The mRNA Expression Levels of General Transcription Factors Altered in Alzheimer Cases Possibly Due to Amyloid Beta 1-42 Exposure.

Given the global gene expression alterations associated with amyloid beta (Aβ), a hallmark of Alzheimer's disease (AD) pathology, this study aimed to investigate its potential role in modulating gene expression through the regulation of specific transcription factors (TFs). Using a combination of protein-protein interaction prediction tools and transcriptional regulatory interaction databases, we identified JUN, FOS, ATF2, ATF4, RELA, NF-κB, SMAD3, STAT1, STAT3, and SP1 as potential candidate TFs that might be involved in Aβ1-42 related pathways. We then conducted in vitro studies to demonstrate a direct effect of Aβ on these TFs and a case-control study to investigate any alterations of selected TFs in human samples. In vitro studies included HEK293 T cells treated with 0.09 µM and 10 µM Aβ1-42. The expression levels of the TFs were assessed by qRT-PCR. The mRNA expression levels of selected target transcription factors that have the highest PPI scores, namely JUN, FOS, and RELA, were also investigated in blood samples from core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker-confirmed AD cases and plasma ALZpath pTau217-confirmed healthy subjects. In vitro studies indicated that the mRNA expression of most of the TFs was altered due to either the dose of Aβ or the period of treatments. JUN, FOS, NFKB, and SP1 mRNA expression were increased, while STAT1 and ATF2 were decreased within 24 hours of at least one dose of Aβ treatment. At 48 hours of treatment, FOS, STAT1, STAT3, ATF2, and SP1 were higher, whereas RELA, SMAD3, and NFKB were lower in Aβ-treated groups. At 72h of treatments, the ATF4 and NFKB expressions were high, whereas JUN FOS, RELA, STAT1, STAT3, ATF2, and SP1 were low in Aβ treated groups. Human samples showed that the mRNA levels of JUN and RELA were significantly higher in blood samples from AD cases compared to those from healthy individuals. Alterations in the expression levels of TFs in response to Aβ exposure may explain the alterations of the expression levels of genes that these TFs regulate. Given that, understanding the transcriptional effects of Aβ and its regulatory role on TFs may provide a perspective for the physiological roles of Aβ and the molecular pathways underlying AD pathogenesis.