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J Biol Chem. 2015 Oct 23;290(43):26043-50. doi: 10.1074/jbc.M115.679043. Epub 2015 Sep 15.

Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2).

Author information

1
From the Department of Neuroscience and.
2
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.
3
the Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361005, China.
4
From the Department of Neuroscience and the Neurobiology of Disease Graduate Program, Mayo Clinic, Jacksonville, Florida 32224 and.
5
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.

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.

KEYWORDS:

Alzheimer disease; TREM2; apolipoprotein; apolipoprotein E (apoE); microglia; neuroinflammation

PMID:
26374899
PMCID:
PMC4646257
DOI:
10.1074/jbc.M115.679043
[Indexed for MEDLINE]
Free PMC Article

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