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 在没有痴呆的尸检中，大约30%-50%的人患有高水平的阿尔茨海默氏症 疾病(AD)病理学。即使在阿尔茨海默病人群中，细胞特征与认知能力下降的相关性最大 不是淀粉样蛋白或tau蛋白，而是突触密度。然而，这种突触丧失背后的分子机制是 不清楚。我们已经开始通过对树枝晶进行三维(3D)建模来探索它们的分子基础 脊椎。这些结果表明，脊柱的结构重塑不仅与认知能力下降有关，而且 具体涉及对阿尔茨海默病的认知弹性。突触重构是非常有可能的基础 认知韧性，因为它是短期记忆的基础，可以影响多个认知过程。 这就提出了一些重要的问题：1)驱动大脑皮质结构重构的突触信号通路是什么？ 坚韧的个体保持认知能力的脊椎？2)我们能确定药物的治疗靶点吗？ 在高危患者中重新定位或采用新的治疗方法来利用这些机制？这项提议的目标是 结合定量蛋白质组学、磷酸化蛋白质组学构建AD认知复原力预测模型 蛋白质组学、脊柱3D建模和生前功能磁共振成像(FMRI) 来自相同个体的大脑区域。从计算模型中，候选的治疗蛋白质靶点将 在AD的细胞和动物模型中优先考虑并严格验证。为支持这一点而获得的新数据 Goal将测量人类富含突触的部分中的~12,000个蛋白质和~30,000个磷酸化位点 大脑对AD病理有不同程度的适应能力。在相同的情况下，创新的高分辨率 树突结构的成像和3D重建将测量细胞的弹性表型。系统 生物学方法将把我们的数据与现有的组学相结合，包括AMP-AD，并提出具体的 驱动韧性的突触蛋白。这些预测将在人脑结构和 与神经成像相比，在同一组人类中获得的功能。韧性的最佳候选者 然后将在疾病的细胞和动物模型中筛选弹性表型。人类临床， 来自宗教教团研究和快速记忆和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，以完成拟议的目标。