The Triggering Receptor Expressed on Myeloid Cells 2: A Molecular Link of Neuroinflammation and Neurodegenerative Diseases

Jochen Walter

doi:10.1074/jbc.r115.704981

Abstract

The triggering receptor expressed on myeloid cells (TREM) 2 is a member of the immunoglobulin superfamily of receptors and mediates signaling in immune cells via engagement of its co-receptor DNAX-activating protein of 12 kDa (DAP12). Homozygous mutations in TREM2 or DAP12 cause Nasu-Hakola disease, which is characterized by bone abnormalities and dementia. Recently, a variant of TREM2 has also been associated with an increased risk for Alzheimer disease. The selective expression of TREM2 on immune cells and its association with different forms of dementia indicate a contribution of this receptor in common pathways of neurodegeneration.

Highlights

In humans, two homologous genes on chromosomes 6p21 encode two similar proteins, TREM1 and TREM2 [1, 3]
Mutations in TREM2 or DNAX-activating protein of 12 kDa (DAP12) are associated with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, called Nasu-Hakola disease (NHD), which is characterized by bone abnormalities and dementia [6, 9, 10]
Recent genetic studies indicate an association of TREM2 variants with Alzheimer disease (AD) and other neurodegenerative disorders [6, 11]

Summary

MINIREVIEW crossmark

The Triggering Receptor Expressed on Myeloid Cells 2: A Molecular Link of Neuroinflammation and Neurodegenerative Diseases*. Knockdown of endogenous TREM2 in primary microglia decreased phagocytic activity and increased transcription of pro-inflammatory cytokines and nitric oxide synthase-2 [36] These findings were consistent with previous observations obtained with macrophages from TREM2 knock-out mice that suggested an anti-inflammatory role of this receptor [31, 38]. Rare homozygous or compound mutations in TREM2 have been identified in cases with FTDlike symptomatic presentation in the absence of associated lesions in the bone system, differing in the clinical symptoms from NHD [40, 45, 47,48,49] (Table 1) Another rare variant of TREM2 with an R47H substitution has recently been associated with an increased risk for late-onset AD [50, 51]

Molecular Genetics of Alzheimer Disease

Findings

Conclusions