在Alzheimer病(AD)病人早期即存在脑内Sigma受体表达的下降，而Sigma受体激动剂能够明显减低AD导致的认知功能障碍。但目前对Sigma受体表达的调控及其与AD发生发展的关系仍不明确。我们的预实验结果提示，Aβ作为AD的主要致病物质，可以明显减低动物脑内Sigma受体的表达，但其作用机制还有待进一步探讨。为此，我们提出假说，Aβ可能通过增加钙离子内流而增加蛋白激酶DLK、Calcineurin的活性以及增加内质网蛋白Bip与 E3连接酶HRD-1的相互作用，从基因转录和蛋白降解方面下调Sigma受体的表达。为了验证这一假说，我们将在体外神经元模型和在体AD动物模型中，运用多种分子生物学技术，从分子、细胞、以及动物整体水平探讨Aβ对Sigma受体表达的调节作用机制。将从Aβ对Sigma受体表达的调节这一视点为阐释AD的发病机制提供新的思路，为AD的干预提供新的靶点。

The expression of Sigma receptor decreased dramatically even the the early stages of Alzheimer disease (AD), while sigma receptor agonist can significantly reduce the cognitive dysfunction in AD. However, the regulation of Sigma receptor expression and its relationship with AD remains unclear. Our experimental results suggest that Aβ as the main cause of AD, significantly reduces the Sigma receptor expression in animal brain, but its mechanism remains to be further explored. To this end, we propose the hypothesis, Aβ through calcium influx may increase the activity of protein kinase DLK and Calcineurin as well as the interaction between endoplasmic reticulum protein BiP and E3 ligase enzyme HRD-1. Thus, downregulate gene transcription and promote protein degradation of Sigma receptor. By employing Aβ interfering neurons in vitro and AD animal model in vivo, we will explore the mechanism by which Aβ downregulate the expression of Sigma receptor. This will help to explain the pathogenesis of AD from the aspect of Aβ regulated Sigma receptor expression and provide a new target for the intervention of AD.