Heme Oxygenase 1 Inhibits Adult Neural Stem Cells Proliferation and Survival via Modulation of Wnt/β-Catenin Signaling

  • J Alzheimers Dis. 2020;76(2):623-641. doi: 10.3233/JAD-200114.
Zizhen Si  1 ,  Xue Wang  1 ,  Yuchun Kang  1 ,  Xidi Wang  1  2  3 ,  Changhui Sun  1 ,  Yuanxin Li  1 ,  Jiakun Xu  1 ,  Jiajia Wu  1 ,  Zhujun Zhang  1 ,  Ling Li  1 ,  Yahui Peng  1  2  3 ,  Jihong Li  1  2  3 ,  Chongran Sun  4 ,  Yang Hui  1  2  3 ,  Xu Gao  1  2  3
Affiliations
  • 1. Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China.
  • 2. Key Laboratory of Cardiovascular Medicine Research (Harbin Medical University), Ministry of Education, Harbin, China.
  • 3. State-Province Key Laboratories of Biomedicine-Pharmaceutics of China.
  • 4. Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University Medical School, Zhejiang, China.
PMID: 32568195 DOI: 10.3233/JAD-200114
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.

Keywords
Adult hippocampal neurogenesis; age-related neurodegenerative diseases; canonical Wnt/β-catenin pathway; heme oxygenase 1; neural stem cell.
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