Cognitive Dysfunction in Transgenic Mouse Model of Alpha-Synucleinopathy

α-突触核蛋白病转基因小鼠模型的认知功能障碍

• 批准号: 8331739
• 负责人: JAMES CLEARY
• 金额: --
• 依托单位: MINNEAPOLIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8331739
• 关键词: Accounting; Affect; Age; Aging; Alpha-Synuclein transgenic mouse; Amyloid; Amyloid deposition; Area; Brain; Chronic; Clinical; Cognitive; Cognitive deficits; Cytoplasmic Inclusion; Defect; Dementia; Deposition; Disease; Environmental Exposure; Environmental Risk Factor; Epidemiologic Studies; Etiology; Exhibits; Exposure to; Future; Genes; Histologic; Human; Impaired cognition; Laboratory Study; Lead; Lewy Body Dementia; Limbic System; Link; Military Personnel; Mitochondria; Modeling; Morbidity - disease rate; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Parkinson Disease; Parkinson' s Dementia; Pathogenesis; Pathology; Patients; Persons; Pesticides; Population; Prosencephalon; Proteins; Quality of life; Risk; Rodent; Role; Services; Substantia nigra structure; Symptoms; Testing; Therapeutic Intervention; Toxic Environmental Substances; Transgenic Mice; Ubiquitin; Veterans; Wild Type Mouse; alpha synuclein; base; beta amyloid pathology; cognitive function; dopaminergic neuron; environmental stressor; in vivo; mortality; mouse model; mutant; neuropathology; novel therapeutic intervention; pars compacta; pesticide exposure; pesticide poisoning; synucleinopathy; tau Proteins

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.

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，其特征是皮质下神经元群的变性，包括黑质、致密部（SNpc）的多巴胺能神经元，以及多个神经元群中存在由α-突触核蛋白组成的细胞质包涵体。虽然运动异常是帕金森病最明显的特征，但非运动异常，例如痴呆，是帕金森病患者最衰弱的因素。因此，了解PD痴呆和其他α-突触核蛋白病的神经病理学基础对于有效治疗干预这些疾病至关重要。在本提案中，我们旨在了解 PD 和 LBD 等 α-突触核蛋白病中认知功能障碍/痴呆的神经病理学基础。人体研究表明，皮质边缘区域中 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。值得注意的是，我们在表达 A53T 突变体 α-Syn 的转基因小鼠中观察到了类似 PD 的认知缺陷。我们将确定 A53T 转基因小鼠认知缺陷的神经病理学基础，并使用可诱导的 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，从而加剧 A53T 转基因小鼠的认知缺陷。最后，我们将测试环境中暴露于与 PD 相关的化合物（例如杀虫剂）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，这些研究将为可能导致人类α-突触核蛋白病痴呆的潜在因素提供体内实验测试。这些结果将与人类 α-突触核蛋白病的发病机制直接相关，并带来新的治疗方法来减轻与 PD 和其他 α-突触核蛋白病相关的非运动异常。