Formononetin Protects Neurons Against Hypoxia-Induced Cytotoxicity Through Upregulation of ADAM10 and sAβPPα

Article type: Research Article

Authors: Sun, Miao^{a; 1} | Zhou, Ting^a | Zhou, Liang^{a; 1} | Chen, Qiang^{b; *} | Yu, Yan^a | Yang, Huan^a | Zhong, Kaiyin^a | Zhang, Ximeng^a | Xu, Feng^c | Cai, Shaoqing^c | Yu, Albert^a | Zhang, Hui^d | Xiao, Ruizhong^d | Xiao, Dongsheng^d | Chui, Dehua^{a; d; *}

Affiliations: [a] 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 | [b] Department of Neurology, Ningbo Beilun Hospitals, Ningbo, China | [c] Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University, Beijing, China | [d] Department of Neurology, Peking University Third Hospital, Beijing, China

Correspondence: [*] Correspondence to: Dr. Dehua Chui, Neuroscience Research Institute, Peking University Health Science Center, 38 Xueyuan Road, Hai Dian District, 100191, Beijing, China. E-mail: [email protected] and Dr. Qiang Chen, Department of Neurology, Ningbo Beilun Hospitals, Ningbo 315806, China. E-mail: [email protected].

Note: [1] These authors contributed equally to this paper.

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.

Keywords: ADAM10, amyloid-β protein precursor (AβPP), formononetin, soluble-AβPPα

DOI: 10.3233/JAD-2011-110506

Journal: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 795-808, 2012