A postnatal genetic ablation of EphA4 in the forebrain was established in the APPPS1 mouse model of AD, followed by a battery of cognitive tests at 9 months of age to investigate cognitive function upon EphA4 loss.
AβOs aberrantly activate EphA4 leading to dendritic spine elimination. c-Abl is activated in AβOs exposed neurons and in AD patient's brain, and the inhibition of activated c-Abl ameliorates cognitive deficits in AD mouse model.
As demonstrated in our combined computational and experimental approaches, repurposing of FDA-approved drugs to inhibit EphA4 may provide an alternative fast-track approach for identifying and developing new treatments for AD.
These results demonstrate a novel role for SORLA as a physiological and pathological EphA4 modulator, which attenuates synaptotoxic EphA4 activation and cognitive impairment associated with Aβ-induced neurodegeneration in AD.
In addition, EphA4 has been found to play a role in cancer biology as well as in the pathogenesis of several neurological disorders such as stroke, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and Alzheimer's disease.