CSF Tau Biomarker-guided Development of Hsp90 Inhibitors for Alzheimer's Disease

项目描述（由申请人提供）：研究及相关其他项目信息项目摘要/摘要阿尔茨海默病（AD）的神经退行性变可能是由脑组织中A¿as斑块沉积引起的。然而，关于含tau的神经原纤维缠结（nft）在AD中的作用的研究较少。越来越多的证据表明，含有tau的nft是AD和其他神经退行性疾病发生和发展的重要组成部分。在本研究中，通过抑制分子伴侣蛋白Hsp90靶向tau通路作为一种有希望的影响AD疾病进展的新途径。这项资助的目标是通过计算机建模和物理化学性质预测来优化两种结构不同的支架，以产生新的脑渗透性Hsp90抑制剂作为AD治疗药物。随后，这些化合物将用于临床开发，用于使用CSF生物标志物治疗AD，以及改善认知，用于体内疗效测定。

DESCRIPTION (provided by applicant): Research & Related Other Project Information Item 7. Project Summary/Abstract Neurodegeneration in Alzheimer's disease (AD) may result from deposition of A¿ as plaques in brain tissue. However, less effort has been made to elucidate the role of tau- containing neurofibrillary tangles (NFTs) in AD. Accumulating evidence suggests that tau containing NFTs is an important component in the initiation and progression of AD and other neurodegenerative diseases. In this proposal the tau pathway is targeted through inhibition of the molecular chaperone Hsp90 as a promising new approach to affect the disease progression of AD. The goal of this grant is to optimize two structurally distinct scaffolds aided by in silico modeling and physical-chemical property predictions in order to generate novel brain permeable Hsp90 inhibitors as AD therapeutics. Subsequently, these compounds will be clinically developed for the treatment of AD using CSF biomarkers, as well as improved cognition, for in vivo efficacy determinations. PUBLIC HEALTH RELEVANCE: Research & Related Other Project Information Item 8. Project Narrative This research is focused on identifying potential drug candidates to treat Alzheimer's disease (AD) and in this way it addresses NIA's priorities to support research on health and disease in the aged. Furthermore, this project targets the tau pathway as a promising new approach to affect the disease progression of AD.