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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References
Olney, J. W. & DeGubareff, T. Glutamate and the pathophysiology of hypotoxic-ishemic brain damage. Ann. Neurol. 271 , 557–559 (1978).
Choi, D.W. Calcium: still center stage in hypoxic-ischemic neuronal death. Trends Neurosci. 18, 58–60 (1996).
Greenamyre, J.T. & Young, A.B. Excitatory amino acids and Alzheimer's disease. Neurobiol. Aging 10, 593–602 (1989).
Mattson, M.P. et al. β-amyloid precursor protein metabolites and loss of neuronal calcium homeostasis in Alzheimer's disease. Trends Neurosci. 16, 409–415 (1993).
Hardy, J. Amyloid, the presenilins and Alzheimer's disease. Trends Neurosci. 20, 154–159 ( 1997).
Kim, T.W. & Tanzi, R.E. Presenilins and Alzheimer's disease. Curr. Opin. Neurobiol. 7, 683– 688 (1997).
Zhou, Q., Quaife, C.J. & Palmiter, R.Î. Targeted disruption of the tyrosine hydroxylase gene reveals that catecholoamines are required for mouse fetal development. Nature 374, 640–643 (1995).
Nagy, A. et al. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc. Natl. Acad. Sci. USA 90 , 8424–8428 (1993).
Guo, Q. et al. Alzheimer's presenilin mutation sesnsitizes neural cells to apoptosis induced by trophic factor withdrawal and amyloid β-peptide: involvement of calcium and oxyradicals. J. Neurosci. 17, 4212–4222 (1997).
Guo, Q., Christakos, S., Robinson, N. & Mattson, M.P. Calbindin blocks the pro-apoptotic actions of mutant presenilin-1: reduced oxidative stress and preserved mitochondrial function. Proc. Natl. Acad. Sci. USA 95, 3227–3232 (1998).
Scheuner, D. et al. The amyloid β protein deposited in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nature Med. 2, 864–870 ( 1996).
Borchelt, D.R. et al. Familial Alzheimer's disease-linked presenilin 1 variants elevate Aβ1-42/1-40 ratio in vitro and in vivo. Neuron 17, 1005–1013 ( 1996).
Duff, K. et al. Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1. Nature 383, 710– 713 (1996).
Wong, P.C. et al. Presenilin 1 is required for Notch1 and Dll1 expression in the paraxial mesoderm. Nature 387, 288–292 (1997).
Shen, J. et al. Skeletal and CNS defects in Presenilin-1-deficient mice. Cell 89, 629–639 ( 1997).
Qian, S. et al. Mutant human presenilin 1 protects presenilin 1 null mouse against embryonic lethality and elevates Aβ1-42/43 expression. Neuron 20, 611–617 ( 1998).
Davis, J.A. et al. An Alzheimer's disease-linked PS1 variant rescues the developmental abnormalities of PS1-deficient embryos. Neuron 20, 603–609 (1998).
Bruce, A. J. et al. Altered neuronal and microglial responses to brain injury in mice lacking TNF receptors. Nature Med. 2, 788–794 (1996).
White, R.J. & Reynolds, I.J. Mitochondrial depolarization in glutamate-stimulated neurons: an early signal specific to excitotoxin exposure. J. Neurosci. 16, 5688– 5697 (1996).
Mattson, M.P., Lovell, M.A., Furukawa, K. & Markesbery, W.R. Neurotrophic factors attenuate glutamate-induced accumulation of peroxides, elevation of intracellular Ca2+ concentration, and neurotoxicity and increase antioxidant enzyme activities in hippocampal neurons. J. Neurochem. 65, 1740–1751 (1995).
Mattson, M.P. Antigenic changes similar to those seen in neurofibrillary tangles are elicited by glutamate and calcium influx in cultured hippocampal neurons. Neuron 4, 105–117 ( 1990).
Koh, J., Yang, L.L. & Cotman, C.W. β-amyloid protein increases the vulnerability of cultured cortical neurons to excitotoxic damage. Brain Res. 533, 315–320 ( 1990).
Mattson, M. P. et al. β-amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J. Neurosci. 12, 376–389 ( 1992).
Mattson, M.P. et al. Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of β-amyloid precursor protein. Neuron 10, 243–254 ( 1993).
Ancolio, K., Marambaud, P., Dauch, P. & Checler, F. β-secretase-derived product of β-amyloid precursor protein is decreased by presenilin 1 mutations linked to familial Alzheimer's disease. J. Neurochem. 69, 2494–2499 (1997).
Guo, Q., Robinson, N. & Mattson, M.P. Secreted APPβ counteracts the pro-apoptotic action of mutant presenilin-1 by activation of NF-κβ and stabilization of calcium homeostasis J. Biol. Chem. 273, 12341–12351 (1998).
Wolozin, B. et al. Participation of presenilin 2 in apoptosis: enhanced basal activity conferred by an Alzheimer mutation. Science 274, 1710–1713 (1996).
Grynkiewicz, G., Poenie, M. & Tsien, R.Y. A new generation of calcium indicators with greatly improved fluorescence properties. J. Biol. Chem. 260, 3440–3450 (1985).
Keller, J.N. et al. Increased sensitivity to mitochondrial toxin-induced apoptosis in neural cells expressing mutant presenilin-1 is linked to perturbed calcium homeostasis and enhanced oxyradical production. J. Neurosci. 18, 4439–4450 (1998).
Goodman, Y. & Mattson, M.P. Ceramide protects hippocampal neurons against excitotoxic and oxidative insults, and amyloid b-peptide toxicity. J. Neurochem. 66, 869– 872 (1996).
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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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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DOI: https://doi.org/10.1038/4789
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