生物金属离子对老年痴呆症关键酶γ分泌酶调控作用的研究

Alzheimer's disease (AD) is a high incidence disease and there are currently no good diagnostic methods and treatment. A major reason of it is that the occurrence of AD is still not known. The dimers of amyloid beta (Aβ) and the ratio of Aβ40 to Aβ42/43 are likely the features of AD in the early phase. All the Aβ peptides with different lengths are generated from the substrate APP-C100 by the enzyme γ-secretase. Biometals are closely related with to the pathological features of AD, which can affect the production of Aβ peptides, but the exact mechanism of it remains unclear. The proposed project aims to study the interaction between metal ions, Aβ, and γ-secretase, to discover the unknown molecular mechanism that underlying the metal ion's modulation to the production of Aβ peptides, and to clarify the specific roles of different metal ions in the AD pathological process. The preliminary studies have demonstrated that Cu2+ and Zn2+ can modulate γ-secretase's activity, affect Aβ's generation or the ratio of Aβ40 and Aβ42/43 through distinct mechanisms. Among that, Zn2+ has been showed to target the substrate and induces the dimers of APP-C100. This modulates the specificity of γ-secretase and subsequently leads to an increase of Aβ43 production. The study of this APP-C100 dimer and its small molecular specific binders may provide biomarkers and probe tools for early molecular diagnosis of AD.

老年痴呆症（AD）的发病率很高，目前没有很好的诊断方法和治疗措施，其主要原因是发病机制仍不明确。淀粉样蛋白Aβ二聚体以及Aβ40同Aβ42/43 比例的改变为AD起始阶段的主要特征。不同长短的Aβ多肽都是由γ分泌酶催化底物APP-C100而产生。生物金属离子（Cu2+、Zn2+等）同AD的病理特征密切相关，其可以影响Aβ产生，但具体机理仍不明确。本项目旨在研究金属离子、Aβ和γ分泌酶的相互作用关系，去发现金属离子调控Aβ产生的未知分子机理，并阐明不同金属离子在AD病理过程中的具体作用。前期研究结果发现，金属离子Cu2+和Zn2+可调控γ分泌酶活性，影响Aβ的产生或Aβ40与Aβ42/43的比例。其中Zn2+可通过诱导底物APP-C100产生二聚体，调节γ分泌酶的特异性而提高Aβ43产物的生成。通过研究诱导生成的APP二聚体和其小分子特异结合物，将可能为AD的早期分子诊断提供理论基础和工具。