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.

中文翻译：

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血红素加氧酶1通过调节Wnt /β-Catenin信号传导抑制成人神经干细胞的增殖和存活。

背景技术成人海马神经发生对于更新海马神经回路和维持海马认知功能至关重要，并且与年龄相关的神经退行性疾病密切相关。血红素加氧酶1（HO-1）是一种应激蛋白，可催化血红素降解为游离铁，联肝素和一氧化碳。HO-1水平升高构成阿尔茨海默氏病，帕金森氏病和许多其他与年龄有关的神经退行性疾病的病理特征。目的在这里我们研究HO-1在成人海马神经发生中的确切作用。方法为探讨HO-1过表达对成年神经干细胞（aNSCs）的影响并阐明其机制，构建了Tg（HO-1）。对转基因小鼠和aNSC进行神经球分析，克隆分析，和BrdU标记检测增殖和自我更新能力。LiCl，MG132，CHX和IGF-1处理用于研究HO-1调节的信号通路。结果HO-1过表达在体内和体外降低了亚NSZs在SGZ中的增殖能力并诱导了其凋亡。此外，HO-1过表达失活了规范的WNT /β-catenin途径。重新激活经典的WNT /β-catenin途径可在HO-1过表达时挽救aNSC的增殖和存活。更重要的是，在HO-1过表达的aNSC中，AKTS473和GSK3βS9的磷酸化明显降低。AKT信号传导的重新激活证明HO-1通过AKT /GSK3β信号传导途径抑制了Wnt /β-catenin信号传导途径。