Toward a unified therapeutics approach targeting putative amyloid-β oligomer receptors

Cognitive decline in Alzheimer’s disease (AD) is associated with synaptic loss (1) and network dysfunction (2). The mechanisms involved are not fully understood; however, recent evidence indicate that the neurotoxicity of amyloid-β (Aβ) oligomers is mediated by interactions with synaptic receptors (3). In PNAS, Fu et al. demonstrate that soluble Aβ oligomers trigger synaptic loss and dysfunction via activation of erythropoietin-producing hepatocellular A4 receptor (EphA4) (4). Remarkably, blockade of EphA4 reversed the functional deficits in the hippocampus in animal models of AD. Moreover, based on molecular docking studies, they identify rhynchophylline as a novel EphA4 inhibitor that, following oral administration, rescued the Aβ oligomer-induced deficits in neurotransmission in amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice. In agreement with these findings, a recent study by Vargas et al. showed that Eph4 activation via c-Abl mediates the synaptic damage triggered by Aβ oligomers (5). Together, these studies point to EphA4 as a novel mediator of AD-associated synaptic dysfunction and support the notion that Aβ oligomer receptors might be viable therapeutic targets for this disease.