AD是痴呆最常见类型。诸多研究结果提示钙超载是Aβ和tau蛋白诱导神经元变性和突触缺失的重要病理生理过程，Aβ通过影响NMDARs、VGCC及其它离子通道的活性和敏感性，使钙离子进入细胞内，出现钙超载，诱导tau蛋白过度磷酸化并改变突触可塑性，降低LTP，升高LTD，从而导致认知功能下降，因此提出控制钙超载可以作为修饰AD病程的关键位点。我们前期的研究已经证实TAT-CBD3能够在体外通过CaV2.2/NMDARs/NCX三条途径减少钙离子内流，抑制钙超载，起到神经保护作用。本项目选取3×Tg AD转基因小鼠模型为研究对象，拟应用分子生物学技术，构建表达NT4-6His-TAT-CBD3的rAAV，通过滴鼻法对AD小鼠进行治疗，并通过一系列实验对TAT-CBD3改善认知功能的作用及其机制进行深入研究，为新型钙离子拮抗剂TAT-CBD3成为AD早期治疗药物提供理论依据。

AD is the most common type of dementia. Numerous of studies indicated that calcium overload is the key process of pathophysiology in Aβ and tau induced neuronal degeneration and synapses deficiency. Aβ caused calcium influx,even calcium overload through affecting the activity and sensitivity of NMDARs, VGCC and other calcium channels, induced tau hyperphosphorylation and the changes of synapse plasticity, leading to LTP reduction and LTD elevation, thus, caused cognitive dysfunction. Hence, a viewpoint was proposed that calcium is the key target as modifying AD process. In our previous experiments, we have demonstrated TAT-CBD3 could decrease calcium influx in CaV2.2/NMDARs/NCX triple pathways in vitro, inhibit calcium overload, protect neurons from death. Our project chooses APP/PS1/Tau triple transgenic AD mice as research objects. We construct rAAV/NT4-TAT-6His-CBD3 with molecular biotechniques to treat the AD transgenic mice by intranasal administration. Then we lucubrate the effect and mechanism of treatment by animal behavior test, biochemical test, electrophysiological techniques and calcium imaging, providing fundamental basis for TAT-CBD3 to be a novel therapeutic drug of the early stage of AD.