ApoE4-associated phospholipid dysregulation contributes to development of Tau hyper-phosphorylation after traumatic brain injury

Jiqing Cao, Farida El Gaamouch, James S. Meabon, Kole D. Meeker, Li Zhu, Margaret B. Zhong, John Bendik, Gregory Elder, Ping Jing, Jiahong Xia, Wenjie Luo, David G. Cook, Dongming Cai

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The apolipoprotein E4 (ApoE4) genotype combines with traumatic brain injury (TBI) to increase the risk of developing Alzheimer's Disease (AD). However, the underlying mechanism(s) is not well-understood. We found that after exposure to repetitive blast-induced TBI, phosphoinositol biphosphate (PIP2) levels in hippocampal regions of young ApoE3 mice were elevated and associated with reduction in expression of a PIP2 degrading enzyme, synaptojanin 1 (synj1). In contrast, hippocampal PIP2 levels in ApoE4 mice did not increase after blast TBI. Following blast TBI, phospho-Tau (pTau) levels were unchanged in ApoE3 mice, whereas in ApoE4 mice, levels of pTau were significantly increased. To determine the causal relationship between changes in pTau and PIP2/synj1 levels after TBI, we tested if down-regulation of synj1 prevented blast-induced Tau hyper-phosphorylation. Knockdown of synj1 decreased pTau levels in vitro, and abolished blast-induced elevation of pTau in vivo. Blast TBI increased glycogen synthase kinase (GSK)-3β activities in ApoE4 mice, and synj1 knockdown inhibited GSK3β phosphorylation of Tau. Together, these data suggest that ApoE proteins regulate brain phospholipid homeostasis in response to TBI and that the ApoE4 isoform is dysfunctional in this process. Down-regulation of synj1 rescues blast-induced phospholipid dysregulation and prevents development of Tau hyper-phosphorylation in ApoE4 carriers.

Original languageEnglish (US)
Article number11372
JournalScientific reports
Issue number1
StatePublished - Dec 1 2017
Externally publishedYes

Bibliographical note

Funding Information:
We thank Dr. Pietro De Camilli (Yale School of Medicine) for providing synj1 haploinsufficiency mice. Antibody p369 was generously provided by Dr. Paul Greengard. This work was supported by funding from Alzheimer Association (NIRP14-304720), Department of Veteran Affairs RR&D Service SPiRE (1I21RX001558-01A1), NIH R01 (1R01AG048923-01), NIH RF1 (1RF1AG054014) (DC); and by the Department of Veterans Affairs Office of Research and Development Medical Research Service (RDIS# 0005), the University of Washington Friends of Alzheimer’s Research, University of Washington Royalty Research Fund (DGC); and the Northwest Network Mental Illness Research, Education and Clinical Center (JSM). Confocal microscopy studies were supported by James J. Peters VA Medical Center Research Core Facility. We thank Dr. William Netzer and Dr. Christopher Cardozo for critical reading of the manuscript.

Publisher Copyright:
© 2017 The Author(s).


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