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

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.

Inflammation: the link between comorbidities, genetics, and Alzheimer’s disease

“…Interestingly, a link was also recently made between ApoE4, TBI, and tau phosphorylation. Cao and colleagues found that ApoE4 knock-in mice had significantly more phosphorylated tau following blast TBI than ApoE3 knock-in mice, via activation of GSK3β [ 271 ]. In addition, recent transcriptional profiling of ApoE4 and ApoE3 knock-in mice at 14 days post-TBI found significant upregulation in TREM2, TYROBP, C-type lectin domain containing 7A, Cd68, and CX3CR1 compared to the sham control [ 272 ].…”

Apolipoprotein E regulates the maturation of injury-induced adult-born hippocampal neurons following traumatic brain injury

“…ApoE4 is also linked to a greater incidence of moderate or severe contusions [35] as well as concussions [36]. ApoE4 genotype combined with TBI is thought to increase the risk of developing Tauopathy and Alzheimer's Disease [37] as well as post-traumatic epilepsy [38] and impaired spontaneous blood brain barrier repair [24]. Neurogenesis is affected in an ApoE isoform-dependent manner after both ischemic stroke [39] and controlled cortical impact [17] in mouse models but not after concussion [40].…”

Brain and blood biomarkers of tauopathy and neuronal injury in humans and rats with neurobehavioral syndromes following blast exposure

“…Prior studies have addressed tau processing in experimental animal models of blast TBI, with many reporting elevated levels of tau in brain or blood [21,[46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65]. Two studies reported the presence of tau oligomers following blast exposure [59,61] and others have suggested that p-tau metabolism following blast may be regulated by APOE genotype [62]. P-tau-like accumulations have also been observed in mouse retinal neurons and glia following blast injury [66], and in the superficial layers of the cerebral cortex [21].…”