Pathological tau aggregates cause cognitive decline in neurodegenerative tauopathies, including Alzheimer’s disease (AD). These aggregates are prevalent within intracellular compartments. Current tau immunotherapies have shown limited efficacy in clearing intracellular tau aggregates and improving cognition in clinical trials. In this study, we developed toxic tau conformation–specific monoclonal antibody-2 (TTCM2), which selectively recognized pathological tau aggregates in brain tissues from patients with AD, dementia with Lewy bodies (DLB), and progressive supranuclear palsy (PSP). TTCM2 potently inhibited tau-seeding activity, an essential mechanism underlying tauopathy progression. To effectively target intracellular tau aggregates and ensure rapid delivery to the brain, TTCM2 was loaded in micelles (TTCM2-ms) and administered through the intranasal route. We found that intranasally administered TTCM2-ms efficiently entered the brain in hTau-tauopathy mice, targeting pathological tau in intracellular compartments. Moreover, a single intranasal dose of TTCM2-ms effectively cleared pathological tau, elevated synaptic proteins, and improved cognitive functions in aged tauopathy mice. Mechanistic studies revealed that TTCM2-ms cleared intracellular, synaptic, and seed-competent tau aggregates through tripartite motif-containing 21 (TRIM21), an intracellular antibody receptor and E3 ubiquitin ligase known to facilitate proteasomal degradation of cytosolic antibody-bound proteins. TRIM21 was found to be essential for TTCM2-ms–mediated clearance of tau pathology. Our study collectively provides evidence of the effectiveness of nasal tau immunotherapy in targeting and clearing intracellular tau pathology through TRIM21 and enhancing cognition in aged tauopathy mice. This study could be valuable in designing effective tau immunotherapies for AD and other tauopathies.

中文翻译：

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鼻腔 tau 免疫疗法可清除老年 tau 病小鼠的细胞内 tau 病理并改善认知功能


病理性 tau 聚集体会导致神经退行性 tau 蛋白病的认知能力下降，包括阿尔茨海默病 （AD）。这些聚集体普遍存在于细胞内区室中。目前的 tau 免疫疗法在临床试验中显示清除细胞内 tau 聚集体和改善认知方面的疗效有限。在这项研究中，我们开发了毒性 tau 构象特异性单克隆抗体-2 （TTCM2），它选择性地识别 AD 、路易体痴呆 （DLB） 和进行性核上性麻痹 （PSP） 患者脑组织中的病理性 tau 聚集体。TTCM2 有效抑制 tau 播种活性，这是 tau 蛋白病进展的重要机制。为了有效靶向细胞内 tau 聚集体并确保快速递送到大脑，TTCM2 被加载到胶束 （TTCM2-ms） 中并通过鼻内途径给药。我们发现鼻内给药的 TTCM2-ms 有效地进入 hTau-tau 病小鼠的大脑，靶向细胞内区室中的病理性 tau。此外，单次鼻内剂量的 TTCM2-ms 可有效清除老年 tau 病小鼠的病理性 tau、升高突触蛋白并改善认知功能。机制研究表明，TTCM2-ms 通过包含三联基序 21 （TRIM21） 清除细胞内、突触和种子感受态 tau 聚集体，TRIM21 是一种细胞内抗体受体和 E3 泛素连接酶，已知可促进胞质抗体结合蛋白的蛋白酶体降解。发现 TRIM21 对于 TTCM2-ms 介导的 tau 病理清除至关重要。我们的研究共同提供了鼻腔 tau 免疫疗法通过 TRIM21 靶向和清除细胞内 tau 病理以及增强老年 tau 病小鼠认知的有效性的证据。 这项研究对于为 AD 和其他 tau 蛋白病设计有效的 tau 免疫疗法可能很有价值。