APOE4 reduces hippocampal expression of phosphoglycerate kinase 1 and sodium potassium pump to enhance seizure susceptibility in mice

Alzheimer's disease (AD) is the leading cause of dementia, characterized by the deposition of amyloid-β plaques and neurofibrillary tangles composed of hyperphosphorylated tau. Seizures have also emerged as a prevalent clinical feature of AD and are associated with APOE4, the major genetic risk factor of AD. However, the mechanism by which APOE4 induces seizures and neuronal hyperexcitability is incompletely understood. We discovered that human APOE4 targeted replacement mice showed increased seizure severity and seizure-induced death at 5.5-7 but not 2-3 months of age compared to APOE3 mice using the kainic acid model of status epilepticus which preferentially arises from the hippocampus. While Tau burden alone did not alter seizure susceptibility in mice, APOE4 together with Tau burden enhanced seizure severity in female mice. Notably, APOE4 was associated with decreased hippocampal levels of sodium/potassium-ATPase, ATP-generating glycolytic enzymes, including phosphoglycerate kinase 1 (PGK1) and pyruvate kinase M, and ATP. While inhibition of Na⁺/K⁺- ATPase increased hippocampal neuronal activity, pharmacologically stimulating PGK1 with terazosin increased hippocampal ATP levels and decreased seizure severity in APOE4 but not APOE3 mice. Lastly, co-application of lactate dehydrogenase inhibitor sodium oxamate to prevent the conversion of pyruvate to lactate further enhanced hippocampal ATP levels and suppressed seizure severity in APOE4 mice. Together, these findings suggest that reductions in hippocampal expression of sodium/potassium-ATPase and glycolytic enzymes may underlie APOE4-associated hippocampal hyperexcitability, revealing a novel mechanistic insight. Our results also demonstrate potent anti-seizure effects of terazosin, supporting the possibility of repurposing this anti-hypertension drug to mitigate seizure comorbidity in AD.