Department of Neuroscience and Physiology, New York University School of Medicine, New York, N.Y., USA.
Neurodegener Dis. 2014;13(2-3):103-6. doi: 10.1159/000354491. Epub 2013 Sep 11.
Disappointing findings from recent phase III trials on amyloid-β (Aβ) immunotherapy for Alzheimer's disease (AD) have shifted the focus of such treatments to the tau protein. As tau pathology correlates better with the degree of dementia than Aβ plaque burden, it is a more attractive target once cognitive impairments are evident, while Aβ therapies may be better suited for the presymptomatic phase of the disease. Over 12 years ago, we initiated a tau immunotherapy program, seeking to alleviate the functional impairments associated with tau lesions in tauopathies. We have reported that various active and passive tau immunizations diminish tau pathology and improve function, including cognition, in different mouse models. Both extra- and intracellular pathways are likely involved. The antibodies may block the spread of tau pathology via microglial phagocytosis of the antibody-tau complex and facilitate lysosomal tau clearance in neurons after endosomal uptake. We have observed such antibody internalization following intracarotid injection in mice and in various culture models. These include brain slices and primary neurons from tangle mice as well as human neuroblastoma cell lines. Antibody targeting of different intracellular protein aggregates, including α-synuclein, Aβ and superoxide dismutase has been reported by others. Now, several laboratories have confirmed and extended our findings using various active and passive tau immunizations in different models, thereby clearly establishing the feasibility of this approach for clinical trials. We are also working on imaging approaches to monitor tau pathology, its consequences and the efficacy of treatments. Dire need exists for such diagnostic methods for tauopathies. Overall, therapies and diagnostic tools targeting tau pathology have a great potential for AD and other tauopathies.
最近针对阿尔茨海默病（AD）淀粉样蛋白-β（Aβ）免疫疗法的 III 期临床试验结果令人失望，这使得此类治疗方法的重点转向了 tau 蛋白。由于 tau 病理学与痴呆程度的相关性优于 Aβ 斑块负担，因此在认知障碍明显时，它是一个更有吸引力的靶点，而 Aβ 疗法可能更适合疾病的无症状前阶段。12 年前，我们启动了 tau 免疫疗法项目，旨在减轻 tau 病中 tau 病变相关的功能障碍。我们已经报告说，各种主动和被动 tau 免疫接种可减少 tau 病理学并改善功能，包括认知，在不同的小鼠模型中。细胞内外途径都可能参与其中。抗体可能通过小胶质细胞吞噬抗体-tau 复合物来阻止 tau 病理学的传播，并在细胞内吞作用后促进神经元溶酶体 tau 清除。我们已经在小鼠和各种培养模型中观察到这种抗体内化。这些包括来自缠结小鼠的脑切片和原代神经元以及人神经母细胞瘤细胞系。其他人已经报道了针对不同细胞内蛋白聚集体（包括 α-突触核蛋白、Aβ 和超氧化物歧化酶）的抗体靶向。现在，几个实验室已经使用不同的主动和被动 tau 免疫接种在不同的模型中证实和扩展了我们的发现，从而清楚地确立了这种方法用于临床试验的可行性。我们还在研究用于监测 tau 病理学、其后果和治疗效果的成像方法。tau 病迫切需要这种诊断方法。总的来说，针对 tau 病理学的治疗方法和诊断工具对 AD 和其他 tau 病具有很大的潜力。
