APOE4 Reduces Glycolytic Enzymes and Sodium Potassium Pump to Enhance Seizure Susceptibility
Abstract number :
1.518
Submission category :
1. Basic Mechanisms / 1B. Epileptogenesis of genetic epilepsies
Year :
2025
Submission ID :
1272
Source :
www.aesnet.org
Presentation date :
12/6/2025 12:00:00 AM
Published date :
Authors :
Presenting Author: Tanveer Singh, PhD – University of Illinois-Urbana Champaign
Emma Bridgeman, BS – University of Illinois-Urbana Champaign
Hayden Noblet, BS – University of Illinois-Urbana Champaign
Annie J Baker, BS – University of Illinois-Urbana Champaign
Kang Yi Yang, BS – University of Illinois at Urbana-Champaign
Sehong Kang, BS MS – University of Illinois-Urbana Champaign
yongjae Lee, BS – University of Illinois-Urbana Champaign
Ki H Lim, BS – University of Illinois-Urbana Champaign
Sarah Lee, BS – University of Illinois-Urbana Champaign
Nicolette Michael Amundsen, BS – University of Illinois-Urbana Champaign
Paul Selvin, PhD – University of Illinois-Urbana Champaign
Hyun Joon Kong, PhD – University of Illinois-Urbana Champaign
Hee Jung Chung, PhD – University of Illinois-Urbana Champaign
Rationale: Alzheimer disease (AD) is the most common form of dementia characterized by amyloid-b plaques and neurofibrillary tangles composed of hyperphosphorylated tau (pTau). Seizures have also emerged as a prevalent feature of AD and are associated with accelerated cognitive decline and APOE4, the major genetic risk factor of AD. In this study, we investigated the age- and sex-dependent effects of APOE4 and phosphorylated tau burden on seizure susceptibility and the mechanism by which APOE4 increases seizures.
Methods: Homozygous male and female human APOE targeted replacement mice, hemizygous PS19 tauopathy model mice, and the double mutant APOE/PS19 mice received a single intraperitoneal injection of either saline or kainic acid (KA, 15 or 30 mg/kg) at 2-3 and 5-7 months of age, after which behavioral seizures were scored using a modified Racine’s scale. Following bioinformatic analysis, western blotting of APOE hippocampal lysate was performed to examine the protein levels of our top gene hits. A subset of APOE4 and APOE4/PS19 mice were treated with terazosin (1 mg/kg) with/out sodium oxamate (1 g/kg) prior to KA injections.
Results: APOE4 mice showed increased seizure severity and seizure-induced death at 5-7 but not 2-3 months of age compared to APOE3 mice regardless of sex. Although KA induced similar seizure severity in PS19 and control mice, APOE4/PS19 females displayed higher seizure susceptibility compared to PS19 females. Interestingly, APOE4 mice showed decreased hippocampal levels of sodium/potassium Na⁺/K⁺- ATPase and key glycolytic enzymes as well as ATP levels compared to APOE3 mice. Inhibition of Na⁺/K⁺- ATPase increased hippocampal activity whereas pharmacologically enhancing glucose oxidation decreased seizure severity in APOE4 and APOE4/PS19 mice.
Conclusions: APOE4 induced an age-dependent increase in seizure susceptibility, along with reduced hippocampal expression of Na⁺/K⁺-ATPase and glycolytic enzymes, as well as decreased ATP levels. These findings suggest that disruption of the electrochemical gradient and impaired ATP production contribute to the APOE4-associated rise in seizure susceptibility.
Funding: This research was supported by the National Institutes of Health under awards R01NS126584 (H.J.C), R01 NS10019, RF1 AG083625 (H.J.C. and P.R.S.), and the Alzheimer’s Association grant (2019-AARG-NTF-644507 to H.J.C. and H.K.).
Basic Mechanisms