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Gamma secretase–mediated Notch signaling worsens brain damage and functional outcome in ischemic stroke

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Abstract

Mice transgenic for antisense Notch and normal mice treated with inhibitors of the Notch-activating enzyme γ-secretase showed reduced damage to brain cells and improved functional outcome in a model of focal ischemic stroke. Notch endangers neurons by modulating pathways that increase their vulnerability to apoptosis, and by activating microglial cells and stimulating the infiltration of proinflammatory leukocytes. These findings suggest that Notch signaling may be a therapeutic target for treatment of stroke and related neurodegenerative conditions.

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Figure 1: Evidence for involvement of γ-secretase and Notch signaling in ischemic stroke.
Figure 2: Notch signaling promotes neuronal apoptosis and enhances leukocyte infiltration in cerebral ischemia.

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Acknowledgements

We thank H. Zhu for technical assistance and B. De Strooper for providing presenilin-deficient cells. This research was supported by the National Institute on Aging Intramural Research Program of the US National Institutes of Health.

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Author notes

  1. Thiruma V Arumugam, Sic L Chan and Dong-Gyu Jo: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, 5600 Nathan Shock Drive, Baltimore, 21224, Maryland, USA

    Thiruma V Arumugam, Sic L Chan, Dong-Gyu Jo, Sung-Chun Tang, Aiwu Cheng, Marc Gleichmann, Eitan Okun, Mohamed R Mughal, Xin Ouyang, Tim Magnus & Mark P Mattson

  2. Department of Molecular & Cellular Physiology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, 71130, Louisiana, USA

    Gokhan Yilmaz & D Neil Granger

  3. Department of Neurology, Stroke Center, National Taiwan University Hospital, Taiwan

    Sung-Chun Tang

  4. Laboratory of Immunology, National Institute on Aging Intramural Research Program, 5600 Nathan Shock Drive, Baltimore, 21224, Maryland, USA

    Vishwa D Dixit

  5. Research Resources Branch, National Institute on Aging Intramural Research Program, 5600 Nathan Shock Drive, Baltimore, 21224, Maryland, USA

    Srinivasulu Chigurupati & Suresh Poosala

  6. Department of Biopharmaceutical Sciences and Cancer Center, University of Illinois, 833 South Wood Street (M/C 865), Chicago, 60612, Illinois, USA

    Lucio Miele

  7. Department of Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, 21205, Maryland, USA

    Mark P Mattson

Authors
  1. Thiruma V Arumugam
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  2. Sic L Chan
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  3. Dong-Gyu Jo
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  4. Gokhan Yilmaz
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  5. Sung-Chun Tang
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  6. Aiwu Cheng
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  7. Marc Gleichmann
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  8. Eitan Okun
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  9. Vishwa D Dixit
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  10. Srinivasulu Chigurupati
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  11. Mohamed R Mughal
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  12. Xin Ouyang
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  13. Lucio Miele
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  14. Tim Magnus
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  15. Suresh Poosala
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  16. D Neil Granger
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  17. Mark P Mattson
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Corresponding author

Correspondence to Mark P Mattson.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Notch signaling promotes neuronal cell death. (PDF 637 kb)

Supplementary Methods (PDF 142 kb)

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Arumugam, T., Chan, S., Jo, DG. et al. Gamma secretase–mediated Notch signaling worsens brain damage and functional outcome in ischemic stroke. Nat Med 12, 621–623 (2006). https://doi.org/10.1038/nm1403

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