EphA4, a transmembrane receptor protein, is part of the receptor tyrosine kinase (RTK) family. It binds to ligands like Ephrins and plays crucial roles in physiological and pathological states. In the central nervous system (CNS), it influences axonal and vascular guidance, and is involved in numerous signaling pathways related to neurodegenerative diseases [4]. Genetic models, such as KO mouse models, are valuable for studying its functions.

In motor neuron disease (MND), EphA4 activation is linked to motor neuron cell death, and its inhibition improves functional outcomes, though the underlying mechanism remains unclear [1]. In brain injury, EphA4 receptor tyrosine kinase restricts efferocytosis in resident microglia and peripheral-derived monocyte/macrophages via the ERK/Stat6/MERTK signaling pathway, and its loss improves functional outcome [2]. In Alzheimer's disease (AD), long-term exercise-induced exosomal miR-532-5p rescues blood-brain barrier function by downregulating EphA4 [3]. EphA4 also regulates Aβ production via BACE1 expression in neurons, with its mRNA levels reduced in AD patients [5]. In experimental glaucoma, EphA4/ephrinA3 reverse signaling induces Müller cell gliosis and production of pro-inflammatory cytokines, contributing to retinal ganglion cell death [6].

In summary, EphA4 is involved in multiple biological processes, especially in the CNS. Studies using KO/CKO mouse models have revealed its roles in diseases like MND, AD, and glaucoma, highlighting its potential as a therapeutic target for neurological disorders.