Neurofibrillary Tangle-Induced Dementia in AD

描述（由申请人提供）：阿尔茨海默氏痴呆症（AD）是老年人最常见的认知障碍。AD的病理特征是淀粉样斑块和神经原纤维缠结（NFT）。最近的实验提供了淀粉样蛋白病理和nft之间的微弱联系。然而，在广泛的神经退行性疾病（统称为“牛头病”）中，nft可以在没有淀粉样蛋白病理的情况下发生。这表明nft本身复杂地参与了神经退行性过程。尽管神经原纤维缠结的形成在AD的发病机制中起着核心作用，但对于导致nft的主要蛋白质成分tau的纤维聚集的体内分子事件知之甚少。本研究旨在阐明导致NFT形成的关键分子机制，目的是确定新的治疗干预靶点，以减轻AD中NFT的形成。在这项研究中，我们将确认与NFT病理相关的许多新基因的失调，并使用高通量功能验证分析来表征这种基因失调在NFT形成和AD的病因学中的作用。我们的初步结果使我们假设CD47信号通路有助于tau代谢异常。阿尔茨海默病NFT形成与神经元细胞死亡和痴呆。这一假设是由AD患者和非痴呆对照个体的NFT和非NFT神经元的严格表达谱产生的。我们建议在mRNA、蛋白和功能水平上验证这一途径，并测试其他失调基因在NFT发病机制中的作用。关于含有神经原纤维缠结的神经元中相对于来自AD和未受影响个体的组织病理学正常神经元的差异表达基因的信息，结合这些差异的功能验证，将极大地增加我们对这种痴呆诱导病理形式发展所涉及的分子机制的理解。此外，了解在神经原纤维缠结形成过程中受影响的细胞信号通路可能为发现治疗和预防缠结诱发的痴呆的干预措施提供新的靶点。重要的是，了解神经原纤维缠结形成的分子基础可能普遍适用于其他神经退行性病变的治疗，如进行性核上性麻痹、匹克病和皮质基底变性。这一建议的成功完成将为阿尔茨海默病的潜在有效治疗干预产生许多新的靶点。

DESCRIPTION (provided by applicant): Alzheimer's dementia (AD) is the most common form of cognitive impairment in older persons. AD is characterized pathologically by amyloid plaques and neurofibrillary tangles (NFT). Recent experiments provide a tenuous link between amyloid pathology and NFTs. However, NFTs can occur without concomitant amyloid pathology in a broad class of neurodegenerative diseases, collectively known as "tauopathies." This suggests that NFTs themselves are intricately involved in neurodegenerative processes. Despite the central role of neurofibrillary tangle formation to the pathogenesis of AD, little is known about the in vivo molecular events leading to the fibrillar aggregation of tau, the predominant protein component of NFTs. This proposal seeks to elucidate the critical molecular mechanisms leading to NFT formation, with the goal of identifying novel targets for therapeutic intervention to alleviate NFT formation in AD. In the proposed study we will confirm dysregulation of numerous novel genes associated with NFT pathology and use high-throughput functional validation assays to characterize the role of this gene dysregulation in the etiology of NFT formation and AD. Our preliminary results lead us to hypothesize that the CD47 signaling pathway contributes to abnormalities in tau metabolism. NFT formation, and neuronal cell death and dementia in AD. This hypothesis has been generated by stringent expression profiles of NFT and non-NFT neurons from AD patients and non-demented control individuals. We propose here to validate this pathway at the mRNA, protein, and functional levels, as well as to test the role of additional dysregulated genes in NFT pathogenesis. Information about the genes that are differentially expressed in neurons containing neurofibrillary tangles relative to histopathologically normal neurons from AD and unaffected individuals, combined with functional validation of those differences will greatly increase our understanding of the molecular mechanisms involved in the development of this dementia-inducing form of pathology. In addition, knowledge of the cellular signaling pathways that are affected during neurofibrillary tangle formation may provide novel targets for the discovery of interventions to treat and prevent tangle- induced dementia. Importantly, understanding the molecular basis for neurofibrillary tangle formation may be generally applicable to the treatment of other neurodegenerative tauopathies, such as progressive supranuclear palsy, Pick's disease, and corticobasal degeneration. Successful completion of this proposal will yield numerous novel targets for potentially efficacious therapeutic intervention in Alzheimer's disease.