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

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.