• Open Access

Notch1 signaling modulates neuronal progenitor activity in the subventricular zone in response to aging and focal ischemia

Authors

  • Fen Sun,

    1. Department of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
    2. Department of Pharmacology & Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, Fort Worth, TX, USA
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  • XiaoOu Mao,

    1. Buck Institute for Research on Aging, Novato, CA, USA
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  • Lin Xie,

    1. Buck Institute for Research on Aging, Novato, CA, USA
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  • Meiping Ding,

    Corresponding author
    1. Department of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
    • Correspondence

      Kunlin Jin, Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA. Tel.: 817 7352579; fax: 817 7350408; e-mail: kunlin.jin@unthsc.edu

      and

      Meiping Ding, Department of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88, Jiefang Road, Hangzhou, Zhejiang 310009, China. Tel.: +86 571 87783769; fax: +86 571 87784750;

      e-mail: yichen@mail.hz.zj.cn

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  • Bei Shao,

    1. Department of Neurology, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
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  • Kunlin Jin

    Corresponding author
    1. Department of Pharmacology & Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, Fort Worth, TX, USA
    2. Buck Institute for Research on Aging, Novato, CA, USA
    • Correspondence

      Kunlin Jin, Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA. Tel.: 817 7352579; fax: 817 7350408; e-mail: kunlin.jin@unthsc.edu

      and

      Meiping Ding, Department of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88, Jiefang Road, Hangzhou, Zhejiang 310009, China. Tel.: +86 571 87783769; fax: +86 571 87784750;

      e-mail: yichen@mail.hz.zj.cn

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Summary

Neurogenesis diminishes with aging and ischemia-induced neurogenesis also occurs, but reduced in aged brain. Currently, the cellular and molecular pathways mediating these effects remain largely unknown. Our previous study has shown that Notch1 signaling regulates neurogenesis in subventricular zone (SVZ) of young adult brain after focal ischemia, but whether a similar effect occurs in aged normal and ischemic animals is unknown. Here, we used normal and ischemic aged rat brains to investigate whether Notch1 signaling was involved in the reduction of neurogenesis in response to aging and modulates neurogenesis in aged brains after focal ischemia. By Western blot, we found that Notch1 and Jagged1 expression in the SVZ of aged brain was significantly reduced compared with young adult brain. Consistently, the activated form of Notch1 (Notch intracellular domain; NICD) expression was also declined. Immunohistochemistry confirmed that expression and activation of Notch1 signaling in the SVZ of aged brain were reduced. Double or triple immunostaining showed that that Notch1 was mainly expressed in doublecortin (DCX)-positive cells, whereas Jagged1 was predominantly expressed in astroglial cells in the SVZ of normal aged rat brain. In addition, disruption or activation of Notch1 signaling altered the number of proliferating cells labeled by bromodeoxyuridine (BrdU) and DCX in the SVZ of aged brain. Moreover, ischemia-induced cell proliferation in the SVZ of aged brain was enhanced by activating the Notch1 pathway and was suppressed by inhibiting the Notch1 signaling. Reduced infarct volume and improved motor deficits were also observed in Notch1 activator–treated aged ischemic rats. Our data suggest that Notch1 signaling modulates the SVZ neurogenesis in aged brain in normal and ischemic conditions.

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