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

基本信息

批准号：
10201513
负责人：
Christopher A. Gaiteri
金额：
$ 107.95万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10201513
关键词：
3-Dimensional Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos 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

项目摘要

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.

项目概要大约 30%-50% 进行尸检但未患痴呆症的人患有高水平的阿尔茨海默病疾病（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，这种突触损失背后的分子机制是不清楚。我们已经开始通过树突的三维 (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，而且与认知能力下降有关。特别是与 AD 的认知弹性有关。突触重塑作为基础是非常合理的认知弹性，因为它是短期记忆的基础，可以影响多种认知过程。这就提出了重要的问题：1）驱动结构重塑的突触信号通路是什么？脊柱可以维持有弹性的个体的认知能力？ 2）我们能否确定药物的治疗靶点重新定位或新的治疗方法来利用高危患者的这些机制？该提案的目标是通过整合定量蛋白质组学、磷酸化组学，建立 AD 认知弹性的预测模型蛋白质组学、脊柱 3D 建模以及死前功能磁共振成像 (fMRI) 跨越两个来自同一个人的大脑区域。根据计算模型，候选治疗蛋白靶标将在 AD 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富含突触的部分中约 12,000 个蛋白质和约 30,000 个磷酸化位点大脑对 AD 病理有不同程度的恢复能力。在相同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（包括 AMP-AD）整合起来，并提出具体的建议驱动弹性的突触蛋白。这些预测将在人脑结构和与在同一组人类中获得的神经影像进行比较。复原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。人体临床，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数据将结合 AMP-AD 数据进行研究，以完成提出的目标。