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

TitleApoE4-associated phospholipid dysregulation contributes to development of Tau hyper-phosphorylation after traumatic brain injury.
Publication TypeJournal Article
Year of Publication2017
AuthorsCao J, Gaamouch FEl, Meabon JS, Meeker KD, Zhu L, Zhong MB, Bendik J, Elder G, Jing P, Xia J, Luo W, Cook DG, Cai D
JournalSci Rep
Volume7
Issue1
Pagination11372
Date Published2017 09 12
ISSN2045-2322
Abstract

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 (PIP) levels in hippocampal regions of young ApoE3 mice were elevated and associated with reduction in expression of a PIP degrading enzyme, synaptojanin 1 (synj1). In contrast, hippocampal PIP 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 PIP/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.

DOI10.1038/s41598-017-11654-7
Alternate JournalSci Rep
PubMed ID28900205
PubMed Central IDPMC5595858
Grant ListI21 RX001558 / RX / RRD VA / United States
P30 DK017047 / DK / NIDDK NIH HHS / United States
R01 AG048923 / AG / NIA NIH HHS / United States
RF1 AG054014 / AG / NIA NIH HHS / United States