EphA4 regulates Aβ production via BACE1 expression in neurons

细胞生物学 生产(经济) 表达式(计算机科学) 神经科学 计算生物学 业务 生物 计算机科学 宏观经济学 经济 程序设计语言
作者
K. Tamura,Yung‐Wen Chiu,Azusa Shiohara,Yukiko Hori,Taisuke Tomita
出处
期刊:The FASEB Journal [Wiley]
卷期号:34 (12): 16383-16396 被引量:9
标识
DOI:10.1096/fj.202001510r
摘要

Several lines of evidence suggest that the aggregation and deposition of amyloid-β peptide (Aβ) 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 Aβ 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 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. Moreover, 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. Our results indicate a novel mechanism of Aβ regulation by EphA4, which is involved in AD pathogenesis.
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