Emergence of a seizure phenotype in aged apolipoprotein epsilon 4 targeted replacement mice
Abstract
The apolipoprotein ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) and is associated with earlier age of onset. The incidence of spontaneous seizures has been reported to be increased in sporadic AD as well as in the early onset autosomal dominant forms of AD. We now report the emergence of a seizure phenotype in aged apolipoprotein E4 (apoE4) targeted replacement (TR) mice but not in age-matched apoE2 TR or apoE3 TR mice. Tonic-clonic seizures developed spontaneously after 5 months of age in apoE4 TR mice and are triggered by mild stress. Female mice had increased seizure penetrance compared to male mice, but had slightly reduced overall seizure severity. The majority of seizures were characterized by head and neck jerks, but 25% of aged apoE4 TR mice had more severe tonic-clonic seizures which occasionally progressed to tonic extension and death. Aged apoE4 TR mice progressed through pentylenetetrazol-induced seizure stages more rapidly than did apoE3 TR and apoE2 TR mice. Electroencephalographic (EEG) recordings revealed more frequent bursts of synchronous theta activity in the hippocampus of apoE4 TR mice than in apoE2 TR or apoE3 TR mice. Cortical EEG recordings also revealed sharp spikes and other abnormalities in apoE4 TR mice. Taken together, these findings demonstrate the emergence of an age-dependent seizure phenotype in old apoE4 TR mice in the absence of human amyloid-β peptide (Aβ) overexpression, suggesting increased centra…
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Homozygous human APOE4 but not APOE3 targeted replacement mice display spontaneous seizures following exposure to mild stress after 7 months of age independent of Aβ deposition.
“homozygous human APOE4 but not APOE3 targeted replacement mice (herein termed E4 and E3 mice) display spontaneous seizures following exposure to mild stress after 7 months of age independent of Aβ deposition (Hunter et al., 2012; Lamoureux et al., 2021)”
From APOE4 reduces hippocampal expression of phosphoglycerate kinase 1 and sodium potassium pump to enhance seizure susceptibility in mice (2026) · cites this paper as Hunter et al., 2012
APOE4 alone can increase seizure susceptibility in young adult mice independent of Aβ overproduction.
“APOE4 alone can increase seizure susceptibility in young adult mice (Fig. 1) independent of Aβ overproduction (Hunter et al., 2012; Lamoureux et al., 2021)”
From APOE4 reduces hippocampal expression of phosphoglycerate kinase 1 and sodium potassium pump to enhance seizure susceptibility in mice (2026) · cites this paper as Hunter et al., 2012
APOE4 induces hyperactivity in the hippocampal formation and decreases seizure threshold in aged APOE-targeted replacement mice.
“prior studies demonstrating that APOE4 induces hyperactivity in the hippocampal formation and decreases seizure threshold in aged mice using APOE-targeted replacement mice (Hunter et al., 2012; Lamoureux et al., 2021; Nuriel et al., 2017)”
From APOE4 reduces hippocampal expression of phosphoglycerate kinase 1 and sodium potassium pump to enhance seizure susceptibility in mice (2026) · cites this paper as Hunter et al., 2012
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- Authors
- Hunter, J. M., Cirrito, J. R., Restivo, J. L., Kinley, R. D., Sullivan, P. M., Holtzman, D. M., Koger, D., Delong, C., Lin, S., Zhao, L., Liu, F., Bales, K., & Paul, S. M.
- Affiliations
- Eli Lilly (United States) (US)
- Washington University in St. Louis (US)
- Duke University (US)
- Cornell University (US)
- Corresponding author
- Paul, Steven M.
- ORCID
- Venue
- Brain Research
- Publisher
- Elsevier BV
- Published
- 2012-07
- Volume
- 1467
- Pages
- 120-132
- ISSN
- 0006-8993 (ISSN-L)
- OpenAlex
- W2016638160
- Cited by
- 45
- References
- 12
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 4 · 2023: 2 · 2022: 3 · 2021: 5 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 1 · 2016: 2 · 2015: 2 · 2014: 4 · 2013: 4 · 2012: 2
- FWCI
- 2.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eli Lilly and Company
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- APOE ε4, spontaneous seizures, tonic-clonic seizures, late-onset Alzheimer's disease, pentylenetetrazole-induced seizures, hippocampal theta activity
- MeSH terms
- Aging, Animals, Behavior, Animal, Body Weight, Cerebral Cortex, Convulsants, Electroencephalography, Enzyme-Linked Immunosorbent Assay, Hippocampus, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Pentylenetetrazole, Phenotype, Seizures, Biomarkers, Amyloid beta-Peptides, Mice, Apolipoprotein E4
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