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Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice

Abstract

Excitotoxicity, a form of neuronal injury in which excessive activation of glutamate receptors results in cellular calcium overload1,2, has been implicated in the pathogenesis of Alzheimer disease3,4 (AD), although direct evidence is lacking. Mutations in the presenilin-1 (PS1) gene on chromosome 14 are causally linked to many cases of early-onset inherited AD (refs. 5,6 ). We generated PS1 mutant mice (PS1M146VKI) that express the PS1 M146V targeted allele at normal physiological levels. Although PS1M146VKI mice have no overt mutant phenotype, they are hypersensitive to seizure-induced synaptic degeneration and necrotic neuronal death in the hippocampus. Cultured hippocampal neurons from PS1M146VKI mice have increased vulnerability to death induced by glutamate, which is correlated with perturbed calcium homeostasis, increased oxidative stress and mitochondrial dysfunction. Agents that suppress calcium influx or release and antioxidants protect neurons against the excitotoxic action of the PS1 mutation. These findings establish a direct link between a genetic defect that causes AD and excitotoxic neuronal degeneration, and indicate new avenues for therapeutic intervention in AD patients.

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Figure 1: Generation of PS1M146VKI mice.
Figure 2: Enhanced seizure-induced excitotoxic necrosis in hippocampus of PS1 mutant knock-in mice.
Figure 3: Disruption of cellular calcium homeostasis contributes to the excitotoxicity-enhancing action of mutant PS1.
Figure 4: Glutamate-induced oxidative stress is enhanced in hippocampal neurons from PS1 mutant knock-in mice.
Figure 5: Agents that stabilize calcium homeostasis and antioxidants counteract the excitotoxicity-enhancing action of mutant PS1.

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Acknowledgements

We thank J.N. Keller and A.J. Bruce-Keller for discussions. This work was supported by grants to M.P.M. from the NIH (NIA and NINDS), to C.B.W. from the NIA, to B.L.S. from the University of Washington Nathan Shock Center for Excellence in the Basic Biology of Aging, and to G.M.M. from the NIA.

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Correspondence to Mark P. Mattson.

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Guo, Q., Fu, W., Sopher, B. et al. Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice. Nat Med 5, 101–106 (1999). https://doi.org/10.1038/4789

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