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Full Length Article | Open Access

Hippocampal overexpression of TREM2 ameliorates high fat diet induced cognitive impairment and modulates phenotypic polarization of the microglia

Min Wua,b,1, Maolin Liaoa,b,1, Rongfeng Huanga,b, Chunxiu Chenb,c, Tian Tiand, Hongying Wanga,b, Jiayu Lia,b, Jibin Lic, Yuxiang Sune, Chaodong Wue, Qifu Lia, Xiaoqiu Xiaoa,b( )
Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China
The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China
Department of Nutrition and Food Hygiene, School of Public Health and Management, Chongqing Medical University, Chongqing 400016, PR China
Department of Neurology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, PR China
Department of Nutrition and Food Science, Texas A&M University, College Station, TX 77843, USA

Peer review under responsibility of Chongqing Medical University.

1 Equal contributors.

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Abstract

Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) share several common pathophysiological features. Rare variants of triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk of developing AD, suggesting the involvement of TREM2 and innate immunity in AD development. It is still unknown whether TREM2 is related to cognitive impairment in T2DM. Here, we investigated the effects of the hippocampal overexpression of TREM2 on cognitive in long-term high-fat diet (HFD)-fed mice. Male C57BL/6J mice were maintained on HFD for 50 weeks. TREM2 was overexpressed in the hippocampus 36 weeks after HFD feeding using adeno-associated virus vector (AAV)-mediated gene delivery. The results showed that the HFD feeding induced rapid and persistent weight gain, glucose intolerance and significant impairments in learning and memory. Compared with AAV-con, AAV-TREM2 significantly ameliorated cognitive impairment without altering body weight and glucose homeostasis in HFD mice. The overexpression of TREM2 upregulated the synaptic proteins spinophilin, PSD95 and synaptophysin, suggesting the improvement in synaptic transmission. Dendritic complexity and spine density in the CA1 region were rescued after TREM2 overexpression. Furthermore, TREM2 markedly increased the number of iba-1/Arg-1-positive microglia in the hippocampus, suppressed neuroinflammation and microglial activation. In sum, hippocampal TREM2 plays an important role in improving HFD-induced cognitive dysfunction and promoting microglial polarization towards the M2 anti-inflammatory phenotype. Our study also suggests that TREM2 might be a novel target for the intervention of obesity/diabetes-associated cognitive decline.

Keywords

NeurodegenerationObesityDiabetesNeuroinflammationMicroglial polarizationTREM2

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Genes & Diseases
Volume 9 Issue 2,
March 2022
Pages 401-414
DOI: 10.1016/j.gendis.2020.05.005
Cite this article:
Wu M, Liao M, Huang R, et al. Hippocampal overexpression of TREM2 ameliorates high fat diet induced cognitive impairment and modulates phenotypic polarization of the microglia. Genes & Diseases, 2022, 9(2): 401-414. https://doi.org/10.1016/j.gendis.2020.05.005

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Received: 13 March 2020
Revised: 09 May 2020
Accepted: 12 May 2020
Published: 21 May 2020
© 2020, Chongqing Medical University. Production and hosting by Elsevier B.V.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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