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Cited by 62Alzheimer's disease research and treatmentsTraumatic Brain Injury ResearchTraumatic Brain Injury and Neurovascular Disturbances

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

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Cao, Jiqing, Gaamouch, Farida El, Meabon, James S., Meeker, Kole D., Zhu, Li, Zhong, Margaret B., Bendik, John, Elder, Gregory +5 more·2017·Scientific Reports
DOI 10.1038/s41598-017-11654-7PMC PMC5595858
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Abstract

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.

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  • Single, severe TBI is associated in humans and mouse models with widespread hyperphosphorylated tau pathology, and mice with APOE ε4 compared with APOE ε3 allele have more hippocampal hyperphosphorylated tau after TBI.

    “Single, severe TBI is associated in humans, and mouse models, with widespread hyperphosphorylated tau pathology, and mice with APOE ε4 compared to APOE ε3 allele have more hippocampal hyper-phosphorylated tau after TBI.64, 65”

    From Dementia prevention, intervention, and care: 2020 report of the Lancet Commission (2020) · cites this paper as [65]

    The Results section on hippocampal pTau reports significantly higher levels after blast exposure in ApoE4 mice than in ApoE3 mice. The Introduction mentions tau pathology in human TBI cases and animal models, but does not establish the claim about widespread hyperphosphorylated tau after a single, severe TBI. The Discussion describes this study as using repetitive blast exposure, and the Results say its pTau changes were confined to the hippocampus (page numbers unavailable). (LLM, conf=0.88)

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Authors
Cao, J., Gaamouch, F. E., Meabon, J. S., Meeker, K. D., Zhu, L., Zhong, M. B., Bendik, J., Elder, G., Jing, P., Xia, J., Luo, W., Cook, D. G., & Cai, D.
Affiliations
  • James J. Peters VA Medical Center (US)
  • University of Washington (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • Central Hospital of Wuhan (CN)
  • Weill Cornell Medicine (US)
  • United States Department of Veterans Affairs (US)
Corresponding author
  • Cook, David G.
  • Cai, Dongming
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2017-09-12
Volume
7
Issue
1
Pages
11372-11372
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-017-11654-7
PMC
PMC5595858
OpenAlex
W2753769236
Cited by
62
References
9
Citations by year
2026: 3 · 2025: 5 · 2024: 6 · 2023: 3 · 2022: 5 · 2021: 7 · 2020: 19 · 2019: 9 · 2018: 4 · 2017: 1
FWCI
6.68
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Veterans Affairs (I01 BX003380, I01RX002290, I21 RX001558, 1i21rx001558-01a1)
  • Yale University
  • Office of Research and Development
  • University of Washington
  • National Institutes of Health (NIH-R01)
  • National Institute on Aging (RF1AG054014, R01AG048923)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK017047)
  • NIH Clinical Center
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
  • Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
Keywords
APOE ε4, traumatic brain injury, SYNJ1, phospholipid homeostasis, glycogen synthase kinase-3β, hippocampus, Alzheimer's disease risk, APOE isoforms
MeSH terms
Brain Injuries, Traumatic, Phosphoinositide 5-Phosphatases, Animals, Brain, Cell Line, Hippocampus, Mice, Transgenic, Phospholipids, Phosphoric Monoester Hydrolases, Phosphorylation, tau Proteins, Mice, Apolipoprotein E3, Apolipoprotein E4

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