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TREM1 facilitates microglial phagocytosis of amyloid beta

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Abstract

As the most common type of neurodegenerative disease, Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β peptide (Aβ) within the brain. Triggering receptor expressed on myeloid cells (TREM) 1 is an immune receptor expressed by mononuclear phagocytes including monocytes and microglia, coupling with TYRO protein tyrosine kinase binding protein to regulate immune reactions. Emerging evidence indicates that rs6910730G, an intronic variant of TREM1, is associated with an increased Aβ neuropathology in the brains of elderly subjects, but the underlying mechanisms remain unclear. Here, using two independent cohorts of healthy individuals, we provided evidence that rs6910730G reduced the ability of human monocytes for Aβ phagocytosis, and this reduction was likely attributed to a decreased monocytic TREM1 expression. By knockdown and overexpression of Trem1 in mouse primary microglia, we showed that TREM1 facilitated microglial phagocytosis of Aβ. In support of this finding, knockdown of Trem1 in the brains of APP/PSEN1 mice increased Aβ1–42 levels and total amyloid burden, whereas selective overexpression of Trem1 on microglia or activation of Trem1 signaling by an agonistic antibody ameliorated Aβ neuropathology and rescued AD-related spatial cognitive impairments. Altogether, these findings uncover the role of TREM1 in microglial Aβ clearance, and establish TREM1 as a potential therapeutic target for AD.

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Acknowledgments

This work was supported by National Natural Science Foundation of China (81501092, 81500916), China Postdoctoral Science Foundation (2015M580448, 2016T90480), Natural Science Foundation of Jiangsu Province (BK20150091), and “Six Talent Summit” Foundation of Jiangsu Province (2016-WSN-180).

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Authors and Affiliations

  1. Department of Neurology, Nan**g First Hospital, Nan**g Medical University, No.68, Changle Road, Nan**g, Jiangsu, People’s Republic of China

    Teng Jiang, Ying-Dong Zhang, Qing Gao, Jun-Shan Zhou & Jian-Quan Shi

  2. Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No.5, Donghai Middle Road, Qingdao, Shandong, People’s Republic of China

    **-Chen Zhu, Huan Lu, Lan Tan & **-Tai Yu

  3. Department of Pathophysiology, Nan**g Medical University, Nan**g, People’s Republic of China

    Qi Chen

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  1. Teng Jiang
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Correspondence to Ying-Dong Zhang, Lan Tan or **-Tai Yu.

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All procedures performed in this study involving human participants were in accordance with the ethical standards of Nan**g First Hospital and Qingdao Municipal Hospital and with the declaration of Helsinki. A written informed consent was obtained from each participant. Meanwhile, all procedures performed in this study involving animals were in accordance with the ethical standards of Nan**g First Hospital and Qingdao Municipal Hospital.

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Jiang, T., Zhang, YD., Gao, Q. et al. TREM1 facilitates microglial phagocytosis of amyloid beta. Acta Neuropathol 132, 667–683 (2016). https://doi.org/10.1007/s00401-016-1622-5

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