ApoE4-associated phospholipid dysregulation contributes to development of Tau hyper-phosphorylation after traumatic brain injury.
Jiqing CaoFarida El GaamouchJames S MeabonKole D MeekerLi ZhuMargaret B ZhongJohn BendikGregory ElderPing JingJiahong XiaWenjie LuoDavid G CookDongming CaiPublished in: Scientific reports (2017)
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.
Keyphrases
- traumatic brain injury
- cognitive decline
- high fat diet
- severe traumatic brain injury
- high fat diet induced
- high glucose
- mild cognitive impairment
- diabetic rats
- mild traumatic brain injury
- cerebrospinal fluid
- protein kinase
- insulin resistance
- poor prognosis
- magnetic resonance
- drug induced
- fatty acid
- type diabetes
- endothelial cells
- adipose tissue
- magnetic resonance imaging
- multiple sclerosis
- high frequency
- cell proliferation
- mouse model
- electronic health record
- skeletal muscle
- white matter
- functional connectivity
- blood brain barrier
- stress induced