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Cell-type-specific and high-resolution profiling of postsynaptic proteomes altered in Alzheimer's disease model mice

阿尔茨海默病模型小鼠突触后蛋白质组的细胞类型特异性和高分辨率分析

基本信息

批准号：
10045381
负责人：
Joongkyu Park
金额：
$ 42.35万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10045381
关键词：
Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Amyloid beta-Protein Biochemical Brain Dementia Dependovirus Deposition Development Electrophysiology (science)Enterobacteria phage P1 Cre recombinase Face Failure Functional disorder Goals Health Health Care Costs Heterogeneity Hippocampus (Brain)Impairment Intrabody Long-Term Potentiation Maps Memory Memory Loss Memory impairment Methods Microscopy Mission Molecular Mus Mutation Neurodegenerative Disorders Neurofibrillary Tangles Neurons Pathogenesis Pathologic Population Proteins Proteome Proteomics Public Health Recombinant Antibody Recording of previous events Research Resolution Senile Plaques Specimen Synapses Synaptic Transmission Synaptic plasticity Systems Development Techniques Tissue Expansion United States National Institutes of Health base brain tissue calmodulin-dependent protein kinase II cell type cognitive function excitatory neuron familial Alzheimer disease innovation memory recall method development molecular dynamics mouse model neuron loss neuropathology postsynaptic recombinase spatiotemporal therapeutic target transgenic model of alzheimer disease

项目摘要

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is the most common cause of dementia with progressive loss of memory and cognitive functions. In several AD model mice, the deficits in memory and cognitive functions are highly correlated with an impairment in basal synaptic transmission and synaptic plasticity. Intriguingly, many of the AD model mice show significant deficits in synaptic transmission and plasticity before the development of b-amyloid deposits, which is a typical hallmark of AD pathology. Thus, synaptic dysfunction is a potentially important component of AD pathogenesis. However, to understand the synaptic dysfunction in AD at molecular levels, we face a significant obstacle, which is heterogeneity at multiple levels, due to neuronal heterogeneity and synaptic history (synaptic plasticity). There is, therefore, a critical need to develop a biochemical method that can analyze synaptic molecular constituents in a spatiotemporal manner to understand in substance the synaptic molecular alterations involved in AD. Here, the overall objective in this application is the development of systems-type biochemical methods that enable cell-type-specific and high-resolution profiling of postsynaptic proteomes. The rationale for this project is that these method developments are likely to advance the isolation of molecularly homogeneous postsynaptic proteomes, which will ultimately provide more substantive maps of synaptic protein changes that contribute to the synaptic dysfunction seen in AD. To attain the overall objectives, the following two specific aims will be pursued: 1) Develop cell-type-specific profiling methods of postsynaptic proteomes using Cre recombinase-dependent strategies; and 2) Develop high- resolution profiling methods to identify sub-synaptic proteomes. This innovation in postsynaptic proteomics is expected to allow us to isolate postsynaptic proteomes from the defined population of synapses and sub-synaptic domains in AD model mice. More substantive profiles of synaptic molecular alterations in AD model mice will provide a significant advance in the understanding of synaptic dysfunction in AD at molecular levels and new opportunities for discovering therapeutic targets of AD.

项目总结/文摘