TDP-43 drives synaptic and cognitive deterioration following traumatic brain injury

Fei Gao, Mei Hu, Jian Zhang, Jack Hashem, Chu Chen

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Traumatic brain injury (TBI) has been recognized as an important risk factor for Alzheimer’s disease (AD). However, the molecular mechanisms by which TBI contributes to developing AD remain unclear. Here, we provide evidence that aberrant production of TDP-43 is a key factor in promoting AD neuropathology and synaptic and cognitive deterioration in mouse models of mild closed head injury (CHI). We observed that a single mild CHI is sufficient to exacerbate AD neuropathology and accelerate synaptic and cognitive deterioration in APP transgenic mice but repeated mild CHI are required to induce neuropathological changes and impairments in synaptic plasticity, spatial learning, and memory retention in wild-type animals. Importantly, these changes in animals exposed to a single or repeated mild CHI are alleviated by silencing of TDP-43 but reverted by rescue of the TDP-43 knockdown. Moreover, overexpression of TDP-43 in the hippocampus aggravates AD neuropathology and provokes cognitive impairment in APP transgenic mice, mimicking single mild CHI-induced changes. We further discovered that neuroinflammation triggered by TBI promotes NF-κB-mediated transcription and expression of TDP-43, which in turn stimulates tau phosphorylation and Aβ formation. Our findings suggest that excessive production of TDP-43 plays an important role in exacerbating AD neuropathology and in driving synaptic and cognitive declines following TBI.

Original languageEnglish (US)
Pages (from-to)187-210
Number of pages24
JournalActa Neuropathologica
Volume144
Issue number2
DOIs
StatePublished - Aug 2022
Externally publishedYes

Keywords

  • Mild closed head injury
  • Neurodegeneration
  • Neuroinflammation
  • Synaptic plasticity
  • TDP-43
  • Tau phosphorylation
  • Traumatic brain injury

ASJC Scopus subject areas

  • Clinical Neurology
  • Cellular and Molecular Neuroscience
  • Pathology and Forensic Medicine

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