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

• Published in: Nature communications Vol. 10; no. 1; p. 1365
• Main Authors: Zhong, Li, Xu, Ying, Zhuo, Rengong, Wang, Tingting, Wang, Kai, Huang, Ruizhi, Wang, Daxin, Gao, Yue, Zhu, Yifei, Sheng, Xuan, Chen, Kai, Wang, Na, Zhu, Lin, Can, Dan, Marten, Yuka, Shinohara, Mitsuru, Liu, Chia-Chen, Du, Dan, Sun, Hao, Wen, Lei, Xu, Huaxi, Bu, Guojun, Chen, Xiao-Fen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.03.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 13/51; 14/63; 38; 38/88; 42/35; 45; 631/378/1689/1283; 631/378/371; 82/80; 82/83; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer Disease - therapy; Alzheimer's disease; Amyloid; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - metabolism; Animals; Animals, Newborn; Brain; Brain - drug effects; Brain - metabolism; Brain - pathology; Brain research; Cell Movement - drug effects; Cell Proliferation - drug effects; Cerebrospinal fluid; Clustering; Dependovirus - genetics; Dependovirus - metabolism; Depletion; Disease Models, Animal; Female; Gene Expression; Genetic Vectors - chemistry; Genetic Vectors - metabolism; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Health risk assessment; Health risks; Humanities and Social Sciences; Humans; Injections, Intraventricular; Laboratories; Long-term potentiation; Long-Term Potentiation - drug effects; Long-Term Potentiation - physiology; Male; Medicine; Membrane Glycoproteins - administration & dosage; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Memory tasks; Mice; Microglia; Microglia - drug effects; Microglia - metabolism; Microglia - pathology; Migration; multidisciplinary; Myeloid cells; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neuroprotection; Neurosciences; Neurotoxicity; Older people; Pathology; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Phenotype; Phenotypes; Plaque, Amyloid - genetics; Plaque, Amyloid - metabolism; Plaque, Amyloid - pathology; Plaque, Amyloid - therapy; Primary Cell Culture; Proteins; Proteolysis; Receptors, Immunologic - administration & dosage; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Recombinant Fusion Proteins - administration & dosage; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Roles; Science; Science (multidisciplinary); Senile plaques; Spatial analysis; Spatial memory; Spatial Memory - drug effects; Spatial Memory - physiology; Stereotaxic Techniques; Toxicity; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-09118-9

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. TREM2 is a genetic risk factor for Alzheimer’s disease, and soluble TREM2 (sTREM2) in the CSF correlates with AD progression. Here the authors study the role of sTREM2 in a mouse model of Alzheimer’s disease, and find it reduces amyloid accumulation and increases the numbers of plaque-associated microglia which correlates with improved behavioural function in the mice.