Tau-dependent cognitive deficits in alpha-synucleinopathies

α-突触核蛋白病中 Tau 依赖性认知缺陷

• 批准号: 10112975
• 负责人: Alfonso Araque
• 金额: $ 55.08万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-15 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10112975
• 关键词: Acute; Animal Model; Basal Ganglia; Behavioral; Biological; Biology; Cell Culture Techniques; Cells; Clinical; Cognitive deficits; Cytoplasmic Inclusion; Defect; Dementia; Dementia with Lewy Bodies; Diagnosis; Disease; Electrophysiology (science); Exhibits; Functional disorder; Future; Hippocampus (Brain); Human; Impaired cognition; In Vitro; Knockout Mice; Lead; Lewy Bodies; Lewy neurites; Long-Term Potentiation; MAPT gene; Mediating; Memory; Memory impairment; Morbidity - disease rate; Motor; Mus; Neurodegenerative Disorders; Neurons; Parkinson Disease; Parkinson' s Dementia; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; PrP; Preparation; Slice; Synapses; Synaptic plasticity; Tissues; alpha synuclein; cohort; disability; dopaminergic neuron; effective therapy; in vivo; mild cognitive impairment; mortality; motor disorder; mouse model; mutant; nervous system disorder; non-motor symptom; postsynaptic; pre-formed fibril; synucleinopathy; tau Proteins; tau aggregation; tau expression; tau phosphorylation; therapy development

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.

摘要/摘要： 帕金森病 (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，死亡率的相对增幅最大。 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，以及称为路易体和路易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。 以及超出基底神经节的临床发现。尤其是大多数PD患者 符合轻度认知障碍进展为痴呆的二次诊断标准， 是疾病发病率和死亡率的重要因素。新兴的观点是， α-突触核蛋白 (αS) 异常可能是帕金森病运动和非运动症状的原因 和路易体痴呆症（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 物种会产生认知能力下降 tau 依赖性突触后机制 2）由外源性αS原纤维/寡聚物引起的MAPT依赖性突触后缺陷有助于 散发性 PD 和 DLB 的认知缺陷。确定认知的机制基础 针对 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 用于 αS 依赖性突触和认知缺陷； 2) 确定是否突变αS依赖AMPAR 缺陷和记忆缺陷是由多种途径引起的； 3）判断是否海马 αS 病理学和体细胞树突 tau 蛋白错位与 PD 痴呆相关； 4） 确定外源性致病性 αS 是否会诱导突触前和/或突触后缺陷；和 5) 确定致病性 αS 是否会导致 tau 依赖型突触可塑性和记忆缺陷 方式。