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

路易体痴呆(DLB)和帕金森病痴呆(PDD)统称为路易体 痴呆症(LBDS)是仅次于阿尔茨海默病(AD)的第二大认知障碍。病人 LBDS患者患有帕金森病相关的运动缺陷和执行功能障碍，注意力和 视觉空间处理，反映皮质功能障碍。从病理上讲，LBD的特点是 α-突触核蛋白的皮质聚集体(α-SYN)称为路易氏病理(Lp)。LBD患者的认知障碍是 这是制度化和死亡率的主要原因。目前还没有任何治疗方法可以阻止LBD的进展。 LBDS领域的杰出科学家已经提供了数据，支持刘易斯的组合 与阿尔茨海默病中发现的类似，tau的病理和聚集在一起是强烈的 与认知任务的表现下降有关。在阿尔茨海默病中，突触的丢失是 与认知能力下降的相关性最强。最近，包括我们在内的几个实验室都有证据表明 大脑皮层的突触缺失可能会导致LBDS的认知变化。我们建议，两者的存在 突触处的α-突触核蛋白和tau聚集体协同作用导致突触变性。 LBDS。我们认为α-syn和tau在突触前终末的相互作用导致突触变性。 这项提议将结合多个研究人员的专业知识来测试1)阿尔法- 突触核蛋白和tau促进突触变性；2)突触前终末是否有小集合体 α-突触核蛋白和tau蛋白均显示患者前额叶皮质变性增强。 来自路易身体痴呆症。我们将使用新型抗体选择性地检测寡聚体和病理 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，称为扩展 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路传输技术，可以放大低丰度突触信号，并允许 一次成像&gt；5蛋白质。这项提案的结果将推动LBD领域从1)开始 为了阐明导致LBDS突触丢失和认知改变的机制，以及2)确定 以α-突触核蛋白/tau相互作用为靶点可以防止突触丢失和认知能力下降。

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.