EphA4 regulates Aβ production via BACE1 expression in neurons

Abstract BackgroundSeveral lines of evidence suggest that the aggregation and deposition of amyloid-β peptide (Aβ) initiate the pathology of Alzheimer disease (AD). Recently, a genome- wide association study demonstrated that a single-nucleotide polymorphism proximal to the EPHA4 gene, which encodes a receptor tyrosine kinase, is associated with AD risk. However, the molecular mechanism of EphA4 in the pathogenesis of AD, particularly in Aβ production, remains unknown.MethodsTo clarify the molecular regulatory mechanism of EphA4 in detail, we performed several pharmacological and biological experiments both in vitro and in vivo. In addition, we referred to two public RNAseq datasets to confirm the changes in EPHA4 mRNA expression levels in the brains of AD patients.ResultsWe demonstrated that EphA4 is responsible for the regulation of Aβ production. Pharmacological inhibition of EphA4 signaling and knockdown of Epha4 led to increased Aβ levels accompanied by increased expression of β-site APP cleaving enzyme 1 (BACE1), which is an enzyme responsible for Aβ production. On the other hand, EPHA4 overexpression and activation of EphA4 signaling via ephrin ligands decreased Aβ levels. In particular, the sterile-alpha motif domain of EphA4 was necessary for the regulation of Aβ production. Finally, EPHA4 mRNA levels were significantly reduced in the brains of AD patients, and negatively correlated with BACE1 mRNA levels.ConclusionsOur results indicate a novel mechanism of Aβ regulation by EphA4, which is involved in AD pathogenesis.