Research Paper Volume 12, Issue 20 pp 20862—20879

TREM2 ameliorates neuroinflammatory response and cognitive impairment via PI3K/AKT/FoxO3a signaling pathway in Alzheimer’s disease mice

Yaping Wang1,2, , Yan Lin2,3, , Linhan Wang2,3, , Hongrui Zhan1, , Xiaoting Luo2,4, , Yanyan Zeng1, , Wen Wu1, , Xingmei Zhang2, , Fang Wang2, ,

  • 1 Department of Rehabilitation, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
  • 2 Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
  • 3 The First Affiliated Hospital, Southern Medical University, Guangzhou 510515, China
  • 4 Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China

Received: June 6, 2020       Accepted: August 8, 2020       Published: October 16, 2020      

https://doi.org/10.18632/aging.104104
How to Cite

Copyright: © 2020 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) has been shown with a neuroprotective function against inflammation and neuronal injury in Alzheimer’s disease (AD). However, the TREM2 induced anti-inflammatory mechanism is still not well known. In this study it has been demonstrated that the expression of TREM2 was upregulated in hippocampus of 5xFAD mice, whereas TREM2 knock-out mediated by AAV significantly increased the levels of pro-inflammatory cytokines and aggravated cognitive defect. Additionally, FoxO3a, a downstream member of the PI3K/AKT pathway, could be activated by TREM2 defect via the PI3K/AKT signaling in 5xFAD mice. That suggests TREM2-induced protection is associated with the PI3K-FoxO3a axis. On the contrary, overexpression of TREM2 alleviated the LPS-induced inflammatory response and induced M2 phenotype microglia in vitro. This phenomenon can be abolished by applying the PI3K inhibitor LY294002, suggesting FoxO3a not only participates in TREM2-induced anti-inflammation response, but is also involved in regulating the phenotype of microglia. Taken together, our results show that the protective functions of TREM2, both in inflammatory response and cognitive impairment as well as in the decrease of M1 phenotype microglia, are related to PI3K/AKT/FoxO3a signaling pathway in AD mice.

Abbreviations

AD: Alzheimer's Disease; TREM2: Triggering receptor expressed on myeloid cells 2; OFT: Open Filed Test; MWM: Morris Water Maze; DG: dentate gyrus; CNS: Central nervous system; Iba-1: Ionized calcium-binding adaptor molecule 1; FoxO3a: Forkhead box O3a; DMEM: Dulbecco’s modified Eagle’s medium; FBS: Fetal bovine serum; PBS: Phosphate buffer saline; LPS: Lipopolysaccharide; IL-1β: Interleukin-1 beta; TNF-α: Tumor Necrosis Factor alpha; IL-6: Interleukin-6.