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 Wen, Huaxi Xu, Guojun Bu () and Xiao-Fen Chen ()
Additional contact information
Li Zhong: Institute of Neuroscience, School of Medicine, Xiamen University
Ying Xu: Institute of Neuroscience, School of Medicine, Xiamen University
Rengong Zhuo: School of Medicine, Xiamen University
Tingting Wang: Institute of Neuroscience, School of Medicine, Xiamen University
Kai Wang: Institute of Neuroscience, School of Medicine, Xiamen University
Ruizhi Huang: Institute of Neuroscience, School of Medicine, Xiamen University
Daxin Wang: Institute of Neuroscience, School of Medicine, Xiamen University
Yue Gao: Institute of Neuroscience, School of Medicine, Xiamen University
Yifei Zhu: Institute of Neuroscience, School of Medicine, Xiamen University
Xuan Sheng: Institute of Neuroscience, School of Medicine, Xiamen University
Kai Chen: Institute of Neuroscience, School of Medicine, Xiamen University
Na Wang: Institute of Neuroscience, School of Medicine, Xiamen University
Lin Zhu: Institute of Neuroscience, School of Medicine, Xiamen University
Dan Can: Institute of Neuroscience, School of Medicine, Xiamen University
Yuka Marten: Mayo Clinic
Mitsuru Shinohara: Mayo Clinic
Chia-Chen Liu: Mayo Clinic
Dan Du: School of Medicine, Xiamen University
Hao Sun: Institute of Neuroscience, School of Medicine, Xiamen University
Lei Wen: School of Medicine, Xiamen University
Huaxi Xu: Neuroscience Initiative, Sanford-Burnham-Prebys Medical Discovery Institute
Guojun Bu: Mayo Clinic
Xiao-Fen Chen: Institute of Neuroscience, School of Medicine, Xiamen University

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09118-9

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