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

确定赋予阿尔茨海默病突触弹性的治疗靶点

• 批准号: 10412994
• 负责人: Christopher A. Gaiteri
• 金额: $ 105.03万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10412994
• 关键词: 3-Dimensional; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloidosis; Animal Disease Models; Animal Model; Architecture; Attention; Autoimmune Diseases; Automobile Driving; Autopsy; Binding; Brain; Brain region; CRISPR/Cas technology; Cell model; Characteristics; Clinical/Radiologic; Cognition; Cognitive; Computer Models; Data; Dementia; Dendrites; Dendritic Spines; Development; Drug Targeting; Exhibits; Experimental Models; Exposure to; Functional Magnetic Resonance Imaging; Genes; Goals; Human; Impaired cognition; Individual; Link; Measures; Memory; Molecular; Monitor; Morphology; Neurons; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Phosphorylation; Phosphorylation Site; Population; Prefrontal Cortex; Proteins; Proteome; Proteomics; Research; Risk; Short-Term Memory; Signal Pathway; Structure; Synapses; System; Systems Biology; Testing; Therapeutic; Tissues; Validation; Vertebral column; Work; base; cancer therapy; cognitive ability; cognitive process; density; high resolution imaging; hippocampal pyramidal neuron; human model; innovation; memory process; morphometry; mouse model; neuroimaging; novel; novel strategies; phosphoproteomics; predictive modeling; predictive test; prevent; reconstruction; religious order study; resilience; scale up; tau Proteins; therapeutic candidate; therapeutic evaluation; therapeutic protein; therapeutic target; three-dimensional modeling

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.

项目摘要 大约30％-50％的没有痴呆痴呆的尸检的人具有高水平的阿尔茨海默氏症 疾病（AD）病理学。即使在广告人群中，细胞特征也与认知能力下降最相关 不是淀粉样蛋白或tau，而是突触密度。但是，这种突触损失背后的分子机制是 不清楚。我们已经开始通过树突状的三维（3D）建模来探索它们的分子基础 刺。这些结果表明，刺的结构重塑不仅与认知能力下降有关，而且有关 特别涉及对AD的认知弹性。突触重塑是高度合理的 认知弹性是因为它是短期记忆的基础，并且可能影响多个认知过程。 这提出了重要的问题：1）驱动结构重塑的突触信号通路是什么 保持弹性个体的认知能力的刺？ 2）我们可以确定药物的治疗靶标 重新定位或新颖的治疗方法以利用AT风险患者的这些机制？该提议的目的是 通过整合定量蛋白质组学，磷酸化来建立对AD的认知弹性的预测模型 蛋白质组学，刺的3D建模和两个跨两个磁场功能磁共振成像（fMRI） 来自同一个人的大脑区域。从计算模型中，候选治疗蛋白靶标将 在AD的细胞和动物模型中得到优先级并严格验证。获得的新数据以支持这一点 目标将测量约12,000个蛋白质和〜30,000个磷酸化位点，该位点来自人类的突触富分。 对AD病理学的韧性不同程度的大脑。在同一情况下，创新的高分辨率 树突结构的成像和3D重建将测量弹性的细胞表型。系统 生物学方法将使我们的数据与包括AMP-AD在内的现有OMICS集成，并提出特定的数据 驱动弹性的突触蛋白。这些预测将以人脑结构和 通过与神经成像进行比较，在同一集人类中获得的功能。弹性的最高候选人 然后将筛选疾病的细胞和动物模型中的弹性表型。人类临床， 来自宗教秩序研究和Rush记忆和老化项目的放射学和病理数据将 与AMP-AD数据结合研究以完成建议的目标。