Novel Approaches to Understand the Pathogenesis and Treat Alzheimer's Disease

总体方案摘要/摘要 在这份题为《了解阿尔茨海默氏症发病机制和治疗阿尔茨海默氏症的新方法》的P01提案中 疾病“，我们试图更好地了解AD的异质性发病机制以及它是如何 受载脂蛋白E亚型的影响。载脂蛋白E4等位基因是晚发性高血压的主要遗传危险因素 AD与脑实质中淀粉样斑块沉积增加密切相关。 晚期血管淀粉样变性；以及增强的Aβ寡聚。APOE还参与了 突触可塑性、葡萄糖代谢、线粒体功能和血管完整性。目前，没有 关于不同的载脂蛋白E基因型如何在AD的发病机制中起作用的共识。相关研究 在本P01的三个项目中提出的将有助于阐明载脂蛋白E在AD中的这一复杂角色。因此，本P01为 解决一个意义重大的问题。我们提出了一种综合的、多学科的研究努力 将具有广泛成功协作历史的调查人员聚集在一起，他们拥有以下方面的专业知识 包括蛋白质组学、生物信息学、神经病理学、AD小鼠模型、免疫学、µMRI、 µPET、药物化学和生物标志物研究。在所有项目中，我们将应用我们的创新蛋白质组学 方法(在蛋白质组学/神经病理学核心B的辅助下)和使用常见的AD模型和 行为评估(在转基因/行为核心C的帮助下)，以及最先进的 使用SiMoA和P01 Investigator的BioMarker技术开发了µMRI方法，以确保协同 在所有P01研究中。生物统计和生物信息学核心将确保P01的科学严谨性 (核心D)。本P01的三个项目集中在载脂蛋白E(ApoE)亚型的不同作用上 参与：1)全面无偏蛋白质组学评估的AD斑块和血管淀粉样蛋白的发展 AD病理学谱(项目1)；2)针对Aβ/apoE相互作用的创新治疗方法 (项目2)；以及3)对我们针对异常构象的新型治疗性免疫调节的反应 (项目3)。我们的共同努力有望加强我们对不同影响的理解 载脂蛋白E亚型对AD发病机制的影响并加速发现有效的治疗方法 应对这些不同的角色。

OVERALL PROGRAM SUMMARY/ABSTRACT In this P01 proposal entitled: “Novel Approaches to Understand the Pathogenesis and Treat Alzheimer’s Disease”, we seek to gain a better understanding of the heterogeneous pathogenesis of AD and how it is influenced by apolipoprotein (apo) E isotypes. The apoE4 allele is the major genetic risk factor for late-onset AD and has been strongly associated with increased amyloid plaques deposition in brain parenchyma and advanced vascular amyloid pathology; as well as, enhanced Aβ oligomerization. ApoE is also involved in synaptic plasticity, glucose metabolism, mitochondrial function, and vascular integrity. Currently, there is no consensus on how different apoE genotypes contribute to the pathogenesis of AD. The interrelated studies proposed in the three projects of this P01 will help elucidate this complex role of apoE in AD. Hence this P01 is addressing an issue of great significance. We propose an integrated, multidisciplinary research endeavor that brings together investigators with an extensive history of successful collaboration, who have expertise in diverse areas including proteomics, bioinformatics, neuropathology, AD mouse models, immunology, µMRI, µPET, medicinal chemistry and biomarker studies. Across all projects we will apply our innovative proteomic methods (with the assistance of the proteomics/neuropathology Core B) and use of common AD models and behavioral assessments (with the assistance of the transgenic/behavioral Core C), along with state-of-the-art biomarker technology using SIMOA and P01 investigator developed µMRI methodologies, to ensure synergism across all P01 studies. Scientific rigor of the P01 will be ensure by the Biostatistics and Bioinformatics Core (Core D). The three projects of this P01 are focused on the differential role apolipoprotein E (apoE) isoforms play in: 1) AD plaque and vessel amyloid development as assessed by unbiased proteomics across the full spectrum of AD pathology (Project 1); 2) innovative therapeutic approaches that target the Aβ/apoE interaction (Project 2); and 3) responses to our novel therapeutic immunomodulation that targets abnormal conformation (Project 3). Combined our efforts are anticipated to enhance our understanding of the differential effects of apoE isotypes on AD pathogenesis and accelerate the discovery of effective therapeutic approaches that address these diverse roles.