Tau-dependent cognitive deficits in alpha-synucleinopathies

总结/摘要： 帕金森病（Parkinson's disease，PD）是第二常见的迟发性神经退行性疾病 在所有神经系统疾病中死亡率的相对增加最大。PD是 传统上被认为是一种运动障碍，其特征是多巴胺能神经元的丧失， SNpc，以及称为Lewy小体和Lewy小体的纤维状细胞质内含物的存在。 神经突然而，在病理学的推动下，对PD的更全球化的视角正在发展 以及基底神经节以外的临床表现特别是，大多数PD患者 符合轻度认知功能障碍的二级诊断标准， 是疾病发病率和死亡率的重要因素。新出现的观点是， α-突触核蛋白（αS）的异常可能是PD运动和非运动症状的原因 路易体痴呆症（Dementia with Lewy Bodies，DLB）值得注意的是，我们最近发现异常的αS可以 通过微管相关蛋白tau（MAPT）在体外和体内引起突触后缺陷 依赖机制在本提案中，我们将直接确定以下假设：1） 致病性αS种类产生认知下降tau依赖性突触后机制， 2)外源性αS纤维/寡聚体引起的MAP依赖性突触后缺陷有助于 散发性PD和DLB的认知缺陷。确定认知的机械基础 在α-突触核蛋白病的缺陷，我们提出以下目标：1）确定是否需要tau蛋白 对于αS依赖性突触和认知缺陷; 2）确定突变的α S依赖性AMPAR是否 缺陷和记忆缺陷是由多个途径引起的; 3）确定海马是否 αS病理学和体树突tau蛋白定位错误与PD痴呆相关; 4） 确定外源性致病性αS是否诱导突触前和/或突触后缺陷;以及5） 确定致病性αS是否诱导tau依赖性突触可塑性和记忆缺陷。 方式

Summary/Abstract: Parkinson’s disease (PD) is the second most common late-onset neurodegenerative disease with the largest relative increase in mortality rates among all neurological disorders. PD is traditionally considered a motor disorder, characterized by the loss of dopaminergic neurons of the SNpc, and the presence of fibrillar cytoplasmic inclusions called Lewy bodies and Lewy neurites. However, a more global perspective on the PD is developing, motivated by pathological and clinical findings that extend beyond the basal ganglia. In particular, the majority of PD patients meet criteria for a secondary diagnosis of mild cognitive impairment that progresses dementia, a significant contributor to disease morbidity and mortality. The emerging view is that the abnormalities in α-synuclein (αS) may be responsible for motor and non-motor symptoms in PD and Dementia with Lewy Bodies (DLB). Significantly, we recently found that abnormal αS can cause post-synaptic deficits in vitro and in vivo via a microtubule associated protein tau (MAPT) dependent mechanism. In this proposal, we will directly determine the following hypothesis: 1) Pathogenic αS species produce cognitive decline tau-dependent post-synaptic mechanisms and 2) MAPT-dependent postsynaptic deficits caused by exogenous αS fibrils/oligomers contribute to cognitive deficits in sporadic PD and DLB. To determine the mechanistic basis for cognitive deficits in α-synucleinopathy, we propose following aims: 1) Determine whether tau is required for αS dependent synaptic and cognitive deficits; 2) Determine if mutant αS-dependent AMPAR deficits and memory deficits are caused by multiple pathways; 3) Determine whether hippocampal αS pathology and somatodendritic tau mislocalization correlates with dementia in PD; 4) Determine if exogenous pathogenic αS induces pre- and/or post-synaptic deficits; and 5) Determine if pathogenic αS induces defects in synaptic plasticity and memory in a tau dependent manner.