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

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

doi:10.1038/s41598-017-11654-7

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 (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.

Highlights

traumatic brain injury (TBI) is one of the most consistently identified environmental risks for late onset neurodegeneration and sporadic AD1
We have recently shown that ApoE proteins are critical determinants of brain phospholipid homeostasis and that the apolipoprotein E4 (ApoE4) isoform is dysfunctional in this process[28]
We have recently shown that ApoE4 induces reduction in brain PIP2 levels in both aged ApoE4 human and mouse brains

Summary

Introduction

TBI is one of the most consistently identified environmental risks for late onset neurodegeneration and sporadic AD1. We have shown that reduction of synj[1] accelerates lysosomal clearance of Aβ in APP/PS1 transgenic mice[33], and rescues AD-related cognitive deficits by restoring brain PIP2 homeostasis in ApoE4 mice[28]. Based on these findings, we tested the hypotheses that ApoE proteins regulate changes in brain phospholipid homeostasis in response to TBI and that ApoE4-associated phospholipid dysregulation may promote development of TBI-associated amyloid and Tau pathologies. We utilize well-established experimental models of human ApoE variants[34,35,36,37] and a battlefield-relevant mouse model of blast-induced TBI24–26 to investigate the effects of ApoE isoforms on brain phospholipid composition, Aβ accumulation and Tau hyper-phosphorylation after blast-induced neurotrauma

Methods

Results

Conclusion