Evaluation of the neurovascular unit in the setting of pathogenesis and treatment of autosomal dominant Alzheimer disease

项目总结 这项提议的总体目标是支持候选人的职业发展和过渡到 一名独立研究人员。概述的培训计划将使申请者具备必要的技能 在丰富、跨学科和协作的环境中进行创新研究，促进 探索临床研究和试验的新途径。通过利用多模式成像技术和 分子和细胞蛋白质组学方法，候选人将加强已经强大的背景在 神经成像，学习和整合新的方法，以更全面地了解阿尔茨海默氏症 阿尔茨海默病(AD)的病因学和病理生理学，并有助于潜在的AD新疗法的成功。β- 淀粉样蛋白(Aβ)是AD进展过程中最早积累的生物标志物之一，是最具靶向性的因素 进行治疗干预。然而，其他组成部分，如血管和炎症/免疫变化， 也发生在AD进展过程中，增加了充分描述AD发病机制的复杂性。这个 神经血管单位(NVU)与AD的血管、免疫和Aβ变化的研究有关，因为它包括 神经元-星形胶质细胞信号转导和血脑屏障，在Aβ清除中起作用。与年龄相关的 晚发性AD(LOAD)的合并症很难与AD相关的改变区分开来 疾病的发展。这项提议旨在将年龄与疾病相关的变化与血管联系起来。 和免疫成分，并了解这些疾病相关变化对抗Aβ治疗的影响 结果。这将通过研究常染色体显性AD(ADAD)的这些因素来实现，ADAD是一种罕见的形式 阿尔茨海默病的遗传病因已知，且症状起病年龄较早。先前利用蛋白质组学进行的研究 评估NVU中断的方法和成像侧重于负载人群。目标1的目标是 这项建议是评估已知ADAD相关突变携带者和有标记的NVU的变化 并生成NVU变化的蛋白质组学图谱。目标2的目标是定义 相对于其他已建立的疾病进展标志，NVU中断的暂时性和关联性。 目标3的目的也是为了确定NVU中断对Aβ清除疗法结果的影响 AS治疗副作用的发生率以及与主要临床和认知结果的关系。 这项拟议的研究项目的成功完成将提高我们对血管和 阿尔茨海默病的免疫相关过程及其与A-β的关系、AD的病理生理及其机制 对治疗相关A-β改变的影响。

PROJECT SUMMARY The overall objective of this proposal is to support the candidate’s career development and transition to that of an independent researcher. The outlined training plan will equip the applicant with the necessary skills to conduct innovative research in a rich, interdisciplinary, and collaborative environment, facilitating the investigation of new avenues of clinical research and trials. By utilizing multimodal imaging techniques and molecular and cellular proteomic approaches, the candidate will reinforce an already strong background in neuroimaging, learn and integrate new approaches to gain a greater holistic understanding of Alzheimer disease (AD) etiology and pathophysiology, and contribute to the success of potential new therapies for AD. β- amyloid (Aβ), one of the earliest biomarkers to accumulate during AD progression, is the most targeted factor for therapeutic intervention. However, other components, such as vascular and inflammatory/immune changes, also occur during AD progression, adding to the complexity of fully characterizing AD pathogenesis. The neurovascular unit (NVU) is relevant to the study of vascular, immune, and Aβ changes in AD, as it comprises neuronal-astrocyte signaling and the blood-brain barrier, which play a role in Aβ clearance. Age-related comorbidities in late-onset AD (LOAD) are challenging to distinguish from AD-related changes involved in the progression of the disease. This proposal aims to disconnect age- from disease-related changes to vascular and immune components and to understand the impact of these disease-related changes on anti-Aβ treatment outcomes. This will be accomplished by studying these factors in autosomal dominant AD (ADAD), a rare form of AD with a known genetic etiology and with early age of symptom onset. Previous studies utilizing proteomic approaches and imaging to assess NVU disruption have focused on LOAD populations. The goal of Aim 1 of this proposal is to assess changes in the NVU in known carriers of ADAD-related mutations and with markers of vascular changes and generate a proteomic profile of NVU changes. The goal of Aim 2 is to define the temporality and association of NVU disruption relative to other established markers of disease progression. The goal of Aim 3 is to define the influence of NVU disruption on outcomes of Aβ clearance therapies, as well as on the incidence of treatment side effects and the association with primary clinical and cognitive outcomes. Successful completion of this proposed research project will improve our understanding of the vascular- and immune-related processes involved in AD and their relationship with Aβ, the pathophysiology of AD, and their influence on treatment-related Aβ changes.