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


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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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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Correspondence to Mark P Mattson.

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The authors declare no competing financial interests.

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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).

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