Departments of Neuroscience and Physiology, and Psychiatry, Neuroscience Institute, New York University Grossman School of Medicine, New York, NY, USA.
J Alzheimers Dis. 2024;101(s1):S129-S140. doi: 10.3233/JAD-231238.
The tau protein undergoes pathological changes in Alzheimer's disease and other tauopathies that eventually lead to functional impairments. Over the years, several therapeutic approaches have been examined to slow or halt the progression of tau pathology but have yet to lead to an approved disease-modifying treatment. Of the drugs in clinical trials that directly target tau, immunotherapies are the largest category and mostly consist of antibodies in different stages of development. There is a reasonable optimism that at least some of these compounds will have a clinically meaningful efficacy. This view is based on the significant although modest efficacy of some antibodies targeting amyloid-β in Alzheimer's disease and the fact that tau pathology correlates much better with the degree of dementia than amyloid-β lesions. In Alzheimer's disease, clearing pathological tau may therefore improve function later in the disease process than when removing amyloid-β. This review provides a brief update on the active and passive clinical tau immunization trials with insight from preclinical studies. Various epitopes are being targeted and some of the antibodies are said to target extracellular tau but because almost all of pathological tau is found intracellularly, the most efficacious antibodies should be able to enter the cell.
在阿尔茨海默病和其他神经tau 病中，tau 蛋白发生病理性改变，最终导致功能障碍。多年来，已经研究了几种治疗方法来减缓或阻止 tau 病理的进展，但尚未导致批准的疾病修饰治疗。在针对 tau 的临床试验药物中，免疫疗法是最大的类别，主要由不同开发阶段的抗体组成。有合理的乐观认为，其中至少一些化合物将具有临床意义上的疗效。这种观点基于以下事实：针对淀粉样蛋白-β的一些抗体在阿尔茨海默病中具有显著但适度的疗效，并且 tau 病理与痴呆程度的相关性远高于淀粉样蛋白-β病变。因此，在阿尔茨海默病中，清除病理性 tau 可能比清除淀粉样蛋白-β更能改善疾病后期的功能。本文简要介绍了正在进行的主动和被动临床 tau 免疫试验，并结合临床前研究提供了一些见解。正在针对各种表位，一些抗体被认为针对细胞外 tau，但由于几乎所有病理性 tau 都存在于细胞内，因此最有效的抗体应该能够进入细胞。
