Cognitive Dysfunction in Transgenic Mouse Model of Alpha-Synucleinopathy

描述（由申请人提供）： 帕金森病（PD）是一种常见的迟发性进行性神经退行性疾病，其特征在于皮质下神经元群体的变性，包括黑质、峡部（SNpc）的多巴胺能神经元，以及在多个神经元群体中存在由α-突触核蛋白组成的细胞质内含物。虽然运动异常是PD最明显的特征，但非运动异常，如痴呆，是PD患者最衰弱的因素。因此，了解PD和其他α-突触核蛋白病中痴呆的神经病理学基础对于这些疾病的有效治疗干预至关重要。在这项提案中，我们的目标是了解认知功能障碍/痴呆的神经病理学基础，如PD和LBD的α-突触核蛋白病。人类研究将皮质边缘区中α-突触核蛋白病理学以及β-淀粉样蛋白病理学的存在与PD/LBD病例中的痴呆相关联。值得注意的是，我们在表达A53 T突变体α-Syn的转基因小鼠中观察到PD样认知缺陷。我们将确定A53 T转基因小鼠认知缺陷的神经病理学基础，并使用诱导型α-突触核蛋白转基因小鼠模型来探索α-突触核蛋白异常、神经变性和认知缺陷之间的因果关系。我们还将研究明显的淀粉样蛋白沉积如何与α-突触核蛋白异常相互作用，以加剧A53 T转基因小鼠的认知缺陷。最后，我们将测试环境暴露于PD相关化合物（如杀虫剂）是否会促进小鼠的α-突触核蛋白病理学和认知功能障碍。总体而言，这些研究将提供可能导致人类α-突触核蛋白病痴呆的潜在因素的体内实验测试。该结果将与人类α-突触核蛋白病的发病机制直接相关，并导致新的治疗方法，以减轻与PD和其他α-突触核蛋白病相关的非运动异常。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a common late onset progressive neurodegenerative disease characterized by degeneration of subcortical neuronal populations, including dopaminergic neurons of substantia nigra, pars compacta (SNpc), and presence of the cytoplasmic inclusions composed of alpha-synuclein in multiple neuronal populations. While the motoric abnormalities are most obvious feature of PD, non-motoric abnormalities, such as dementia, are the most debilitating factors for PD patients. Thus, understanding the neuropathological basis for dementia in PD and other alpha- synucleinopathies are essential for effective therapeutic intervention of these diseases. In this proposal, we aim to understand the neuropathological basis for cognitive dysfunction/dementia in alpha-synucleinopathies such as PD and LBD. Human studies correlate the presence of alpha- synuclein pathology, as well as beta-amyloid pathology, in cortical-limbic areas correlate with dementia in PD/LBD cases. Significantly, we observed PD-like cognitive deficits in transgenic mice expressing A53T mutant alpha-Syn. We will determine the neuropathological basis for cognitive deficit in the A53T transgenic mice and use inducible alpha-synuclein transgenic mouse model to explore the causal links between alpha-synuclein abnormalities, neurodegeneration, and cognitive deficits. We will also study how overt amyloid deposition interacts with alpha-synuclein abnormalities to exacerbate cognitive deficits in A53T transgenic mice. Finally, we will test whether environmental exposure to PD-relevant compounds, such as pesticides, promotes both alpha-synuclein pathology and cognitive dysfunction in mice. Overall, these studies will provide in vivo experimental tests of potential factors that could contribute to dementia in human alpha-synucleinopathies. The results will be directly relevant to the pathogenesis of human alpha-synucleinopathies and lead to new therapeutic approaches to alleviate non-motoric abnormalities associated with PD and other alpha-synucleinopathies.