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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.

项目总结