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.

有效减少脑实质中聚集的 tau 蛋白有望减少发育和 散发性和家族性阿尔茨海默病（AD）、进行性核上性麻痹（PSP）的进展， 然而，额颞叶痴呆 (FTD) 和其他 tau 蛋白病的降低途径是减少 tau 蛋白聚集。 人们对大脑知之甚少，而神经炎症是神经退行性疾病的另一个标志。 最近表明，磷酸化 tau 病理学的进展是由小胶质细胞驱动的，并且 小胶质细胞激活形成了 tau 蛋白聚集和脑损伤之间的关键联系。 一个新的假设是鼻内施用 MyD88 的野生型 TLR2 相互作用结构域 (wtTIDM) 肽抑制 P301S 转基因小鼠的小胶质细胞炎症并减少 tau 蛋白病变 通过 TLR2，该拨款提案的积极成果将勾勒出 TLR2 和 TLR2 之间的新串扰。 tau蛋白病并描述wtTIDM肽选择性靶向TLR2的激活状态是否减少缠结 病理学，强调发现了一种有前景的鼻内药物，可以减少 AD、PSP、 FTD 和其他 tau蛋白病。 行政补充：TLR2存在于大脑的不同细胞类型中，例如，在大脑中。 除了小胶质细胞外，TLR2也在神经元中表达，因此，在这里，我们将研究其作用。 tau 蛋白病中的神经元和小胶质细胞 TLR2 以及 wtTIDM 肽介导的 tau 蛋白病清除 P301S 转基因小鼠认知行为的改善。