins (PS1/PS2) regulate proteolysis of beta-amyloid precursor protein (betaAPP) and affect its intracellular trafficking. Here, we demonstrate that a PS1-interacting protein, phospholipase D1 (PLD1), affects intracellular trafficking of betaAPP. Overexpression of PLD1 in PS1wt cells promotes generation of betaAPP-containing vesicles from the trans-Golgi network. Conversely, inhibition of PLD1 activity by 1-butanol decreases betaAPP 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 betaAPP-containing vesicles from the trans-Golgi network in FAD mutant cells. Surface delivery of betaAPP 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.
Cai
Dongming
D
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.
Zhong
Minghao
M
Wang
Runsheng
R
Netzer
William J
WJ
Shields
Dennis
D
Zheng
Hui
H
Sisodia
Sangram S
SS
Foster
David A
DA
Gorelick
Fred S
FS
Xu
Huaxi
H
Greengard
Paul
P
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002384:Catalysis; D002478:Cells, Cultured; D004198:Disease Susceptibility; D005786:Gene Expression Regulation; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D016501:Neurites / Q000378:metabolism* / Q000473:pathology; D010739:Phospholipase D / Q000235:genetics / Q000378:metabolism*; D053764:Presenilin-1; D021381:Protein Transport
D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D053764:Presenilin-1; D010739:Phospholipase D; C106801:phospholipase D1