Zheng Nan, Yuan Peng, Li Changhao, Wu Jun, Huang Jian
College of Life Science, Wuhan University, Wuhan, Hubei, P.R. China.
J Alzheimers Dis. 2015;45(2):659-71. doi: 10.3233/JAD-142517.
Beta-secretase (BACE1) controls an essential step for the generation of amyloid- peptide (Aβ). As Aβ forms the principle pathologies in Alzheimer’s disease, lowering A production by inhibiting BACE1 is a plausible therapeutic approach. In the present study, we identified a natural polyphenol, luteolin, as a potent inhibitor of BACE1 transcription inhuman embryonic kidney 293 (HEK293) and human neuroblastoma (SH-SY5Y) cell lines. Luteolin is capable of suppressing the activation of BACE1 promoter by NF-κB signaling. We further characterized that luteolin interferes with NF-κB signaling by with both directly and indirectly disrupting p65 complex formation. In addition, we discovered that estrogen receptor mediates luteolin’s effect in inhibiting NF-κB signaling inhibiting and BACE1 transcription. Interestingly, the beneficial effects of luteolin may be attributed to selective activation profiles of luteolin to different estrogen receptor subtypes. Our study reports luteolin as a potent BACE1-inhibiting compound, providing useful information in understanding estrogen receptor- and NF-κB-mediated signaling and in regulating BACE1 expression.
β-分泌酶（BACE1）控制着淀粉样肽（Aβ）生成的关键步骤。由于Aβ是阿尔茨海默病的主要病理成分，通过抑制BACE1来降低Aβ的产生是一种可行的治疗方法。在本研究中，我们鉴定出一种天然多酚——木犀草素，它是人类胚胎肾293（HEK293）和人神经母细胞瘤（SH-SY5Y）细胞系中BACE1转录的有效抑制剂。木犀草素能够抑制NF-κB信号通路对BACE1启动子的激活。我们进一步证实，木犀草素通过直接和间接破坏p65复合物的形成来干扰NF-κB信号通路。此外，我们发现雌激素受体介导了木犀草素抑制NF-κB信号通路和BACE1转录的作用。有趣的是，木犀草素的有益作用可能归因于其对不同雌激素受体亚型的选择性激活模式。我们的研究报道了木犀草素是一种有效的BACE1抑制化合物，为理解雌激素受体和NF-κB介导的信号通路以及调节BACE1表达提供了有用的信息。
