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.

由β位淀粉样前体蛋白裂解酶1（β-site APP cleaving enzyme-1, BACE1）介导的过量β淀粉样蛋白（amyloid-β, Aβ）生成，是阿尔茨海默病（Alzheimer's disease, AD）发病机制的核心环节，但活性位点BACE1抑制剂因疗效与安全性局限在临床试验中遭遇失败。靶向BACE1转录提供了一种正交策略，有望实现与神经元功能兼容的、部分且依赖于情境的抑制效果。我们构建了比率型BACE1启动子报告基因（ratiometric BACE1 promoter reporter），并对1200种临床在用药物（普雷斯特维克，Prestwick）文库进行了筛选。氯己定（chlorhexidine, CHX）脱颖而出，成为BACE1启动子活性的最强抑制剂，其抑制效果呈现明确的剂量-反应关系，且在有效浓度下未检测到细胞毒性。在神经元系统中，氯己定可降低BACE1的mRNA与蛋白水平，并使淀粉样前体蛋白（APP）的加工途径偏离β分泌酶通路。在SH-swAPP细胞中，氯己定可下调BACE1的mRNA与蛋白水平，并降低C99/C83比值（即β剪切与α剪切的比值）。上述结果证实，在人神经母细胞瘤细胞系（human neuroblastoma lines）中，BACE1的转录下调是氯己定的主要作用机制。本研究首次确认氯己定是一种此前未被发现的BACE1转录调控因子，并提供了体内证据，证明通过老药新用制剂（repurposed agent）抑制BACE1可减轻淀粉样蛋白病理损伤并改善认知功能。