RESUMO
Several lines of evidence suggest that the aggregation and deposition of amyloid-ß peptide (Aß) initiate the pathology of Alzheimer's 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 Aß production, remains unknown. Here, we performed several pharmacological and biological experiments both in vitro and in vivo and demonstrated that EphA4 is responsible for the regulation of Aß production. Pharmacological inhibition of EphA4 signaling and knockdown of Epha4 led to increased Aß levels accompanied by increased expression of ß-site APP cleaving enzyme 1 (BACE1), which is an enzyme responsible for Aß production. Moreover, EPHA4 overexpression and activation of EphA4 signaling via ephrin ligands decreased Aß levels. In particular, the sterile-alpha motif domain of EphA4 was necessary for the regulation of Aß production. Finally, EPHA4 mRNA levels were significantly reduced in the brains of AD patients, and negatively correlated with BACE1 mRNA levels. Our results indicate a novel mechanism of Aß regulation by EphA4, which is involved in AD pathogenesis.
