title: Formononetin protects neurons against hypoxia-induced cytotoxicity through upregulation of ADAM10 and sAβPPα.
abstract: Formononetin, an active constituent of the Chinese herb Astragali Radix, has been reported to have beneficial effects for Alzheimer's disease (AD). Yet the mechanism of this effect remains to be elucidated. The present study shows that formononetin increases soluble-AβPPα (sAβPPα) secretion and thus protects human-AβPP Swedish mutation cell (N2a-AβPP cell) from hypoxia-induced apoptosis. Using hypoxic N2a-AβPP cell as an in vitro model of AD-like pathology, we confirmed that regular treatment with formononetin could have neuroprotective effects, followed respectively by reduced caspase 3 activity and increased cell viability. Strikingly, our data revealed that the caspase 3-blocking effect of formononetin was largely mediated by stimulation of α-secretase cleavage of AβPP, and increasing the secretion of its soluble form, sAβPPα. Moreover, the protective effect of formononetin was totally inhibited by TAPI-2, an α-secretase complex inhibitor, suggesting the role of the sAβPPα pathway in the neuroprotective response to formononetin. We also found that the stimulative effect of formononetin on α-secretase activity was mainly conducted by upregulating ADAM10 expression at the transcriptional level. Altogether, our study provides novel insights into how formononetin mediates stimulation of the ADAM10-sAβPPα pathway and exerts a neuronal protective effect.
authors.affiliation: Neuroscience Research Institute and Department of Neurobiology, Key Laboratory for Neuroscience, Ministry of Education and Ministry of Public Health, Health Science Center, Peking University, Beijing, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Sun
authors.forename: Ting
authors.initials: T
authors.lastname: Zhou
authors.forename: Liang
authors.initials: L
authors.lastname: Zhou
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chen
authors.forename: Yan
authors.initials: Y
authors.lastname: Yu
authors.forename: Huan
authors.initials: H
authors.lastname: Yang
authors.forename: Kaiyin
authors.initials: K
authors.lastname: Zhong
authors.forename: Ximeng
authors.initials: X
authors.lastname: Zhang
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.forename: Shaoqing
authors.initials: S
authors.lastname: Cai
authors.forename: Albert
authors.initials: A
authors.lastname: Yu
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Ruizhong
authors.initials: R
authors.lastname: Xiao
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Xiao
authors.forename: Dehua
authors.initials: D
authors.lastname: Chui
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D016564:Amyloid beta-Protein Precursor; D007529:Isoflavones; D008565:Membrane Proteins; D018696:Neuroprotective Agents; C007768:formononetin; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human