Abstract：
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.
摘要：
病理性tau聚集体导致神经退行性tau病变的认知下降，包括阿尔茨海默病（AD）。这些聚集体在细胞内区室中普遍存在。当前的tau免疫疗法在临床试验中在清除细胞内tau聚集体和改善认知方面显示出有限的功效。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），选择性识别AD患者脑组织中的病理性tau聚集体，路易体痴呆（DLB），和进行性核上性麻痹（PSP）。TTCM2有效抑制了tau播种活性，tau蛋白病进展的基本机制。为了有效地靶向细胞内tau聚集体并确保快速递送到大脑，将TTCM2加载到胶束(TTCM2-ms)中并通过鼻内途径施用。我们发现，鼻内给药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有效清除病理性tau，突触蛋白升高，并改善老年tau蛋白病小鼠的认知功能。机制研究表明，TTCM2-ms清除细胞内，突触，通过含三方基序的21（TRIM21）和具有种子能力的tau聚集体，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tau免疫疗法在通过TRIM21靶向和清除细胞内tau病理以及增强老年tau病变小鼠认知方面的有效性的证据。这项研究对于为AD和其他tau蛋白病设计有效的tau免疫疗法可能是有价值的。
