APOE-Glia Crosstalk in Epilepsy: Mechanisms, Controversies, and Therapeutic Perspectives

Temporal lobe epilepsy (TLE) is a common type of focal epilepsy that is prone to developing into drug-resistant epilepsy (DRE). It is often accompanied by neuroinflammation, lipid metabolism disorders, and cognitive impairment. However, its underlying pathological mechanisms remain incompletely understood. As a pivotal lipid transporter in the central nervous system (CNS), apolipoprotein E (APOE) exists as three isoforms: APOE ε2, ε3 and ε4. The APOE ε4 allele represents a high-risk genetic variant for neurological disorders. More and more evidences suggest that APOE gene polymorphisms may modulate seizure susceptibility, severity, and clinical outcomes, indicating that APOE plays an important role in the pathogenesis of epilepsy. Glial homeostasis disruption acts as a core driver of epilepsy. Notably, following epileptic injury, APOE expression significantly increases, with a dynamic shift in its cellular source. Activated microglia replace astrocytes as the main source of APOE. APOE may mediate interactions between microglia and astrocytes, promoting the formation of lipid-accumulating reactive astrocytes (LARAs), and thereby driving a vicious cycle involving inflammation, lipid metabolism disruption, and neuronal excitotoxicity, contributing to hippocampal sclerosis (HS) and worsening of DRE. Although significant progress has been made, the mechanistic understanding underlying APOE-glia crosstalk in epileptogenesis remains incomplete, and the clinical translation potential of targeting APOE requires further validation. This review summarizes current knowledge on the role of APOE in epilepsy, with a focus on its regulatory effects on glial cell function, providing insights into the pathogenesis of refractory epilepsy and informing potential therapeutic strategies.