title: Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2).
abstract: Several heterozygous missense mutations in the triggering receptor expressed on myeloid cells 2 (TREM2) have recently been linked to risk for a number of neurological disorders including Alzheimer disease (AD), Parkinson disease, and frontotemporal dementia. These discoveries have re-ignited interest in the role of neuroinflammation in the pathogenesis of neurodegenerative diseases. TREM2 is highly expressed in microglia, the resident immune cells of the central nervous system. Along with its adaptor protein, DAP12, TREM2 regulates inflammatory cytokine release and phagocytosis of apoptotic neurons. Here, we report apolipoprotein E (apoE) as a novel ligand for TREM2. Using a biochemical assay, we demonstrated high-affinity binding of apoE to human TREM2. The functional significance of this binding was highlighted by increased phagocytosis of apoE-bound apoptotic N2a cells by primary microglia in a manner that depends on TREM2 expression. Moreover, when the AD-associated TREM2-R47H mutant was used in biochemical assays, apoE binding was vastly reduced. Our data demonstrate that apoE-TREM2 interaction in microglia plays critical roles in modulating phagocytosis of apoE-bound apoptotic neurons and establish a critical link between two proteins whose genes are strongly linked to the risk for AD.
authors.affiliation: From the Department of Neuroscience and.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Atagi
authors.affiliation: From the Department of Neuroscience and the Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Chia-Chen
authors.initials: CC
authors.lastname: Liu
authors.affiliation: From the Department of Neuroscience and.
authors.forename: Meghan M
authors.initials: MM
authors.lastname: Painter
authors.affiliation: the Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Xiao-Fen
authors.initials: XF
authors.lastname: Chen
authors.affiliation: From the Department of Neuroscience and.
authors.forename: Christophe
authors.initials: C
authors.lastname: Verbeeck
authors.affiliation: the Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Honghua
authors.initials: H
authors.lastname: Zheng
authors.affiliation: From the Department of Neuroscience and.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: From the Department of Neuroscience and.
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.affiliation: From the Department of Neuroscience and.
authors.forename: Silvia S
authors.initials: SS
authors.lastname: Kang
authors.affiliation: the Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Huaxi
authors.initials: H
authors.lastname: Xu
authors.affiliation: From the Department of Neuroscience and.
authors.forename: Steven
authors.initials: S
authors.lastname: Younkin
authors.affiliation: From the Department of Neuroscience and.
authors.forename: Pritam
authors.initials: P
authors.lastname: Das
authors.affiliation: From the Department of Neuroscience and the Neurobiology of Disease Graduate Program, Mayo Clinic, Jacksonville, Florida 32224 and.
authors.forename: John D
authors.initials: JD
authors.lastname: Fryer
authors.affiliation: From the Department of Neuroscience and the Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361005, China the Neurobiology of Disease Graduate Program, Mayo Clinic, Jacksonville, Florida 32224 and bu.guojun@mayo.edu.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism*; D017209:Apoptosis; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D010587:Phagocytosis; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D008024:Ligands; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human
keywords: Alzheimer disease; TREM2; apolipoprotein; apolipoprotein E (apoE); microglia; neuroinflammation