Transcriptional modulation of BACE1 in amyloid pathology
Excessive amyloid-ß (Aß) production, driven by ß-site APP cleaving enzyme-1 (BACE1), is central to Alzheimer's disease (AD) pathogenesis, yet active-site BACE1 inhibitors failed in trials due to efficacy and safety limitations. Targeting BACE1 transcription offers an orthogonal strategy that may enable partial, context-dependent suppression compatible with neuronal function. We developed a ratiometric BACE1 promoter reporter and screened 1,200 clinically used molecules (Prestwick). Chlorhexidine (CHX) emerged as the top suppressor of BACE1 promoter activity with a clear dose–response and no detectable cytotoxicity at effective concentrations. In neuronal systems, chlorhexidine reduced BACE1 mRNA and protein, and shifted APP processing away from the ß-secretase pathway. In SH-swAPP cells, chlorhexidine lowered BACE1 mRNA, protein levels and the C99/C83 ratio (ß- vs a-cleavage). These data support transcriptional downregulation of BACE1 as the primary mechanism of action across human neuroblastoma lines. This work identifies chlorhexidine as a previously unrecognized transcriptional modulator of BACE1, provides in vivo evidence that BACE1 repression by a repurposed agent reduces amyloid pathology and rescues cognition.