Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer’s disease model

Li Zhong, Ying Xu, Rengong Zhuo, Tingting Wang, Kai Wang, Ruizhi Huang, Daxin Wang, Yue Gao, Yifei Zhu, Xuan Sheng, Kai Chen, Na Wang, Lin Zhu, Dan Can, Yuka Marten, Mitsuru Shinohara, Chia Chen Liu, Dan Du, Hao Sun, Lei WenHuaxi Xu, Guojun Bu, Xiao Fen Chen

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor genetically linked to the risk for Alzheimer’s disease (AD). A proteolytic product, soluble TREM2 (sTREM2), is abundant in the cerebrospinal fluid and its levels positively correlate with neuronal injury markers. To gain insights into the pathological roles of sTREM2, we studied sTREM2 in the brain of 5xFAD mice, a model of AD, by direct stereotaxic injection of recombinant sTREM2 protein or by adeno-associated virus (AAV)-mediated expression. We found that sTREM2 reduces amyloid plaque load and rescues functional deficits of spatial memory and long-term potentiation. Importantly, sTREM2 enhances microglial proliferation, migration, clustering in the vicinity of amyloid plaques and the uptake and degradation of Aβ. Depletion of microglia abolishes the neuroprotective effects of sTREM2. Our study demonstrates a protective role of sTREM2 against amyloid pathology and related toxicity and suggests that increasing sTREM2 can be explored for AD therapy.

Original languageEnglish (US)
Article number1365
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Zhong, L., Xu, Y., Zhuo, R., Wang, T., Wang, K., Huang, R., Wang, D., Gao, Y., Zhu, Y., Sheng, X., Chen, K., Wang, N., Zhu, L., Can, D., Marten, Y., Shinohara, M., Liu, C. C., Du, D., Sun, H., ... Chen, X. F. (2019). Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer’s disease model. Nature communications, 10(1), [1365]. https://doi.org/10.1038/s41467-019-09118-9