Affiliations: [a] Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China
| [b] Key Laboratory of Cardiovascular Medicine Research (Harbin Medical University), Ministry of Education, Harbin, China
| [c] State-Province Key Laboratories of Biomedicine-Pharmaceutics of China | [d] Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University Medical School, Zhejiang, China
Correspondence:
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Correspondence to: Yang Hui and Xu Gao, Department of Biochemistry and Molecular Biology, Harbin Medical University, 194 XueFu Road Nangang Dist, Harbin 150086, P.R. China. Tel.: +86 451 8667 1684; E-mail: huiyang79@126.com (Y. Hui) and Tel./Fax: +86 451 8708 6131; E-mail: gaoxu6712@163.com (X. Gao).
(Y. Hui).
Note: [1] These authors contributed equally to this work.
Abstract: Background:Adult hippocampal neurogenesis is critical for renewing hippocampal neural circuits and maintaining hippocampal cognitive function and is closely associated with age-related neurodegenerative diseases. Heme oxygenase 1 (HO-1) is a stress protein that catalyzes the degradation of heme into free iron, biliverdin, and carbon monoxide. Elevated HO-1 level constitutes a pathological feature of Alzheimer’s disease, Parkinson’s disease, and many other age-related neurodegenerative diseases. Objective:Here we research the precise role of HO-1 in adult hippocampal neurogenesis. Methods:To explore the effect of HO-1 overexpression on adult neural stem cells (aNSCs) and elucidate its mechanisms, Tg(HO-1) was constructed. The transgenic mice and aNSCs were subjected to neurosphereing assay, clonal analysis, and BrdU labelling to detect the proliferation and self-renewal ability. LiCl, MG132, CHX, and IGF-1 treatment were used to research the signaling pathways which regulated by HO-1. Results:HO-1 overexpression decreased proliferation ability and induced apoptosis of aNSCs in subgranular zoon (SGZ) in vivo and in vitro. Furthermore, HO-1 overexpression inactivated canonical WNT/β-catenin pathway. Re-activate canonical WNT/β-catenin pathway rescued aNSCs proliferation and survival upon HO-1 overexpression. More importantly, phosphorylation of AKTS473 and GSK3βS9 was found to be significantly decreased in HO-1 overexpressed aNSCs. Re-activation of AKT signaling proved that HO-1 inhibited Wnt/β-catenin signaling pathway via AKT/GSK3β signaling pathway. Conclusion:These results demonstrated a critical role of HO-1 in regulating aNSCs survival and proliferation by inhibiting Wnt/β-catenin pathway through repression of AKT/GSK3β, which provide a novel insight into the role of HO-1 in Alzheimer’s disease pathogenesis.
