Mechanistic and therapeutic implications of EphA-4 receptor tyrosine kinase in the pathogenesis of Alzheimer's disease

Erythropoietin-producing hepatoma (Eph) receptors belong to a family of tyrosine kinase receptors that plays a pivotal role in the development of the brain. Eph can be divided broadly into two groups, namely, EphA and EphB, comprising nine and five members, respectively. In recent years, the role of EphA-4 has become increasingly apparent in the onset of Alzheimer's disease (AD). Emerging evidence suggests that EphA-4 results in synaptic dysfunction, which in turn promotes the progression of AD. Moreover, pharmacological or genetic ablation of EphA-4 in the murine model of AD can alleviate the symptoms. The current review summarizes different pathways by which EphA-4 can influence pathogenesis. Since, majority of the studies had reported the protective effect of EphA-4 inhibition during AD, designing therapeutics based on decreasing its enzymatic activity might be necessary for introducing the novel interventions. Therefore, the review described peptide and nanobodies inhibitors of EphA-4 that exhibit the potential to modulate EphA-4 and could be used as lead molecules for the targeted therapy of AD.