Anti tau scFvs - new tools to better understand and treat Alzheimer's disease

阿尔茨海默病是最常见的痴呆症，影响着全球约3500万人，在我们老龄化的社会中患病率不断上升。阿尔茨海默病的进展与淀粉样斑块中淀粉样蛋白- β (Abeta)和神经原纤维缠结中tau蛋白的积累有关。由于Abeta聚集先于tau病理，过去几年的治疗策略主要集中在通过针对Abeta的主动和被动免疫来减少淀粉样斑块负担。尽管在阿尔茨海默病（AD）的小鼠模型中已经取得了令人鼓舞的结果，但这种方法尚未在临床试验中证明是有效的。最近的证据表明，tau蛋白而非β蛋白的积累与患者的临床症状相关，并且tau蛋白病理通过一种迄今未知的机制在细胞间传播。Holtzman博士的实验室之前已经证明，在表达人类tau P301S的转基因小鼠tau病模型中，使用自制的抗tau抗体HJ8.5进行被动免疫可以减少tau的总体积累，减缓疾病的进展。然而，由于血浆中只有一小部分抗体能够穿过血脑屏障，因此用抗体治疗人类神经系统疾病仍然很难作为一种治疗策略。因此，我的项目将侧重于利用靶向中枢神经系统（CNS）的基因治疗方法，提高HJ8.5抗体治疗AD和其他tau相关疾病的可行性。为了实现这一目标，单链片段可变抗体（scFv）将被设计和广泛地在体外和体内测试，该抗体由重链和轻链的可变区组成，由不同的肽连接物连接。scFvs已被证明具有抗原结合特异性，并且由于其体积小，具有良好的组织穿透性，可以很容易地装入腺相关病毒（AAV）中，以便在中枢神经系统中进行治疗递送。除了作为一种潜在的治疗剂，scFvs还将被用作一种生物学工具，进一步阐明细胞外tau在体内细胞间传播中的作用。

Alzheimer's disease is the most common form of dementia, affecting about 35 million people worldwide with an increasing prevalence in our ageing society. The progression of Alzheimer's disease is associated with accumulation of amyloid-beta (Abeta) in amyloid plaques and tau in neurofibrillary tangles. Since Abeta aggregation precedes tau pathology, treatment strategies in the past years have focused on reducing amyloid plaque burden by active and passive immunization targeting Abeta. Although promising results have been achieved in mouse models of Alzheimer's disease (AD) this approach has not yet proven to be effective in clinical trials. Recent evidence suggests that accumulation of tau but not Abeta correlates with clinical symptoms in patients and that tau pathology spreads from cell-to-cell by a so far unknown mechanism. Dr. Holtzman's lab has previously shown that passive immunization with the in house made anti-tau antibody HJ8.5 decreased overall tau accumulation and slowed progression of the disease in a human tau P301S expressing transgenic mouse model of tauopathy. However, treatment of neurological diseases with antibodies remains difficult as a therapeutic strategy in humans due to only a small percentage of antibodies in the plasma being able to cross the blood-brain-barrier. Therefore, my project will focus on improving the feasibility of a treatment of AD and other tau related diseases with the HJ8.5 antibody utilizing a gene therapy approach targeting the central nervous system (CNS). To achieve this, single-chain fragment variable (scFv) antibodies, which consist of the variable region of the heavy and the light chain, connected by different peptide linkers, will be engineered and tested extensively in vitro and in vivo. scFvs have been shown to retain antigen-binding specificity and due to their small size yield good tissue penetration and can be easily packed into an adeno associated virus (AAV) for therapeutic delivery in the CNS. In addition to serving as a potential therapeutic agent, the scFvs will also be used as a biological tool to further elucidate the role of extracellular tau in tau propagation from cell to cell in vivo.