权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Tau-Fyn Interaction and Alzheimer's Disease

Tau-Fyn 相互作用与阿尔茨海默病

基本信息

批准号：
10292907
负责人：
Jonathan R Roth
金额：
$ 1.62万
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：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2021-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10292907
关键词：
3-Dimensional AMPA Receptors Ablation Affect Affinity Age Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease therapeutic Amyloid beta-Protein Automobile Driving Behavioral Assay Binding Biological Assay Biological Models Cognitive Cognitive deficits Dementia Dendrites Dendritic Spines Disease Progression Electroencephalography Epilepsy Functional disorder Genetic Glutamates Goals Hippocampus (Brain)Impaired cognition In Situ In Vitro Knock-out Knockout Mice Lead Learning Ligation MAPT gene Measures Mediating Mediator of activation protein Membrane Modeling Molecular Morphology Mus Mutate Mutation N-Methyl-D-Aspartate Receptors N-Methylaspartate Nerve Degeneration Neurites Neurofibrillary Tangles Neuronal Dysfunction Neurons PXXP Motif Pathogenesis Peptides Phenotype Phosphorylation Phosphotransferases Population Predisposition Proline-Rich Domain Proteins Proto-Oncogene Proteins c-fyn Public Health Role SH3 Domains Scientist Seizures Signal Transduction Structure Synapses System Techniques Testing Therapeutic Vertebral column Work abeta toxicity base behavior test beta amyloid pathology career cognitive testing density excitotoxicity extracellular familial Alzheimer disease gabazine hyperphosphorylated tau immunocytochemistry in vivo inhibitor/antagonist insight member mouse model multi-electrode arrays novel strategies novel therapeutic intervention osmotic minipump overexpression postsynaptic prevent relating to nervous system skills tau Proteins tau interaction therapeutic target therapy development trafficking

项目摘要

Project Summary/Abstract Alzheimer’s disease (AD) is the leading cause of dementia worldwide and its impact will increase exponentially as the population ages. New therapeutic approaches are desperately needed to treat AD. The microtubule- associated protein Tau is has been heavily studies because it aggregates into neurofibrillary tangles within neurons, one of the hallmarks of AD. Genetic knockout of Tau is protective in several models of AD, highlighting its potential as a therapeutic target for AD. Interestingly, Tau reduction also prevents network hyperexcitability, which occurs early in AD and may contribute to neurodegeneration, in these models. Similarly, in a primary neuron culture system, Tau reduction prevents amyloid-β (Aβ) toxicity and glutamate or NMDA-induced excitotoxicity. In short, Tau reduction is protective in a variety of systems, but the mechanism by which it does so is currently unknown. Tau’s central proline-rich region, which is hyperphosphorylated in AD, has several PxxP motifs that mediate binding with SH3 domain–containing proteins including the nonreceptor tyrosine kinase Fyn. Fyn is also an important mediator of network hyperexcitability, as it phosphorylates AMPA and NMDA receptors to strengthen their signaling and regulates dendritic spine dynamics. Exogenous Aβ activates Fyn at the postsynaptic density, leading to NMDAR phosphorylation and excitotoxicity in neurons. Diverse evidence indicates that Tau’s interaction with Fyn could be a critical mediator of Aβ toxicity. Genetic knockout of either Tau or Fyn prevents Aβ toxicity in primary neurons, hyperphosphorylated Tau has a higher affinity for Fyn, and Tau mediates trafficking of Fyn to dendrites in vivo, leading to Aβ-induced cognitive deficits and network hyperexcitability. However, the idea that the Tau-Fyn interaction is a critical mediator of Aβ toxicity has not been directly tested, which is the goal of this project. My overarching hypothesis is that the Tau-Fyn interaction is a critical mediator of Aβ-induced structural and functional abnormalities. I will test this hypothesis using a peptide inhibitor of the Tau-Fyn interaction, Tau-PxxP5/6, developed by previous members of the Roberson lab. I developed a proximity ligation-based assay to confirm that Tau-PxxP5/6 inhibits endogenous Tau-Fyn interaction in situ and found that it prevents Aβ-induced neurite degeneration and membrane trafficking dysfunction. Here, I will determine if Tau-PxxP5/6 prevents Aβ-induced deficits in dendritic spine morphology using 3D morphometric analysis and Aβ- and gabazine-induced network hyperexcitability using multi-electrode arrays. I will also determine if the Fyn-binding region of Tau is the critical region of Tau that mediates Aβ toxicity by transducing Tau knockout neurons with different mutated Tau constructs to prevent Fyn binding. In addition to in vitro studies, I will determine if Tau-PxxP5/6 prevents cognitive deficits, epileptiform activity and seizure susceptibility in vivo using the hAPPJ20 mouse model of AD. The proposed work will provide insights into the molecular mechanisms of Aβ toxicity and could provide a promising therapeutic strategy to treat AD.

项目总结/文摘