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We generated an embryonic deletion of Trem2 (whole body deletion) and induced hippocampa1\u2010 and cortical\u2010specific knockdown of microglial Trem2 at different stages of the AD process in amyloid precursor protein\/Psen1 mice by adeno\u2010associated virus (AAV) infection. AAV infection induced microglial Trem2 overexpression in the hippocampus of wild\u2010type (WT) and thymus cell antigen 1\u2013enhanced green fluorescent protein mice. Mice were subjected to ethological and pathologic tests. Whole body genetic deletion of Trem2 exerted different electrophysiological outcomes between different AD pathologic stages, which results from a complex integration of synaptic loss and amyloid aggregation. Interestingly, knockdown of Trem2 at the early\u2010middle stage of AD (2\u20136 mo) prevents synaptic loss through directly inhibiting microglial phagocytosis, whereas knockdown of Trem2 at the middle\u2010late stage of AD (6\u201310 mo) accelerates synaptic dysfunction because of more severe amyloid deposition caused by the depression of microglial phagocytosis. Additionally, hippocampal overexpression of Trem2 in WT mice results in significant synaptic impairment. Here, with transgenic technology and electrophysiological assay, we revealed that TREM2 up\u2010regulation promotes microglial phagocytosis equally against synapse and amyloid plaques and eventually results in different outcomes. During the early\u2010middle pathologic stage, TREM2 enhancing microglial phagocytosis mainly causes synaptic loss. However, TREM2 up\u2010regulating microglial phagocytosis gradually supports a positive role when amyloid deposition occupies the leading position at the middle\u2010late pathologic stage. In this study, we highlighted that TREM2 triggers synaptic loss during AD pathology development.\u2014Sheng, L., Chen, M., Cai, K., Song, Y., Yu, D., Zhang, H., Xu, G. Microglial Trem2 induces synaptic impairment at early stage and prevents amyloidosis at late stage in APP\/PS1 mice. FASEB J. 33,10425\u201010442 (2019).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201900527r","type":"journal-article","created":{"date-parts":[[2019,6,20]],"date-time":"2019-06-20T15:19:54Z","timestamp":1561043994000},"page":"10425-10442","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":70,"title":["Microglial Trem2 induces synaptic impairment at early stage and prevents amyloidosis at late stage in APP\/PS1 mice"],"prefix":"10.1096","volume":"33","author":[{"given":"Liang","family":"Sheng","sequence":"first","affiliation":[{"name":"Department of Pharmacology School of Basic Medical Science Nanjing Medical University  Nanjing 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