Identifying therapeutic targets that confer synaptic resilience to Alzheimer's disease

项目摘要 大约30%-50%的人来尸检没有痴呆症有高水平的阿尔茨海默氏症 疾病（AD）病理学。即使在AD人群中，细胞特征也与认知能力下降最相关 不是淀粉样蛋白或tau蛋白，而是突触密度然而，这种突触丢失背后的分子机制是 不清楚我们已经开始通过树突状细胞的三维（3D）建模来探索它们的分子基础。 刺这些结果表明，脊柱的结构重塑不仅与认知能力下降有关， 与AD的认知恢复力有关突触重塑是非常合理的基础， 认知弹性，因为它是短期记忆的基础，可以影响多种认知过程。 这就提出了一些重要的问题：1）是什么样的突触信号通路驱动着神经元的结构重塑？ 脊柱来维持弹性个体的认知能力2)我们能确定药物的治疗靶点吗 重新定位或新的治疗，以利用这些机制在风险患者？本提案的目的是 通过整合定量蛋白质组学，磷酸化， 蛋白质组学，脊柱的3D建模，以及两个人的死前功能性磁共振成像（fMRI）， 大脑区域的信息根据计算模型，候选治疗蛋白质靶点将 在AD的细胞和动物模型中优先考虑并严格验证。获得的新数据支持这一点 目标将测量人类突触富集部分中的~ 12，000个蛋白质和~ 30，000个磷酸化位点， 大脑对AD病理学有不同程度的适应性。在相同的情况下， 树突结构的成像和3D重建将测量细胞的恢复表型。系统 生物学方法将整合我们的数据与现有的组学，包括AMP-AD，并提出具体的 突触蛋白驱动恢复力。这些预测将在人类大脑结构方面得到验证， 通过与在同一组人类中获得的神经成像进行比较，恢复力的最佳候选人 然后将在细胞和动物疾病模型中筛选恢复表型。人类临床， 来自宗教秩序研究和拉什记忆与衰老项目的放射学和病理学数据将 结合AMP-AD数据进行研究，以完成提出的目标。

Project Summary Approximately 30%-50% of individuals who come to autopsy without dementia have high levels of Alzheimer's disease (AD) pathology. Even in the AD population, the cellular feature most correlated with cognitive decline is not amyloid or tau, but synaptic density. However, the molecular mechanisms behind this synaptic loss are unclear. We have begun to explore their molecular basis through three dimensional (3D) modeling of dendritic spines. These results show that structural remodeling of spines not only relates to cognitive decline, but specifically relates to cognitive resilience to AD. Synaptic remodeling is highly plausible as the basis for cognitive resilience because it is the basis for short term memory and can affect multiple cognitive processes. This raises important questions: 1) what are the synaptic signaling pathways that drive structural remodeling of spines to maintain cognitive abilities in resilient individuals? 2) Can we identify therapeutic targets for drug repositioning or novel treatments to exploit these mechanisms in at risk patients? The goal of this proposal is to build a predictive model of cognitive resilience to AD by integrating quantitative proteomics, phospho- proteomics, 3D modeling of spines, and antemortem functional magnetic resonance imaging (fMRI) across two brain regions from the same individuals. From computational models, candidate therapeutic protein targets will be prioritized and rigorously validated in cellular and animal models of AD. Novel data acquired to support this goal will measure ~12,000 proteins and ~30,000 phosphorylation sites in synapse-rich fractions from human brains with varying degrees of resilience to AD pathology. In the same cases innovative high resolution imaging and 3D reconstruction of dendritic architecture will measure cellular phenotypes of resilience. Systems biology approaches will integrate our data with existing omics, including AMP-AD, and propose specific synaptic proteins that drive resilience. These predictions will be validated in terms of human brain structure and function by comparison to neuroimaging, acquired in the same set of humans. Top candidates for resilience will then be screened for resilience phenotypes in cellular and animal models of disease. Human clinical, radiologic, and pathologic data, from The Religious Orders Study and the Rush Memory and Aging Project will be studied in combination with AMP-AD data to complete the proposed goals.