PMID- 35224156 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220301 IS - 2352-3042 (Electronic) IS - 2352-4820 (Print) IS - 2352-3042 (Linking) VI - 9 IP - 2 DP - 2022 Mar TI - Hippocampal overexpression of TREM2 ameliorates high fat diet induced cognitive impairment and modulates phenotypic polarization of the microglia. PG - 401-414 LID - 10.1016/j.gendis.2020.05.005 [doi] AB - 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. CI - (c) 2020 Chongqing Medical University. Production and hosting by Elsevier B.V. FAU - Wu, Min AU - Wu M AD - Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China. AD - The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China. FAU - Liao, Maolin AU - Liao M AD - Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China. AD - The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China. FAU - Huang, Rongfeng AU - Huang R AD - Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China. AD - The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China. FAU - Chen, Chunxiu AU - Chen C AD - The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China. AD - Department of Nutrition and Food Hygiene, School of Public Health and Management, Chongqing Medical University, Chongqing 400016, PR China. FAU - Tian, Tian AU - Tian T AD - Department of Neurology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, PR China. FAU - Wang, Hongying AU - Wang H AD - Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China. AD - The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China. FAU - Li, Jiayu AU - Li J AD - Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China. AD - The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China. FAU - Li, Jibin AU - Li J AD - Department of Nutrition and Food Hygiene, School of Public Health and Management, Chongqing Medical University, Chongqing 400016, PR China. FAU - Sun, Yuxiang AU - Sun Y AD - Department of Nutrition and Food Science, Texas A&M University, College Station, TX 77843, USA. FAU - Wu, Chaodong AU - Wu C AD - Department of Nutrition and Food Science, Texas A&M University, College Station, TX 77843, USA. FAU - Li, Qifu AU - Li Q AD - Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China. FAU - Xiao, Xiaoqiu AU - Xiao X AD - Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China. AD - The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China. LA - eng PT - Journal Article DEP - 20200521 PL - Netherlands TA - Genes Dis JT - Genes & diseases JID - 101635967 PMC - PMC8843863 OTO - NOTNLM OT - Diabetes OT - Microglial polarization OT - Neurodegeneration OT - Neuroinflammation OT - Obesity OT - TREM2 EDAT- 2020/05/21 00:00 MHDA- 2020/05/21 00:01 PMCR- 2020/05/21 CRDT- 2022/02/28 05:40 PHST- 2020/03/13 00:00 [received] PHST- 2020/05/09 00:00 [revised] PHST- 2020/05/12 00:00 [accepted] PHST- 2022/02/28 05:40 [entrez] PHST- 2020/05/21 00:00 [pubmed] PHST- 2020/05/21 00:01 [medline] PHST- 2020/05/21 00:00 [pmc-release] AID - S2352-3042(20)30070-2 [pii] AID - 10.1016/j.gendis.2020.05.005 [doi] PST - epublish SO - Genes Dis. 2020 May 21;9(2):401-414. doi: 10.1016/j.gendis.2020.05.005. eCollection 2022 Mar.