Heparan Sulfate 3-O-Sulfation in Transcellular Propagation of Tauopathy in Alzheimer's Disease

硫酸乙酰肝素 3-O-硫酸化在阿尔茨海默氏病 Tau 蛋白病跨细胞传播中的作用

• 批准号: 10054740
• 负责人: ROBERT J LINHARDT
• 金额: $ 259.51万
• 依托单位: RENSSELAER POLYTECHNIC INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054740
• 关键词: Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease therapy; Animal Model; Animals; Binding; Biosensor; Brain; Cell Culture Techniques; Cell Line; Cell surface; Cells; Chemicals; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Core Protein; Data; Dementia; Disaccharides; Disease; Drug Design; Enzymes; Fluorescence Resonance Energy Transfer; Future; Glucosamine; Glucuronic Acids; Goals; Heparan Sulfate Proteoglycan; Heparitin Sulfate; Hippocampus (Brain); Human; Iduronic Acid; Impaired cognition; Injections; Link; MAPT gene; Mass Spectrum Analysis; Mediating; Methods; Microtubule Stabilization; Microtubules; Modification; Molecular; Movement; Mutagenesis; Neurofibrillary Tangles; Neurons; Oligosaccharides; Pathogenesis; Pathologic; Pathology; Pattern; Pharmaceutical Preparations; Physiology; Play; Polysaccharides; Proteins; Public Health; Relaxation; Role; Signal Transduction; Small Interfering RNA; Staging; Structure; Sulfate; Surface; Tauopathies; Testing; Translating; Uronic Acids; Work; base; cell type; design; drug development; drug discovery; hTau Mice; inhibitor/antagonist; insight; migration; mimetics; molecular dynamics; mouse genetics; mouse model; neural network; novel; overexpression; prion-like; protein aggregation; role model; structural biology; sulfotransferase; tau Proteins; tau aggregation; tau interaction; tool; uptake

Neurofibrillary tangles (NFT) is a pathological hallmark of Alzheimer’s disease (AD). NFT is composed of aggregated tau protein and is correlated to cognitive decline in dementia progression. NFT spreads in the brain in a prion-like manner, mediated by the interaction between tau and neuronal surface glycans. The long-term goal is to study the structural details of tau-glycan interaction and to discover drugs to disrupt this interaction for disease-modifying treatment of AD. In this proposal, we will study the tau-heparan sulfate interaction from at the molecular (aim 1), the cellular (aim 2), and organismal level and carry out drug discovery (aim 3).

神经原纤维缠结（NFT）是阿尔茨海默病（AD）的病理标志。NFT由