抗APP铜离子结合域自身抗体在阿尔茨海默病发生发展中的作用和机制研究

The metabolic dysregulation of amyloid precursor protein (APP) leads to the overproduction of amyloid-beta (Aβ) and the development of Alzheimer’s disease (AD). The accumulation of copper in the brain contributes to the pathogenesis of AD. The N-terminal sequence of APP contains the copper binding domain (CuBD). The binding of copper to CuBD is suggested to increase the APP dimerization and Aβ production. The applicant previously found that anti-CuBD autoantibodies exist ubiquitously in human blood, and the levels of anti-CuBD autoantibodies are significantly decreased in AD patients. Moreover, the levels of serum anti-CuBD autoantibodies are positively correlated with the cognitive status, but negatively correlated with the Aβ deposition burden and the disease progression speed. Therefore, we raise our hypothesis that the anti-CuBD autoantibodies may bind to APP and mask the binding site of copper with APP, thus inhibiting the effects of copper in the metabolic dysregulation of APP. The present project aims to 1) investigate the levels of anti-CuBD autoantibodies in AD patients and discuss the diagnostic value of anti-CuBD autoantibodies; 2) reveal the role of anti-CuBD autoantibodies in the metabolism of APP; 3) investigate the therapeutic effects of anti-CuBD autoantibodies for AD. This project is of significance for revealing the novel regulatory mechanism of APP metabolism and find potential therapeutic target for AD.

Aβ前体蛋白（APP）异常代谢导致Aβ过度产生是阿尔茨海默病（AD）发生的重要因素，但其代谢的调控机制不清。过去发现脑内铜离子聚集促进AD发生，铜离子与APP氨基端铜离子结合域（CuBD）结合，导致Aβ过度产生，提示铜离子具有APP代谢调控作用。申请人前期发现：人体存在抗CuBD自身抗体，AD患者血液中该抗体水平降低，且与认知障碍、Aβ沉积及疾病进展显著相关。为此我们提出假说：天然抗CuBD自身抗体是APP代谢的生理性调控因素，该抗体通过封闭CuBD，抑制铜离子对APP代谢的影响，从而减少Aβ产生；抗CuBD自身抗体水平降低可能促进AD发生发展。本研究拟首先探讨AD患者体内抗CuBD自身抗体水平的变化及其临床意义；进一步探讨抗CuBD自身抗体对APP代谢的调控作用和机制；最后探讨抗CuBD自身抗体在AD防治方面的潜在作用。本项目对于揭示APP调控新机制，寻找AD防治靶点具有重要意义。