Chronic hypoxia induces the activation of the Wnt/β-catenin signaling pathway and stimulates hippocampal neurogenesis in wild-type and APPswe-PS1ΔE9 transgenic mice in vivo
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2014-02
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en
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Atribution 4.0 International (CC BY 4.0)
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https://creativecommons.org/licenses/by/4.0/deed.es
Resumen
Hypoxia modulates proliferation and differentiation of cultured embryonic and adult stem
cells, an effect that includes β-catenin, a key component of the canonical Wnt signaling
pathway. Here we studied the effect of mild hypoxia on the activity of the Wnt/β catenin signaling pathway in the hippocampus of adult mice in vivo. The hypoxia-inducible
transcription factor-1α (HIF-1α) was analyzed as a molecular control of the physiological
hypoxic response. Exposure to chronic hypoxia (10% oxygen for 6–72 h) stimulated the
activation of the Wnt/β-catenin signaling pathway. Because the Wnt/β-catenin pathway is
a positive modulator of adult neurogenesis, we evaluated whether chronic hypoxia was
able to stimulate neurogenesis in the subgranular zone (SGZ) of the hippocampal dentate
gyrus. Results indicate that hypoxia increased cell proliferation and neurogenesis in adult
wild-type mice as determined by Ki67 staining, Bromodeoxyuridine (BrdU) incorporation
and double labeling with doublecortin (DCX). Chronic hypoxia also induced neurogenesis
in a double transgenic APPswe-PS11E9 mouse model of Alzheimer’s disease (AD), which
shows decreased levels of neurogenesis in the SGZ. Our results show for the first time
that exposure to hypoxia in vivo can induce the activation of the Wnt/β-catenin signaling
cascade in the hippocampus, suggesting that mild hypoxia may have a therapeutic value
in neurodegenerative disorders associated with altered Wnt signaling in the brain and also
in pathological conditions in which hippocampal neurogenesis is impaired.
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Indexación: Scopus.
Palabras clave
Hypoxia, HIF-1α, Hippocampus, Wnt Signaling Pathway, β-catenin, Neurogenesis, Alzheimer’s Disease
Citación
DOI
10.3389/fncel.2014.00017