Alpha-synuclein aggregate induced synapse loss is a pathological event contributing to Lewy body dementias

α-突触核蛋白聚集诱导的突触丧失是导致路易体痴呆的病理事件

• 批准号: 10204271
• 负责人: Laura A. Volpicelli-Daley
• 金额: $ 76.88万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10204271
• 关键词: Age; Alzheimer' s Disease; Antibodies; Antigens; Area; Attention; Binding; Biological Assay; Brain; Cessation of life; Cognition; Cognition Disorders; Cognitive; Communication; Data; Defect; Dendritic Spines; Dependovirus; Event; Executive Dysfunction; Functional disorder; Future; Goals; Human; Image; Impaired cognition; In Vitro; Injections; Institutionalization; Knockout Mice; Label; Lewy Body Dementia; Lewy body pathology; Ligation; Measures; Microscopy; Microtubules; Modeling; Molecular; Molecular Conformation; Motor; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Parkinson' s Dementia; Pathologic; Pathology; Patients; Performance; Prefrontal Cortex; Presynaptic Terminals; Proteins; Research Personnel; Resolution; Sampling; Scientist; Signal Transduction; Structure; Synapses; Synaptic Cleft; Techniques; Testing; Time; Tissues; Toxic effect; Visuospatial; Width; alpha synuclein; cognitive change; cognitive task; density; experimental study; human subject; human tissue; in vivo; mortality; mouse model; nanoscale; neuron loss; new therapeutic target; novel; novel therapeutics; postsynaptic; prevent; protein aggregation; spatial relationship; synucleinopathy; tau Proteins; tau aggregation; tau interaction

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), collectively called Lewy body dementias (LBDs), are the second most common cognitive disorder after Alzheimer's disease (AD). Patients with LBDs suffer from PD-related motor defects and deficits in executive dysfunction, attention, and visuospatial processing, reflective of cortical dysfunction. Pathologically, LBDs are characterized by abundant cortical aggregates of α-synuclein (α-syn) called Lewy pathology (LP). The cognitive impairments in LBDs are the main cause for institutionalization and mortality. There are no treatments that halt the progression of LBDs. Outstanding scientists in the field of LBDs have provided data supporting that the combination of Lewy pathology and aggregates of tau, similar to those found in Alzheimer's disease, together are strongly associated with reduced performance on cognitive tasks. In Alzheimer's disease, loss of synapses is the strongest correlate of cognitive decline. Recently evidence has emerged from several labs, including ours,that synapse loss in the cortex may contribute to cognitive changes in LBDs. We propose that the presence of both alpha-synuclein and tau aggregates at the synapse synergistically contributes to synapse degeneration in LBDs. We propose the interaction of α-syn and tau at the presynaptic terminal induces synapse degeneration. This proposal will combine the expertise of multiple investigators to test whether 1) the interaction of alpha- synuclein and tau facilitates synapse degeneration and 2) whether presynaptic terminals with small aggregates of both alpha-synuclein and tau show enhanced degeneration in the prefrontal cortex of patients that suffered from Lewy body dementias. We will use novel antibodies that selectively detect oligomeric and pathologic conformation of alpha-synuclein and tau. We will use a novel super-resolution technique called Expansion Microscopy (ExM) that can rapidly and quantitatively provide nanoscale resolution of synapses. We will also use a novel antibody multiplexing technique that can amplify low-abundance synaptic signals and allow imaging of >5 proteins at once. The results of this proposal will move the field of LBDs forward by 1) beginning to elucidate the mechanisms that contribute to synapse loss and cognitive changes in LBDs, and 2) identify if targeting the alpha-synuclein/tau interaction prevents synapse loss and cognitive decline.

路易体痴呆（DLB）和帕金森病痴呆（PDD），统称为路易体 痴呆（LBD）是仅次于阿尔茨海默病（AD）的第二种最常见的认知障碍。患者 患有LBD的人患有PD相关的运动缺陷和执行功能障碍、注意力和智力缺陷 视觉空间处理反映了皮质功能障碍在病理学上，LBD的特征是大量的 α-突触核蛋白（α-syn）的皮质聚集，称为Lewy病理（LP）。LBD的认知障碍是 这是导致住院和死亡的主要原因。没有治疗方法可以阻止LBD的进展。 LBD领域的杰出科学家提供了支持Lewy 病理学和tau的聚集，类似于阿尔茨海默病中发现的那些，一起强烈地 与认知任务的表现下降有关。在阿尔茨海默病中，突触的丧失是 认知能力下降的最强关联。最近，包括我们在内的几个实验室都有证据表明， 皮质突触丢失可能导致LBD的认知变化。我们建议，双方的存在 突触处的α-突触核蛋白和tau聚集体协同地促成突触变性， LBD。我们认为α-syn和tau在突触前末梢的相互作用导致突触变性。 这项提案将联合收割机的专业知识，多个调查，以测试是否1）相互作用的α- 突触核蛋白和tau蛋白促进突触变性和2）是否突触前终末与小聚集体 研究人员发现，在患有阿尔茨海默病的患者中， 路易体失智症我们将使用新的抗体，选择性地检测寡聚和病理性 α-突触核蛋白和tau的构象。我们将使用一种新的超分辨率技术， 显微镜（ExM）可以快速和定量地提供突触的纳米级分辨率。我们还将 使用一种新的抗体多重技术，可以放大低丰度突触信号， 一次成像>5个蛋白质。这一提议的结果将推动LBD领域的发展， 阐明导致LBD中突触丢失和认知变化的机制，以及2）确定是否 靶向α-突触核蛋白/tau相互作用防止突触丧失和认知衰退。

项目成果

Cellular and subcellular localization of Rab10 and phospho-T73 Rab10 in the mouse and human brain.

• DOI: 10.1186/s40478-023-01704-9
• 发表时间: 2023-12-18
• 期刊: Acta neuropathologica communications
• 影响因子: 7.1