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.

有效减少来自大脑实质的总tau将减少发育， 零星和家族性阿尔茨海默氏病（AD）的进展 额颞痴呆（FTD）和其他tauopathies。但是，降低总tau的途径 大脑了解不足。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-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聚集与脑损伤之间的关键联系。在这里，我们想测试 一个新的假设，即myd88的野生型野生型TLR2相互作用域的给药 （WTTIDM）胡椒抑制小胶质细胞注射并减少P301S转基因小鼠的tauopathy 通过TLR2。该赠款提案的积极结果将描述TLR2和 tauopathy并描述WTTIDM肽对TLR2激活状态的选择性靶向减少缠结 病理学，强调发现一种前瞻性鼻内药物，以减少AD，PSP，PSP中的tau病理 FTD和其他tauopathies。 行政补充：TLR2存在于大脑中的不同细胞类型中。例如，在大脑中 除小胶质细胞外，TLR2在神经元中也表达。因此，在这里，我们将调查 在tauopathy和WTTIDM肽介导的tauopathy和WTTIDM介导的清除和小胶质细胞TLR2的神经元和小胶质细胞TLR2中 P301S转基因小鼠的认知行为改善。