Epitope-Specific Targeting of Tau Aggregates.

用于阿尔茨海默病和相关tau蛋白病的Tau免疫疗法已经从证明- 临床概念研究（Sigurdsson，EM，NIH R 01 AG 020197，2001; Asuni AA等，J Neurosci，27，2007） 审判由于tau蛋白病理学与痴呆程度的相关性比淀粉样蛋白-β（Aβ）病理学更好， 在疾病的后期阶段，靶向tau蛋白可能比清除Aβ更有效， 损伤是显而易见的。 尽管在证实和扩展了最初的研究后， 研究中，我们对抗体介导的药物清除机制的了解非常有限。 tau病理学已经获得了一些关于靶向哪些表位和作用机制的见解， 还有许多问题有待澄清。有趣的是，tau抗体在细胞外和细胞内与蛋白质相互作用。 但是每个位点对于tau清除的重要性还没有很好地确定，并且可能是抗体依赖性的。一些 抗体很容易被神经元吸收，而其他抗体则不然，这些差异可能是电荷- 依赖。由于大多数tau蛋白都存在于神经元内，因此将其靶向于那里可能比仅将其用于治疗更有效。 外部神经元 该项目的总体假设是，tau抗体可以减缓tau病理学的进展， 人类具体目的是：1）确定电荷、同种型、亲和力和大小对抗体的影响 有效性和阐明所涉及的机制，和; 2）基于结构的抗体工程 表征以提高功效和用于人源化。为了实现这些目标，我们建立了 与我们大学的研究人员合作，他们有互补的兴趣和专业知识。 该项目将重点关注针对关键tau表位磷酸丝氨酸396，404的抗体，我们 在我们的开创性研究中，它是一个目标，现在已经被几个小组证实是一个可行的目标。 我们将研究电荷、同种型、亲和力和大小如何影响功效。此外，我们将研究如何 抗体摄取和神经胶质细胞影响疗效，评估与抗体相关的蛋白质组学变化， 介导的tau病理清除，以确定所涉及的途径，并工程抗体，以澄清 机制，提高效率。 这个项目应该促进我们对tau免疫疗法的机械理解，以及这些免疫疗法是如何发挥作用的。 可以被改进以治疗阿尔茨海默病和相关的Tau蛋白病，与各种其他疾病直接相关， 蛋白质错误折叠疾病。

Tau immunotherapy for Alzheimer's disease and related tauopathies has advanced from proof-of- concept studies (Sigurdsson, EM, NIH R01AG020197, 2001; Asuni AA et al, J Neurosci, 27, 2007) to clinical trials. Because tau pathology correlates better with the degree of dementia than amyloid-β (Aβ) pathology, it is likely that targeting tau will be more effective than clearing Aβ in the later stages of the disease, when cognitive impairments are evident. Even though a few clinical trials have been initiated after confirmation and extension of the original studies, we have a very limited understanding of the mechanisms involved in antibody-mediated clearance of tau pathology. Some insight has been obtained on which epitopes to target and the mechanism of action but much remains to be clarified. Interestingly, tau antibodies interact with the protein both extra- and intracellularly but the importance of each site for tau clearance is not well defined, and is likely antibody-dependent. Some antibodies are readily taken up into neurons whereas others are not and these differences are likely charge- dependent. As most of tau is found intraneuronally, targeting it there is likely to be more efficacious than only outside neurons. The overall hypothesis of the project is that tau antibodies can slow the progression of tau pathology in humans. The Specific Aims are: 1) To determine how charge, isotype, affinity and size influence antibody efficacy and to clarify the mechanisms involved, and; 2) Antibody engineering based on structural characterization to improve efficacy and for humanization. Towards these aims, we have established collaborations with investigators at our university, who have complementary interests and expertise. The project will focus on antibodies against a key tau epitope, phospho-serine 396,404, which we targeted in our pioneering studies, and it has now been confirmed to be a feasible target by several groups. We will study how charge, isotype, affinity and size influence the efficacy. Furthermore, we will examine how antibody uptake and glial cells influence efficacy, assess proteomic changes associated with antibody- mediated clearance of tau pathology to identify the pathways involved, and engineer the antibodies to clarify mechanisms and improve efficacy. This program should advance our mechanistic understanding of tau immunotherapies and how those can be improved to treat Alzheimer's disease and related tauopathies, with direct relevance to various other protein misfolding disorders.