TREM2 Ameliorates Neuronal Tau Pathology Through Suppression of Microglial Inflammatory Response
- PDF / 2,476,912 Bytes
- 13 Pages / 595.276 x 790.866 pts Page_size
- 54 Downloads / 159 Views
ORIGINAL ARTICLE
TREM2 Ameliorates Neuronal Tau Pathology Through Suppression of Microglial Inflammatory Response Teng Jiang,1,2 Ying-Dong Zhang,1 Qing Gao,1 Zhou Ou,1 Peng-Yu Gong,1 Jian-Quan Shi,1 Liang Wu,1 and Jun-Shan Zhou1,2
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.
Abstract—
KEY WORDS: Alzheimer’s disease; TREM2; tau pathology; microglia; inflammation; tau kinase.
INTRODUCTION Triggering receptor expressed on myeloid cells 2 (TREM2) gene is a recently identified susceptibility gene for Alzheimer’s disease (AD), since a low-frequency variant p.R47H increases the risk of this disease in Caucasians with an odds ratio similar to that of one APOE ε4 allele [3, 15, 24]. Human TREM2 encodes a 230 amino acid type I transmembrane receptor that belongs to the superfamily of immunoglobulin [10, 17]. In the brain, TREM2 was mainly expressed on microglia, the immune cell within the
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10753-018-0735-5) contains supplementary material, which is available to authorized users. 1
Department of Neurology, Nanjing First Hospital, Nanjing Medical University, No. 68, Changle Road, Nanjing, Jiangsu, People’s Republic of China 2 To whom correspondence should be addressed at Department of Neurology, Nanjing First Hospital, Nanjing Medical University, No. 68, Changle Road, Nanjing, Jiangsu, People’s Republic of China. Emails: [email protected]; [email protected]
811 0360-3997/18/0300-0811/0 # 2018 Springer Science+Business Media, LLC, part of S
Data Loading...
