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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. [ABSTRACT FROM AUTHOR]

Ephs form the largest family of receptor tyrosine kinases. They interact with the membrane-bound ligands - ephrins - to control crucial aspects of brain development. EphA4 is the most prominent member of the family in terms of versatility and ability to bind most ephrin ligands. EphA4 regulates brain development by modulating neuronal migration and connectivity. In the present study, we address the involvement of EphA4 in patterning the primary visual cortex (V1) of the marmoset monkey by characterizing the cellular expression profile of EphA4 from late embryonic stages to adulthood. We identified continuous expression on neurons in the cortical plate and mature neocortical layers, similar to that described in the mouse, excluding a role for EphA4 in the formation of borders between visual areas in the marmoset neocortex. In addition to neurons, we also report expression of EphA4 on glial populations, including radial glia and astrocytes. In contrast to what is seen in the mouse, EphA4 expression on astrocytes persists in the adult marmoset V1, including around blood vessels and in the white matter. Robust expression by glial populations, which retain neurogenic properties in the postnatal marmoset, indicates that EphA4 may have acquired additional roles during evolution, with important implications for the benefits of EphA4-blocking therapies following brain injury. [ABSTRACT FROM AUTHOR]

Spinal cord injury often leads to permanent incapacity because long axons cannot regenerate in the CNS. Eph receptors inhibit axon extension through an effect on the actin cytoskeleton. We have previously reported that after injury EphA4 appears at high levels in stumps of corticospinal axons, while a cognate ligand, ephrinB2, is upregulated at the lesion site so as to confine the injured axons. In this study we have infused lesioned spinal cords with a peptide antagonist of EphA4. In treated animals the retrograde degeneration that normally follows corticospinal tract injury is absent. Rather, corticospinal tract axons sprout up to and into the lesion centre. In a behavioural test of corticospinal tract function, peptide treatment substantially improved recovery relative to controls. These results suggest that blocking EphA4 is likely to contribute to a future successful clinical treatment for spinal cord injury. [ABSTRACT FROM AUTHOR]

We have examined the expression of Eph receptors and their ephrin ligands in adult rat spinal cord before and after lesion. Neurons in adult motor cortex express EphA4 mRNA, but the protein is undetectable in uninjured corticospinal tract. In contrast, after dorsal column hemisection EphA4 protein accumulates in proximal axon stumps. One of the ligands for EphA4, ephrinB2, is normally present in the grey matter flanking the corticospinal tract but after injury is markedly up-regulated in astrocytes in the glial scar. The result is that, after a lesion, corticospinal tract axons bear high levels of EphA4 and are surrounded to front and sides by a continuous basket of cognate inhibitory ephrin ligand. We suggest that a combination of EphA4 accumulation in the injured axons and up-regulation of ephrinB2 in the surrounding astrocytes leads to retraction of corticospinal axons and inhibition of their regeneration in the weeks after a spinal lesion. [ABSTRACT FROM AUTHOR]

Abstract The expression of EphB1 and B2 receptors and ephrins-B1, -B2 and -B3 in the retina and superior colliculus of the wallaby (Macropus eugenii ) was examined during the development of the retinocollicular projection, using reverse transcription–polymerase chain reaction and immunohistochemistry. There was an early transient differential expression of EphB2 that was higher in ventral retina and restricted to the outer neuroblast layer, whereas a high ventral to low dorsal gradient of ephrin-B2 expression occurred there throughout the study period. However, there was no dorsoventral gradient of receptors or ligands in retinal ganglion cells or a mediolateral gradient of ephrins in the colliculus. These findings suggest a limited role for these molecules in topographic mapping across the mediolateral colliculus in the wallaby. Early in retinal development there is a complementary pattern of expression of ephrin-B1 and -B2 in the outer neuroblast layer that overlaps with expression of EphB2. Ganglion and amacrine cells also express EphB2. As development proceeds subpopulations of putative horizontal and bipolar cells, also expressing EphB2, come to reside in the inner nuclear layer and ephrin-B1 is expressed throughout the outer nuclear layer. At the same time cells expressing ephrin-B2, and subpopulations of horizontal and bipolar cells come to reside in the inner nuclear layer and there is a corresponding decrease in ephrin-B2 expression in the outer nuclear layer. This pattern of coexpression of receptors and ligands suggests a role for them in cell migration and maintenance of laminar boundaries. [ABSTRACT FROM AUTHOR]