Regulation of human tau expression and tauopathy by alpha-synuclein

项目摘要 混合性神经病变是包括阿尔茨海默氏症在内的痴呆临床综合征的最常见原因 疾病（AD）、路易体痴呆（LBD）和额颞叶痴呆（FTD）。开发新的结构和 条件敲除系以及转基因小鼠系，我们现在提出了一系列的遗传方法 旨在揭示联系α-突触核蛋白（αSyn）和tau生物学、病理学及其 与突触和认知功能的关系。利用来自独立团体的新证据 包括我们自己的，我们将测试中心假设，αSyn表达，独立于αSyn病理，可能 影响生物学tau和/或tau依赖性病理学。根据初步报告中的新发现， 结果，我们将i）检验αSyn选择性调节人类tau蛋白而不是小鼠tau蛋白的假设，ii）检验 预测编码αSyn的SNCA基因的组成性消融会导致tau病理学和tau诱导的 在tau蛋白病模型中的认知缺陷，iii）测试前脑中SNCA的条件性消融 兴奋性神经元在tau蛋白病模型中表现出tau蛋白病和tau蛋白诱导的认知缺陷， 提供了一个临床前原理验证，即靶向这种αSyn/tau偶联可能具有治疗益处 在FTD和LBD的背景下。

Project Summary Mixed neuropathologies are the most common cause of the clinical syndrome of dementia, including Alzheimer's disease (AD), Lewy body dementia (LBD) and frontotemporal dementia (FTD). Exploiting novel constitutive and conditional knockout lines as well as transgenic mouse lines, we now propose a series of genetic approaches designed to uncover key knowledge gaps linking alpha-synuclein (αSyn) and tau biology, pathologies and their relationships to synaptic and cognitive function. Leveraging emerging evidence from independent groups including our own, we will test the central hypothesis that αSyn expression, independent of αSyn pathology, may impact the biology tau and/or tau-dependent pathology. In the light of novel findings reported in the preliminary results, we will i) test the hypothesis that αSyn regulates human tau selectively, but not mouse tau, ii) test the prediction that constitutive ablation of the SNCA gene encoding αSyn alleviates tau pathology and tau-induced cognitive deficits in a model of tauopathy, iii) test the hypothesis that conditional ablation of SNCA in forebrain excitatory neurons alleviates tau pathology and tau-induced cognitive deficits in a model of tauopathy, thereby providing a preclinical proof-of-principle that targeting this αSyn/tau coupling might be therapeutically beneficial in the context of FTD and LBD.