Intranasal TIDM peptide for tauopathy

用于治疗 tau 蛋白病的鼻内 TIDM 肽

• 批准号: 10274908
• 负责人: KALIPADA PAHAN
• 金额: $ 15.7万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10274908
• 关键词: Administrative Supplement; Alzheimer' s Disease; Applications Grants; Bacteria; Behavior; Binding; Brain; Brain Injuries; Cognitive; Development; Engineering; Flagellin; Frontotemporal Dementia; Inflammation; Intranasal Administration; Link; Mediating; Microglia; Molecular Target; Monitor; Mus; Mutate; Natural Immunity; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Outcome; Pathologic; Pathology; Pathway interactions; Peptides; Progressive Supranuclear Palsy; Reporting; Role; Specificity; TLR2 gene; Tauopathies; Testing; Therapeutic; Toll-like receptors; Transgenic Mice; Viral; Virus; adaptive immunity; brain parenchyma; cell type; effective therapy; familial Alzheimer disease; hyperphosphorylated tau; inhibitor/antagonist; neuroinflammation; novel; prospective; tau Proteins; tau aggregation; tau-1

Effective reduction of aggregated tau from the brain parenchyma is expected to reduce the development and progression of both sporadic and familial Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), and other tauopathies. However, pathways for lowering aggregated tau from the brain are poorly understood. Neuroinflammation is another hallmark of neurodegenerative disorders and recently it has been shown that the progression of phospho-tau pathology is driven by microglia and that microglial activation forms the crucial link between tau aggregation and brain damage. Here, we want to test a novel hypothesis that intranasal administration of wild type TLR2-interacting domain of MyD88 (wtTIDM) peptide suppresses microglial inflammation and decreases tauopathy in P301S transgenic mice via TLR2. A positive outcome of this grant proposal will delineate a new crosstalk between TLR2 and tauopathy and describe if selective targeting of activated status of TLR2 by wtTIDM peptide reduces tangle pathology, highlighting the discovery of a prospective intranasal agent to reduce tau pathology in AD, PSP, FTD, and other tauopathies. Administrative supplement: TLR2 is present in different cell types in the brain. For example, in the brain, in addition to microglia, TLR2 is also expressed in neurons. Therefore, here, we will investigate the role of neuronal and microglial TLR2 in tauopathy and wtTIDM peptide-mediated clearance of tauopathy and improvement in cognitive behaviors in P301S transgenic mice.

从脑实质中有效减少聚集的tau预期会减少脑胶质瘤的发生和发展。 散发性和家族性阿尔茨海默病（AD），进行性核上性麻痹（PSP）， 额颞叶痴呆（FTD）和其他tau蛋白病。然而，降低聚集的tau蛋白的途径， 对大脑了解甚少。神经炎症是神经退行性疾病的另一个标志， 最近已经表明磷酸化-tau病理学的进展是由小胶质细胞驱动的 小胶质细胞活化形成tau聚集和脑损伤之间的关键联系。在这里，我们想测试 一种新的假设，鼻内施用MyD 88的野生型TLR 2相互作用结构域， （wtTIDM）肽抑制P301 S转基因小鼠中的小胶质细胞炎症并减少tau蛋白病 通过TLR 2。该资助提案的积极结果将描绘TLR 2和TLR 3之间的新串扰。 并描述了通过wtTIDM肽选择性靶向TLR 2的活化状态是否减少缠结 病理学，突出了一种减少AD，PSP， FTD和其他tau蛋白病。 管理补充：TLR 2存在于大脑中的不同细胞类型中。例如，在大脑中， 除了小胶质细胞，TLR 2也在神经元中表达。因此，在这里，我们将研究 tau蛋白病中的神经元和小胶质细胞TLR 2和wtTIDM肽介导的tau蛋白病的清除， P301 S转基因小鼠认知行为的改善。