Role of amyloid beta 1-42 in the transcriptional control of TREM2 gene

The Aβ1-42 peptide has a significant place in the pathology of Alzheimer's disease(AD). It has been shown that Aβ is localized in the nucleus and can regulate gene expression by binding to DNA like a transcription factor. The triggering receptor(TREM2) expressed on myeloid cells-2 plays a critical role in the neuroinflammatory response that occurs with AD progression. Through TREM2 activation phagocytosis-related pathways are activated. Therefore, changes in TREM2 signaling directly affect the microglial response. Aβ is ligand of TREM2. In a previous study conducted by our group, it was shown that TREM2 expression decreased as a result of Aβ1-42 treatment. In our study, we aimed to investigate the effect of Aβ1-42 on the transcriptional regulation of the TREM2 gene. To this end, 0.1 μM and 1 μM Aβ1-42 were treated to HEK293T cells, and after 24 hours, chromatin immunoprecipitation-quantitative polymerase chain reaction(ChIP-qPCR) technique were performed to investigate possible binding sites of Aβ in the regulatory regions of the TREM2 gene. Binding signals for these regions were calculated using the fold enrichment technique. Binding signals were observed in all 4 targeted regions. We concluded that the binding signal increased significantly in the target containing the flanker region of the gene promoter in the 1 μM Aβ1-42 application group compared to the control and 0.1 μM Aβ1-42 application. With the data we obtained, we suggest a new mechanism that has not been included in the literature, that Aβ may affect the expression of the TREM2 gene by interacting with the regulatory DNA regions. Aβ may reduce the effectiveness of the neuroinflammatory response and phagocytic clearance in AD by changing TREM2 expression through its transcription factor-like function. Further studies on the new mechanism defined between Aβ and TREM2 will provide a better understanding of the cellular processes in the pathology of AD.