Affiliations: [a] College of Life Science, Wuhan University, Wuhan, Hubei, P.R. China | [b] Department of Neurobiology, Yale University School of Medicine, New Haven, CT, USA
Correspondence:
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Correspondence to: Jian Huang, PhD, Room 5105, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, P.R. China. Fax: +86 27 68753582; E-mail: [email protected].
Abstract: Beta-secretase (BACE1) controls an essential step for the generation of amyloid-β peptide (Aβ). As Aβ forms the principle pathologies in Alzheimer's disease, lowering Aβ 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 in human 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 both directly and indirectly disrupting p65 complex formation. In addition, we discovered that estrogen receptor mediates luteolin's effect in inhibiting NF-κB signaling 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 in regulating BACE1 expression.
