TREM1 facilitates microglial phagocytosis of amyloid beta.
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 rs6910730Greduced 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 Aβ1-42levels 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.
Department of Neurology, Nanjing First Hospital, Nanjing Medical University, No.68, Changle Road, Nanjing, Jiangsu, People's Republic of China.
Teng
T
Jiang
Department of Neurology, Nanjing First Hospital, Nanjing Medical University, No.68, Changle Road, Nanjing, Jiangsu, People's Republic of China. zhangyingdong@aliyun.com.
Ying-Dong
YD
Zhang
Department of Neurology, Nanjing First Hospital, Nanjing Medical University, No.68, Changle Road, Nanjing, Jiangsu, People's Republic of China.
Qing
Q
Gao
Department of Neurology, Nanjing First Hospital, Nanjing Medical University, No.68, Changle Road, Nanjing, Jiangsu, People's Republic of China.
Jun-Shan
JS
Zhou
Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No.5, Donghai Middle Road, Qingdao, Shandong, People's Republic of China.
Xi-Chen
XC
Zhu
Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No.5, Donghai Middle Road, Qingdao, Shandong, People's Republic of China.
Huan
H
Lu
Department of Neurology, Nanjing First Hospital, Nanjing Medical University, No.68, Changle Road, Nanjing, Jiangsu, People's Republic of China.
Jian-Quan
JQ
Shi
Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No.5, Donghai Middle Road, Qingdao, Shandong, People's Republic of China. dr.tanlan@163.com.
Lan
L
Tan
Department of Pathophysiology, Nanjing Medical University, Nanjing, People's Republic of China.
Qi
Q
Chen
Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No.5, Donghai Middle Road, Qingdao, Shandong, People's Republic of China. yu-jintai@163.com.
Jin-Tai
JT
Yu
D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology; D001921:Brain / Q000166:cytology / Q000473:pathology*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D010587:Phagocytosis / Q000187:drug effects*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000073871:Triggering Receptor Expressed on Myeloid Cells-1
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000906:Antibodies; D008562:Membrane Glycoproteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D011971:Receptors, Immunologic; C408842:TREM1 protein, human; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; C075222:amyloid beta-protein (1-42)
Alzheimer’s disease; Amyloid-β; Microglia; Monocytes; Phagocytosis; TREM1