A survey of TREM2 antibodies reveals neuronal but not microglial staining in formalin-fixed paraffin-embedded postmortem Alzheimer's brain tissues

Recently, a significant association was identified between a rare rs75932628-T variant encoding R47H in the TREM2 gene and an increased risk for Alzheimer's disease (AD) [ 1 , 2 ]. TREM2 forms a signaling complex with DAP12 expressed on monocytes/macrophages, dendritic cells, osteoclasts, and microglia. Loss-of-function mutations in either DAP12 or TREM2 are identified in patients with Nasu-Hakola disease, a rare autosomal recessive disorder characterized by presenile dementia and multifocal bone cysts. TREM2 binds to bacterial components and Hsp60, although endogenous ligands remain unknown. R47H located within the extracellular immunoglobulin-like domain of TREM2 possibly causes a reduced affinity of TREM2 for putative ligands. Knockdown of TREM2 on mouse microglia inhibits phagocytosis of apoptotic neurons and stimulates production of tumor necrosis factor-alpha (TNFα) and interleukin-1 beta (IL-1β), suggesting a pivotal role for TREM2 in the clearance of damaged neural tissues to resolve damage-induced inflammation. TREM2 is upregulated in amyloid plaque-associated microglia in mouse models of AD, suggesting an active role for TREM2 in the clearance of deposited amyloid-β by microglia. However, the precise pathological role of TREM2-expressing microglia in AD brains remains unknown.