Epitope-Specific Targeting of Tau Aggregates.

利用免疫系统靶向病理性tau蛋白最近成为阿尔茨海默病（AD）和相关tau病的潜在治疗方法。我们之前的研究表明，针对疾病相关的磷酸化tau表位的主动免疫可减少体内脑tau聚集并减缓缠结相关行为表型的进展。tau免疫疗法的前景现在已经被其他研究小组证实。最近有报道称细胞外tau蛋白对tau病理的解剖扩散很重要，并加强了清除病理性tau蛋白的可行性。虽然主动免疫在许多方面对于慢性疾病如阿尔茨海默病是理想的，但它可能固有地导致自身免疫不良反应，而被动免疫可以避免这种不良反应。正如我们的初步研究结果所表明的那样，是否单独使用tau单克隆抗体（mab）可以获得类似的治疗效果，还有待彻底评估。然后，这些单克隆应该进行人源化，用于临床试验。

Harnessing the immune system to target pathological tau protein has recently become attractive as a potential therapy for Alzheimer's disease (AD) and related tauopathies. We previously showed that active immunization targeting a disease-related phospho-tau epitope reduces cerebral tau aggregates in vivo and slows progression of the tangle-related behavioral phenotype. The promise of tau immunotherapy has now been confirmed by other groups. Recent reports that extracellular tau is important for the anatomical spread of tau pathology strengthen as well the feasibility of clearing pathological tau. While the active approach is in many ways ideal for a chronic disease such as AD, it can inherently lead to autoimmune adverse reactions that may be avoided with passive immunization. It also remains to be thoroughly assessed if a similar therapeutic effect can be obtained with tau monoclonal antibodies (mAbs) alone, as our preliminary findings indicate. These monoclonals should then be humanized for clinical trials. Specific Aim 1 is to determine if the efficacy, safety and mechanism of action of tau mAbs is epitope- dependent. We hypothesize that antibody efficacy in clearing tau aggregates may depend on the epitope being targeted and the stage of tau pathology. The ability of monoclonals against various tau epitopes to prevent or reverse tau aggregation, and associated toxicity and cognitive impairments will be assessed in a novel tangle mouse model that is ideal for this purpose. Concurrently, the mechanism and safety of antibody-mediated clearance of pathological tau will be clarified in live animals and brain slice cultures. Prevention or reversal of tau aggregation and/or downstream pathology may be epitope dependent. Certain tau epitopes are more prominently detected in the early stages of tau aggregation whereas other are generated and/or become accessible for antibody-binding in the later stages of the disease. It is also conceivable that targeting some regions of tau may have toxic effects. These studies are likely to have broad implications. They may clarify sequence of events involved in tau pathology, and identify which regions of the tau protein is best to target for immunotherapy, which may apply to other therapies as well. Furthermore, these experiments should identify a candidate monoclonal for clinical trials. Specific Aim 2 is structural characterization of the lead therapeutic tau mAb for its humanization. This procedure is necessary to reduce the immunogenicity of the antibody, and thereby render it safer for human use. It requires structural characterization of its binding site, and regions not critical for antigen binding can then be replaced with human sequences. The important structural information can also facilitate development of small molecule mimetics for therapeutic or diagnostic use. Together, these aims may lead to a novel therapy for AD and related tauopathies.