The hsp90 Cochaperone FKBP51 Regulates tau Structure and Function

项目摘要/摘要 神经精神症状(NPS)，如抑郁症，在阿尔茨海默病(AD)的早期很常见，而且与 患者数量下降的速度更快。阿尔茨海默病的NPS和认知缺陷与tau的积累有关 蛋白。两项与51 kDa FK506结合蛋白(FKBP51)等位基因变异相关的独立研究 在AD中患抑郁症的风险增加。FKBP51还调节tau的蓄积和对神经细胞的毒性。我们 将使用转基因小鼠模型来确定移除或抑制FKBP51对小鼠是否具有保护作用 反对tau的积累。我们还将研究是否有这种风险变异的小鼠与tau结合使用 积累更容易受到NPS的影响。通过这项工作获得的批判性知识将增加我们的 了解FKBP51在调节tau发病机制中的作用，特别是在疾病进展过程中。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FKBP51作为目标和特征 与神经官能症NPS易感性相关的分子图景。

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.