George P and Cynthia Woods Mitchell Center for Neurodegenerative Diseases, Department of Neurology, University of Texas Medical Branch, Galveston, TX 77555-0857, USA.
Curr Alzheimer Res. 2011 Sep;8(6):659-65. doi: 10.2174/156720511796717177.
The aggregation and accumulation of the microtubule-associated protein (Tau) is a pathological hallmark of Alzheimer disease (AD) and many neurodegenerative diseases. For a long time research has focused on neurofibrillary tangles (NFTs) and other large meta-stable inclusions composed of aggregated hyperphosphorylated tau protein. The correlation between these structures and disease progression produced conflicting results; moreover, the mechanism of their formation remains poorly understood. Lately, the significance and toxicity of NFTs have been challenged and a new aggregated tau entity has emerged as the true pathogenic species in tauopathies and a possible mediator of Aβ toxicity in AD; specifically, aggregates of a size intermediate between monomers and NFTs the so-called tau oligomers. Tremendous efforts have been devoted toward the optimization of a safe vaccine for AD by targeting Aβ peptide; despite the disappointing results, these studies produced a wealth of useful knowledge, which should be considered in developing tau-based immunotherapy. Herein, we discuss the evidence supporting the critical role of tau oligomers in AD, the potential and challenges for targeting them by immunotherapy as a novel approach for AD treatment.
微管相关蛋白 (Tau) 的聚集和积累是阿尔茨海默病 (AD) 和许多神经退行性疾病的病理标志。长期以来，研究一直集中在神经纤维缠结 (NFT) 和由聚集的过度磷酸化 Tau 蛋白组成的其他大型亚稳态包含物上。这些结构与疾病进展之间的相关性产生了相互矛盾的结果；此外，其形成机制仍知之甚少。最近，NFT 的意义和毒性受到了挑战，一种新的聚集 Tau 实体已成为 Tau 病中的真正致病物种，并且可能是 AD 中 Aβ 毒性的中介物；具体而言，大小介于单体和 NFT 之间的聚集物，即所谓的 Tau 低聚物。人们投入了巨大的努力来优化针对 Aβ 肽的 AD 安全疫苗；尽管结果令人失望，但这些研究产生了大量有用的知识，在开发基于 Tau 的免疫疗法时应考虑这些知识。在此，我们讨论了支持 Tau 低聚物在 AD 中关键作用的证据，以及通过免疫疗法靶向它们的潜力和挑战，作为 AD 治疗的新方法。
