Traumatic Brain Injury Accelerates the Onset of Cognitive Dysfunction and Aggravates Alzheimer's-Like Pathology in the Hippocampus by Altering the Phenotype of Microglia in the APP/PS1 Mouse Model

Di Wu; Jay Prakash P Kumal; Xiaodi Lu; Yixuan Li; Dongsheng Mao; Xudong Tang; Meitong Nie; Xin Liu; Liang Sun; Bin Liu; Yafang Zhang

doi:10.3389/fneur.2021.666430

Traumatic Brain Injury Accelerates the Onset of Cognitive Dysfunction and Aggravates Alzheimer's-Like Pathology in the Hippocampus by Altering the Phenotype of Microglia in the APP/PS1 Mouse Model

Front Neurol. 2021 Sep 1:12:666430. doi: 10.3389/fneur.2021.666430. eCollection 2021.

Authors

Di Wu¹, Jay Prakash P Kumal^{2

3}, Xiaodi Lu⁴, Yixuan Li^{2

3}, Dongsheng Mao^{2

3}, Xudong Tang^{2

3}, Meitong Nie^{2

3}, Xin Liu⁵, Liang Sun^{2

3}, Bin Liu¹, Yafang Zhang^{2

3}

Affiliations

¹ Department of Neurology, Fourth Affiliated Hospital of Harbin Medical University, Harbin, China.
² Department of Human Anatomy, Harbin Medical University, Harbin, China.
³ Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education, Harbin, China.
⁴ Department of Anesthesiology, Harbin Medical University Cancer Hospital, Harbin, China.
⁵ Department of Neurology, General Hospital of Northern Theater Command, Shenyang, China.

Abstract

An increasing number of studies have suggested that traumatic brain injury (TBI) is associated with some neurodegenerative diseases, including Alzheimer's disease (AD). Various aspects of the mechanism of TBI-induced AD have been elucidated. However, there are also studies opposing the view that TBI is one of the causes of AD. In the present study, we demonstrated that TBI exacerbated the disruption of hippocampal-dependent learning and memory, worsened the reductions in neuronal cell density and synapse formation, and aggravated the deposition of Aβ plaques in the hippocampi of APP/PS1 mice. We also found that TBI rapidly activated microglia in the central nervous system (CNS) and that this effect lasted for at least for 3 weeks. Furthermore, TBI boosted Aβ-related microglia-mediated neuroinflammation in the hippocampi of APP/PS1 mice and the transformation of microglia toward the proinflammatory phenotype. Therefore, our experiments suggest that TBI accelerates the onset of cognitive dysfunction and Alzheimer-like pathology in the APP/PS1 mouse model, at least partly by altering microglial reactions and polarization.

Keywords: Alzheimer's disease; Aβ plaque pathology; microglia; neuroinflammation; traumatic brain injury.