A survey of TREM2 antibodies reveals neuronal but not microglial staining in formalin-fixed paraffin-embedded postmortem Alzheimer's brain tissues
© BioMed Central Ltd 2013
Published: 8 July 2013
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.
Here we found that Iba1-immunoreactive microglia do not express TREM2 in AD and control brains. Previous studies by IHC with uncharacterized antibodies showed that microglia express TREM2 in the mouse and human cerebral cortex, where it is located in the Golgi complex . Although the possibility exists that neuronal staining of TREM2 reflects immunoreactivity of cross-reactive proteins, the validation requires the development of additional antibodies highly specific for distinct epitopes of TREM2. Not all microglia in the mouse brain express TREM2, and its levels are reduced in cultured microglia by exposure to lipopolysaccharide. Microglial phenotype is changeable from a proinflammatory/neurotoxic (M1) trait to an anti-inflammatory/neuroprotective (M2) trait in response to disturbances of brain homeostasis, suggesting that TREM2 expression on microglia is a transient event in vivo, depending on their microenvironment.
This work was supported by grants from the Genome Research Center (GRC) Project and the Grant-in-Aid (C25430054), of the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.
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