TREM2 Ameliorates Neuronal Tau Pathology Through Suppression of Microglial Inflammatory Response

• Published in: Inflammation Vol. 41; no. 3; pp. 811 - 823
• Main Authors: Jiang, Teng, Zhang, Ying-Dong, Gao, Qing, Ou, Zhou, Gong, Peng-Yu, Shi, Jian-Quan, Wu, Liang, Zhou, Jun-Shan
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.06.2018; Springer Nature B.V
• Subjects: Alzheimer's disease; Biomedical and Life Sciences; Biomedicine; Cell culture; Glycogen; Glycogen synthase kinase 3; Immunology; Inflammation; Internal Medicine; Kinases; Lipopolysaccharides; Microglia; Myeloid cells; Neurodegenerative diseases; Original Article; Pathology; Phagocytosis; Pharmacology/Toxicology; Phosphorylation; Rheumatology; Rodents; Tau protein; Transgenic mice; tau pathology; TREM2; Alzheimer’s disease; tau kinase; inflammation; microglia
• ISSN: 0360-3997; 1573-2576
• DOI: 10.1007/s10753-018-0735-5

As a recently identified susceptibility gene for Alzheimer’s disease (AD), triggering receptor expressed on myeloid cells 2 ( TREM2 ) encodes an immune receptor that is uniquely expressed on microglia, functioning as a modulator of microglial functions including phagocytosis and inflammatory response. Several lines of evidence suggest that TREM2 is upregulated and positively correlates with tau pathology in the brains of AD patients. Meanwhile, our recent study showed that knockdown of TREM2 markedly exacerbated neuronal tau hyperphosphorylation in the brains of P301S-tau transgenic mice, implying that TREM2 might exert a protective role against tau pathology under AD context. However, the precise mechanisms underlying this observation remain largely unclear. In this study, by employing a microglial-neuronal co-culture model, we showed that microglial inflammatory response induced by lipopolysaccharide led to tau hyperphosphorylation in neurons via activation of a major tau kinase glycogen synthase kinase 3β, confirming the pathogenic effects of activated microglia on the progression of tau pathology. More importantly, by manipulating TREM2 levels in microglia with a lentiviral-mediated strategy, we demonstrated that TREM2 ameliorated the pathological effects of activated microglia on neuronal tau hyperphosphorylation via suppression of microglial inflammatory response. Taken together, these findings uncover the underlying mechanisms by which TREM2 protects against tau pathology and highlight TREM2 as a potential therapeutic target for AD.