James J. Peters VA Medical Center, Neurology Service, Bronx, NY, 10468, USA.
The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430021, China.
Sci Rep. 2017 Sep 12;7(1):11372. doi: 10.1038/s41598-017-11654-7.
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.
载脂蛋白 E4（ApoE4）基因型与创伤性脑损伤（TBI）结合会增加患阿尔茨海默病（AD）的风险。然而，其潜在机制尚不清楚。我们发现，在反复爆震诱导的 TBI 后，年轻 ApoE3 小鼠海马区的磷酸肌醇双磷酸（PIP）水平升高，并与 PIP 降解酶 synaptojanin 1（synj1）表达减少有关。相比之下，爆震 TBI 后 ApoE4 小鼠的海马 PIP 水平没有增加。在爆震 TBI 后，ApoE3 小鼠的磷酸化 Tau（pTau）水平没有变化，而 ApoE4 小鼠的 pTau 水平显著增加。为了确定 TBI 后 pTau 和 PIP/synj1 水平变化之间的因果关系，我们测试了 synj1 的下调是否可以防止 Tau 的爆震诱导过度磷酸化。synj1 的敲低降低了体外的 pTau 水平，并消除了体内爆震诱导的 pTau 升高。在 ApoE4 小鼠中，爆震 TBI 增加了糖原合酶激酶（GSK）-3β 的活性，而 synj1 的敲低抑制了 Tau 的 GSK3β 磷酸化。总之，这些数据表明，ApoE 蛋白在 TBI 后调节大脑磷脂稳态，并且 ApoE4 同工型在这个过程中功能失调。synj1 的下调挽救了爆震诱导的磷脂失调，并防止了 ApoE4 携带者 Tau 的过度磷酸化的发展。
