HO-1/APP/PSEN1阿尔茨海默病转基因小鼠模型的建立及应用

Disease model is very important for pathogenesis research and treatment of diseas. Now APP/PSEN/TAU triple-transgenic model is the best Alzheimer's disease model. Although APP/PSEN/TAU model can recapitulate the major neuropathological hallmarks of the disease, it is inconsistent with the fact because neurofibrillary tangles doesn't result fromTau mutation in Alzheimer's disease. Maybe the APP/PSEN/TAU triple-transgenic model is not good enough for pathogenesis research or medical development..It is reported that heme oxygenase 1(HO-1) is closely related to Alzheimer's disease. We created a HO-1 transgenic model by overexpressing mouse wild HO-1 gene. The HO-1 transgenic mice show some phenotypes of declined cognitive function, enhanced phosphorylated tau protein and A? oligomer, and destroyed neuron microtube. We also proved overexpression of HO-1 could improve tauopathy in vivo and in vitro. .In this research we plan to create a HO-1/APP/PSEN triple-transgenic model by replace tauP301L by HO-1 gene. The new disease model maybe not only recapitulate the major neuropathological hallmarks but also be consistent with Alzheimer's disease pathomechanism. And identified the Alzheimer's disease model from ethology, morphology and molecular level. In this program we will also study the function and mechanism of HO-1 in Alzheimer's disease using HO-1/APP/PSEN transgenic model.

建立真实模拟阿尔茨海默病(AD)的疾病模型对研究发病机制和治疗策略至关重要，目前APP/PSEN/TAU三转基因小鼠虽然能复制出AD所有病理标志，但AD神经缠结病理并非由tau基因突变引起，因此并不符合真实的病理发生机制。用此模型研究发病机制或开发药物，可能与实际不相符或者达不到预期疗效。.多项研究提示血红素加氧酶1（HO-1）与AD密切相关，我们通过建立HO-1单转基因小鼠发现HO-1过表达能够促进tau过度磷酸化导致tau病理，并对认知功能、A?寡聚化、神经突触和微管结构有显著影响。.本项目拟用HO-1替换tauP301L基因建立HO-1/APP/PSEN转基因小鼠，获得一种新的既能涵盖AD表型又符合AD病理发生机制的模型，并从行为学、形态学和分子水平对模型进行鉴定，同时应用该模型对HO-1在AD中的作用及机制开展研究。

本课题利用转基因技术建立了一种新的阿尔茨海默病动物模型，与现有的阿尔茨海默病模型相比，HO-1/APP/PSEN1三转基因小鼠既能涵盖阿尔茨海默病表型又符合阿尔茨海默病发病状态，可用于基因在体功能分析、疾病发病机制探讨、药物新靶点发现及临床前药效评价等研究，具有重要的科学意义和临床价值。此外，本课题对HO-1在阿尔茨海默病中的作用及机制进行了分析：揭示了HO-1促进tau蛋白磷酸化的作用机制；发现了HO-1上调能促进Aß和tau蛋白的寡聚化水平；证明了HO-1上调影响突触发育及相关机制。