轻度认知功能障碍(MCI)中铁代谢异常对BACE1酶切位点选择的影响及机制研究

轻度认知功能障碍患者(MCI)是发生痴呆的高危人群，识别MCI和研究其发生机制和干预措施，有助于发现最佳干预时机。我们前期临床研究表明贫血、铁蛋白等铁代谢异常相关指标和脑血管疾病预后及认知功能障碍有潜在联系；而脑内铁代谢异常、铁死亡等已证实在痴呆的发病机理中起了重要作用。BACE1是APP酶切和Aβ生成过程的限速酶，申请人研究表明外部因素可以通过改变BACE1在APP蛋白酶切位点的改变促进Aβ生成和痴呆的发生。本研究假设，铁代谢异常通过改变BACE1分泌酶在APP蛋白主要酶切位点的选择，影响Aβ的产生，进而促进认知功能障碍的发生。我们拟临床、细胞及动物研究，从临床上验证铁代谢异常对认知障碍的诊断价值，从细胞动物模型上明确铁代谢异常对BACE1活性及酶切位点改变的作用和机制，并探讨金属螯合BACE1抑制剂干预的作用，为MCI的诊断及干预提供新的证据。

Mild cognitive impairment (MCI) is a transitional stage between normal aging and dementia. Identification of MCI and its underlying pathologic mechanisms can help find target for better use of therapeutic interventions. Our previous clinical study showed that iron metabolism markers such as anemia and ferritin are associated with cognitive dysfunction. Moreover, it has been confirmed that abnormal iron metabolism and ferroptosis in the brain play a key role in the dementia pathology. β-site APP cleaving enzyme 1 (BACE1) is a rate limiting enzyme for amyloid β precursor protein (APP) processing and amyloid β protein (Aβ) production. We found that some external factors could regulate BACE1 cleavage site selection for APP protein, resulting in higher Aβ production and dementia progression. Therefore, in this study, we will explore the diagnostic value of abnormal iron metabolism for cognitive dysfunction in clinical, pathologic and molecular level. Besides, we will explore the effect of abnormal iron metabolism on BACE1 activity and cleavage site selection by using metal chelating BACE1 inhibitors. Our study will provide new evidence for the underlying mechanism in MCI and promising intervention in the future.