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 overload, has been implicated in the pathogenesis of Alzheimer disease (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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KI mouse models with familial AD mutations have been generated to overcome these issues.
“To overcome these issues, KI mouse models with familial AD mutations have been generated [10, 24, 31, 32].”
From Amyloid-β plaque formation and reactive gliosis are required for induction of cognitive deficits in App knock-in mouse models of Alzheimer’s disease (2019) · cites this paper as [31]
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- Authors
- Guo, Q., Fu, W., Sopher, B. L., Miller, M. W., Ware, C. B., Martin, G. M., & Mattson, M. P.
- Affiliations
- University of Kentucky (US)
- University of Washington (US)
- Corresponding author
- Mattson, Mark P.
- Venue
- Nature Medicine
- Published
- 1999-01
- Volume
- 5
- Issue
- 1
- Pages
- 101-106
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- DOI
- 10.1038/4789
- OpenAlex
- W1566528879
- Cited by
- 489
- References
- 2
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 5 · 2023: 6 · 2022: 6 · 2021: 8 · 2020: 16 · 2019: 6 · 2018: 10 · 2017: 10 · 2016: 14 · 2015: 15 · 2014: 11 · 2013: 10 · 2012: 18
- FWCI
- 27.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- presenilin 1, excitotoxicity, hippocampal neurons, neuronal necrosis, Alzheimer's disease, glutamate excitotoxicity, calcium homeostasis, oxidative stress, mitochondrial dysfunction, knock-in mice, calcium channel blockers, antioxidants
- MeSH terms
- Animals, Hippocampus, Kainic Acid, Membrane Proteins, Mice, Inbred C57BL, Neurons, Mice, Knockout, Glutamic Acid, Mice, Presenilin-1
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