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Impaired activity-dependent protein synthesis in dendrites and pathophysiology in tauopathy

树突活性依赖性蛋白质合成受损和 tau 蛋白病的病理生理学

基本信息

批准号：
10670923
负责人：
Tara Tracy
金额：
$ 78.41万
依托单位：
BUCK INSTITUTE FOR RESEARCH ON AGING
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10670923
关键词：
Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease related dementia Biology Complex DLG4 gene Dementia Dendrites Disease Electrophysiology (science)Eukaryotic Initiation Factors Event Foundations Functional disorder Glutamate Receptor Goals Hippocampus Human Impaired cognition Impairment Induced pluripotent stem cell derived neurons Knowledge Label Learning Link Long-Term Potentiation Mass Spectrum Analysis Mediating Memory Memory Loss Memory impairment Messenger RNA Methods Modeling Molecular Monitor Mus Mutation Neuronal Plasticity Neurons Pathogenicity Patients Peptide Initiation Factors Physiological Processes Protein Biosynthesis Protein Dynamics Proteins Proteome Proteomics Puromycin Quality of life Regulation Reporter Research Ribonucleoproteins Role Synapses Synaptic plasticity Tauopathies Therapeutic Intervention Time Transgenic Mice Translating Translation Initiation Translations behavior test density induced pluripotent stem cell innovation knowledge base mRNA Translation mouse model novel therapeutic intervention polysome profiling postsynaptic protein complex response targeted treatment tau Proteins tau interaction tau mutation tau-1 therapeutic target trafficking translatome

项目摘要

PROJECT SUMMARY/ABSTRACT Pathogenic tau in Alzheimer’s disease and related dementias inhibits the plasticity of neuronal connections underlying progressive memory loss. What remains undetermined, however, are the complex and multifactorial molecular events that disrupt synaptic plasticity in neurons with pathogenic tau. This is major gap in our knowledge of the molecular and physiological processes underlying memory loss in Alzheimer’s disease and related dementias. There is a critical need to uncover how plasticity is dysregulated by pathogenic tau to lay the groundwork for new strategies to target plasticity for therapeutic intervention in these diseases. Long-term potentiation (LTP) is a type of plasticity that involves the persistent strengthening of specific connections between neurons in response to increased activity. There is a strong link between memory impairments and obstructed LTP at synapses in transgenic mouse models of Alzheimer’s disease and related dementias, suggesting that the inability of synapses to express LTP is a key factor leading to memory decline. Our preliminary studies suggest that pathogenic tau blocks the activity-dependent de novo protein synthesis in dendrites that is required for LTP expression. Moreover, we found that pathogenic tau downregulates a translation initiation factor that controls activity-dependent mRNA translation during plasticity. The central hypothesis of this proposal is that pathogenic tau blocks the initiation of local protein translation in dendrites and thereby disrupts the dynamics of postsynaptic proteins that establish LTP and the encoding of new memories. To delineate the mechanism by which pathogenic tau inhibits LTP expression, we propose to use both human induced pluripotent stem cell (iPSC)-derived cultured neurons with familial tau mutations, V337M and R406W, that cause dementia and the PS19 tauopathy mouse model. We will establish the effect of pathogenic tau on the active translation of mRNAs into newly synthesized proteins during LTP expression. We will use a combination of methods to monitor the effect of tau on the rate of protein synthesis and on the subset of mRNAs that are actively translated during LTP. We will next determine the impact of pathogenic tau on a critical step in the initiation of protein translation and the extent to which restoring activity-dependent translation initiation can ameliorate LTP and memory impairments in PS19 mice assessed by electrophysiological recordings and behavioral tests of learning and memory. Finally, we will use an unbiased and innovative APEX proteomics approach to establish the impact of pathogenic tau on the dynamic changes in the postsynaptic protein composition during LTP expression that involve both de novo protein synthesis and the reorganization of protein composition to enhance synaptic strength. From these studies, we expect to elucidate the effect of pathogenic tau on dendritic protein synthesis and the regulation of postsynaptic protein dynamics that underlie the complex and multifactorial causes of memory loss in Alzheimer’s disease and related dementias.

项目总结/文摘