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: 10362640
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10362640
• 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： 帕金森氏病（PD）是第二个最常见的晚期神经退行性疾病 所有神经系统疾病中死亡率的相对增加最大。 PD是 传统上认为是一种运动障碍，其特征是失去多巴胺能神经元 SNPC，以及纤维状细胞质夹杂物的存在，称为Lewy Bodies和Lewy 神经。但是，对PD的更全球性观点正在发展，这是由病理学的动机 和临床发现超出了巴萨神经节。特别是大多数PD患者 符合痴呆症的轻度认知障碍次要诊断标准， 疾病发病率和死亡率的重要贡献。新兴的观点是 α-突触核蛋白（αs）的异常可能导致PD运动和非运动症状 和Lewy Bodies（DLB）的痴呆症。值得注意的是，我们最近发现异常α可以 导致突触后通过微管相关蛋白tau（MAPT）定义体外和体内 依赖机制。在此提案中，我们将直接确定以下假设：1） 致病性αs物种产生了认知下降tau依赖性后突触机制和 2）依赖MAPT的突触后定义是由外源性αS纤维/低聚物引起的 散发性PD和DLB的认知缺陷。确定认知的机械基础 α-突触核疾病的缺陷，我们提出以下目的：1）确定是否需要tau 对于αs依赖性合成和认知定义； 2）确定突变αS依赖性AMPAR是否 确定是否海马 αS病理学和体育症tau误差误差与PD中的痴呆相关。 4） 确定外源性致病性α是否诱导前和/或突触后定义； 5） 确定致病性αs是否在依赖性tau中引起突触可塑性和记忆力的缺陷 方式。

项目成果

Orally Bioavailable Prodrugs of ψ-GSH: A Potential Treatment for Alzheimer's Disease.

• DOI: 10.1021/acs.jmedchem.2c00779
• 发表时间: 2022-11-10
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Xie, Wei;Cao, Bin;Zhu, Haizhou;Raza, Abbas;Juckel, Nicholas;Xie, Jiashu;Jiang, Rongrong;Vince, Robert;Lee, Michael K.;More, Swati S.
• 通讯作者: More, Swati S.

γ-Glutamyl-Transpeptidase-Resistant Glutathione Analog Attenuates Progression of Alzheimer's Disease-like Pathology and Neurodegeneration in a Mouse Model.

• DOI: 10.3390/antiox10111796
• 发表时间: 2021-11-10
• 期刊: Antioxidants (Basel, Switzerland)
• 作者: Christopher Kwon YI;Xie W;Zhu H;Xie J;Shinn K;Juckel N;Vince R;More SS;Lee MK
• 通讯作者: Lee MK