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The hsp90 Cochaperone FKBP51 Regulates tau Structure and Function

hsp90 Cochaperone FKBP51 调节 tau 结构和功能

基本信息

批准号：
10607304
负责人：
Laura J Blair
金额：
$ 72.17万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607304
关键词：
Ablation Affect Affective Symptoms Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient Attenuated Behavior assessment Behavioral Biology Brain Cognitive Cognitive deficits Data Disease Progression Electrophysiology (science)FK506 binding protein 5 Functional disorder Goals Health Immune response Impaired cognition Impairment In Vitro Individual Knockout Mice Knowledge Link MAPT gene Mediating Mental Depression Metabolism Mitochondria Modeling Molecular Molecular Chaperones Mood Disorders Mus Neurons Obesity Outcome Pathogenesis Pathologic Pathway interactions Patients Proteins Proteomics Research Respiration Risk Role Short-Term Memory Single Nucleotide Polymorphism Stress Structure Synapses Synaptic plasticity Synaptosomes Tacrolimus Binding Proteins Tauopathies Testing Toxic effect Transgenic Mice Variant Work aged excitatory neuron genetic variant hormonal signals in vivo inhibitor insight knock-down mitochondrial dysfunction mouse development mouse model neuron loss neuropathology neuropsychiatric symptom neurotoxic neurotoxicity polyglutamine resilience risk variant steroid hormone tau Proteins tau aggregation tau mutation tau-1 transcriptomics

项目摘要

Project Summary/Abstract Neuropsychiatric symptoms (NPS), like depression, are common early in Alzheimer’s disease (AD) and correlate with a faster decline in patients. NPS and cognitive deficits in AD have been linked with the accumulation of tau protein. Two independent studies associated an allelic variant in the 51kDa FK506-binding protein (FKBP51) with increased risk for depression in AD. FKBP51 also regulates tau accumulation and toxicity to nerve cells. We will use transgenic mouse models to determine if either removing or inhibiting FKBP51 in mice will be protective against tau accumulation. We will also study whether mice that have this risk variant in combination with tau accumulation are more vulnerable to NPS. The critical knowledge gained through this work will add to our understanding of the role of FKBP51 in regulating tau pathogenesis especially during disease progression. This work will have a positive impact in AD research as we will further validate FKBP51 as a target and characterize the molecular landscape associated with vulnerability to NPS in tauopathies.

项目总结/摘要神经精神症状（Neuropsychiatric symptoms，缩写为EAD），如抑郁症，在阿尔茨海默病（Alzheimer's disease，缩写为AD）的早期很常见，患者数量下降得更快。AD中的认知和认知缺陷与tau蛋白的积累有关蛋白两项独立研究与51 kDa FK 506结合蛋白（FKBP 51）中的等位基因变体相关 AD患者患抑郁症的风险增加。FKBP 51还调节tau的积累和对神经细胞的毒性。我们将使用转基因小鼠模型来确定在小鼠中去除或抑制FKBP 51是否具有保护作用对抗tau蛋白的积累。我们还将研究是否有这种风险变异与tau蛋白结合的小鼠积累更容易受到干扰。通过这项工作获得的关键知识将增加我们的了解FKBP 51在调节tau发病机制中的作用，特别是在疾病进展期间。这这项工作将对AD研究产生积极影响，因为我们将进一步验证FKBP 51作为靶标并表征与tau蛋白病易感性相关的分子景观。