Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model
Open accessAbstract
In light of the rising prevalence of Alzheimer’s disease (AD), new strategies to prevent, halt, and reverse this condition are needed urgently. Perturbations of brain network activity are observed in AD patients and in conditions that increase the risk of developing AD, suggesting that aberrant network activity might contribute to AD-related cognitive decline. Human amyloid precursor protein (hAPP) transgenic mice simulate key aspects of AD, including pathologically elevated levels of amyloid-β peptides in brain, aberrant neural network activity, remodeling of hippocampal circuits, synaptic deficits, and behavioral abnormalities. Whether these alterations are linked in a causal chain remains unknown. To explore whether hAPP/amyloid-β–induced aberrant network activity contributes to synaptic and cognitive deficits, we treated hAPP mice with different antiepileptic drugs. Among the drugs tested, only levetiracetam (LEV) effectively reduced abnormal spike activity detected by electroencephalography. Chronic treatment with LEV also reversed hippocampal remodeling, behavioral abnormalities, synaptic dysfunction, and deficits in learning and memory in hAPP mice. Our findings support the hypothesis that aberrant network activity contributes causally to synaptic and cognitive deficits in hAPP mice. LEV might also help ameliorate related abnormalities in people who have or are at risk for AD.
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Reducing hippocampal hyperexcitability is shown to stall cognitive decline and disease progression in mouse models of AD.
“In contrast, reducing hippocampal hyperexcitability is shown to stall cognitive decline and disease progression in mouse models of AD (Sanchez et al., 2012).”
From APOE4 reduces hippocampal expression of phosphoglycerate kinase 1 and sodium potassium pump to enhance seizure susceptibility in mice (2026) · cites this paper as Sanchez et al., 2012
The paper reports that levetiracetam reduced abnormal spiking and reversed learning and memory deficits and hippocampal remodeling in hAPP mice (opening summary; page unavailable). It does not show that treatment stalled cognitive decline over time or halted disease progression. The Results report no reduction in amyloid levels or early deposition, and the Discussion describes prevention or treatment as a potential benefit requiring further study. (LLM, conf=0.88)
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- Authors
- Sanchez, P. E., Zhu, L., Verret, L., Vossel, K. A., Orr, A. G., Cirrito, J. R., Devidze, N., Ho, K., Yu, G.-Q., Palop, J. J., & Mucke, L.
- Affiliations
- Gladstone Institutes (US)
- Washington University in St. Louis (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-08-06
- Volume
- 109
- Issue
- 42
- Pages
- E2895-903
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3479491
- OpenAlex
- W2168312889
- Cited by
- 638
- References
- 5
- Citations by year
- 2026: 33 · 2025: 40 · 2024: 48 · 2023: 52 · 2022: 40 · 2021: 46 · 2020: 49 · 2019: 46 · 2018: 48 · 2017: 47 · 2016: 51 · 2015: 56 · 2014: 46 · 2013: 33 · 2012: 2
- FWCI
- 27.57
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (1c06rr018928-01)
- National Institute on Aging (AG011385, K23AG038357, R37AG011385, AG022074, P01AG022074, AG023501, R01AG011385, F32AG039220, P50AG023501)
- National Institute of Neurological Disorders and Stroke (NS065780, P30NS065780)
- National Center for Research Resources (RR 18928-01, C06-RR-018928)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- levetiracetam, Alzheimer's disease, amyloid precursor protein transgenic mice, amyloid-beta, neuronal network dysfunction, antiepileptic drugs, synaptic dysfunction, learning and memory impairment, cognitive decline
- MeSH terms
- Levetiracetam, Alzheimer Disease, Analysis of Variance, Animals, Anticonvulsants, Cognition, Cognition Disorders, Electroencephalography, Humans, Immunohistochemistry, Mice, Transgenic, Nerve Net, Piracetam, Synapses, Blotting, Western, Amyloid beta-Protein Precursor, Maze Learning, Mice
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