Open Access
REVIEW
Region-Specific Astrocyte Endfeet Disruption as a Driver of Pyramidal Neuron Death after Ischemia-Reperfusion in the Hippocampus
JOONGBUM MOON1, JI HYEON AHN2, MOO-HO WON3,*
1 Department of Emergency Medicine, Kangwon National University Hospital, School of Medicine, Kangwon National University, Chuncheon, 24289, Republic of Korea
2 Department of Physical Therapy, College of Health Science, Youngsan University, Yangsan, 50510, Republic of Korea
3 Department of Emergency Medicine, School of Medicine, Kangwon National University, Chuncheon, 24341, Republic of Korea
* Corresponding Author: MOO-HO WON. Email: 
(This article belongs to the Special Issue: Cellular and Molecular Insights into Brain Ischemic Insults)
BIOCELL https://doi.org/10.32604/biocell.2025.072635
Received 31 August 2025; Accepted 15 November 2025; Published online 09 December 2025
Abstract
Ischemia-reperfusion (I/R) injury induces region-specific neuronal vulnerability within the hippocampus, with the cornu ammonis 1 (CA1) subfield particularly prone to delayed neuronal death. While intrinsic neuronal factors have been implicated, emerging evidence highlights the decisive contribution of astrocyte endfeet (AEF)—specialized perivascular structures that regulate ion and water homeostasis, glutamate clearance, and blood–brain barrier (BBB) stability. This review synthesizes structural and molecular alterations of AEF across the CA1–CA3 subfields following I/R and their correlation with neuronal fate. In CA1, AEF undergo early-onset swelling and detachment from the vascular basal lamina due to dysfunction of critical proteins such as aquaporin-4 (AQP4) and Kir4.1. These changes impair glutamate uptake, metabolic support, and potassium buffering, contributing to neuronal hyperexcitability and degeneration. In contrast, AEF in CA3 preserves polarity and functional coupling of AQP4 and Kir4.1, conferring regional resilience. At the signaling level, AEF disruption activates mitogen-activated protein kinase (MAPK)/c-Jun N-terminal kinase (JNK) pathways, promotes reactive oxygen species (ROS) accumulation, and induces inducible nitric oxide synthase (iNOS)-mediated inflammation, amplifying neurotoxicity. Furthermore, subfield-specific astrocytic transcriptional profiles modulate inflammatory responses and gliovascular interactions. By reframing AEF not as passive scaffolds but as active regulators of neuronal survival, this review provides novel insight into the astrocyte-dependent mechanisms of hippocampal vulnerability. Therapeutic strategies that preserve AEF structure and function may offer targeted protection against delayed neuronal death in ischemic brain injury.
Keywords
Astrocyte endfeet; hippocampus; ischemia-reperfusion injury; cornu ammonis 1 (CA1) vulnerability; delayed neuronal death; aquaporin-4; neuroinflammation; blood–brain barrier disruption
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