Transcriptional Regulation Of TREM2in Alzheimer’s Disease

As a major characteristic of the aging process, neuroinflammation is involved in the pathogenesis of several aging-related diseases including Alzheimer’s disease (AD). Triggering receptor expressed on myeloid cells2(TREM2) is a newly identified risk gene for AD. TREM2, as an innate immune receptor expressed on the cell membrane, is mainly expressed in immature dendritic cells, osteoclasts, tissue macrophages, and microglia. However, it remains largely unknown how TREM2expression is regulated in different cell-types, such as microglia.Here, we demonstrated that LPS and Aβ treatment could down-regulate the mRNA level of TREM2in microglia, while NF-κB inhibitors can reverse this effect. Furthermore, we characterized upstream regions of the mouse TREM2gene, by sequence analysis and the point mutation technology. We identified a potential NF-κB binding site important for the promoter activity through the luciferase activity analysis. We also screened for small molecular compounds that could modulate TREM2expression with our home-made library. Furthermore, we explored the cell-specific expression of TREM2in mouse brain tissue and discovered that DNA methylation may be important for TREM2expression.In summary, we discovered inflammatory cues, such as LPS and Aβ, could down-regulate the expression level of TREM2. NF-κB appears to be the transcription factor that mediates this effect as NF-κB inhibitors could restore TREM2expression level. In addition, we mapped out the potential binding site for NF-κB on TREM2promoter and found its mutation could enhance TREM2expression. Furthermore, we found TREM2exhibits cell-type specific expression and small molecular compounds could modulate TREM2expression. All these findings improved our understanding about the transcription regulation of TREM2gene, meanwhile, provided new thought for the treatment of AD.