Intranasal TIDM peptide for tauopathy

用于治疗 tau 蛋白病的鼻内 TIDM 肽

• 批准号: 10059127
• 负责人: KALIPADA PAHAN
• 金额: $ 39.25万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10059127
• 关键词: Alzheimer' s Disease; Applications Grants; Bacteria; Binding; Brain; Brain Injuries; Cells; Development; Engineering; Flagellin; Frontotemporal Dementia; Inflammation; Innate Immune System; Intranasal Administration; Link; Microglia; Monitor; Mus; Mutate; Natural Immunity; Neurodegenerative Disorders; Neurofibrillary Tangles; Outcome; Pathologic; Pathology; Pathway interactions; Peptides; Progressive Supranuclear Palsy; 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 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 (Specific aim I) and decreases tauopathy (Specific aim II) in P301S transgenic mice via TLR2. A positive outcome of this cutting-edge R21 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. 1

有效地减少脑实质中聚集的tau有望减少发育和 散发性和家族性阿尔茨海默病、进行性核上性瘫痪(PSP)、额颞叶痴呆的进展 (FTD)，以及其他tauopathy。然而，降低大脑中聚集的tau的途径很差。 明白了。神经炎是神经退行性疾病的另一个标志，最近它已经 研究表明，磷酸化tau病理的进展是由小胶质细胞驱动的，而小胶质细胞的激活 形成了tau聚集和脑损伤之间的关键联系。在这里，我们想测试一个新的假设 鼻腔注射野生型TLR2-MyD88(WtTIDM)多肽对小鼠的抑制作用 P301S转基因小鼠的小胶质细胞炎症(特异性目标I)和减少焦虑症(特异性目标II) 通过TLR2。这项尖端的R21赠款提案的积极结果将勾勒出 并描述了wtTIDM肽对TLR2激活状态的选择性靶向是否减少 缠绕病理学，强调了一种潜在的鼻腔用药的发现，以减少AD的tau病理， PSP、FTD和其他tauopathy。 1