Investigating the role of Kv3.4 potassium channels in neurodegenerative pathways of relevance to Alzheimer's Disease.

阿尔茨海默病（AD）占痴呆症病例的近2/3，并且影响世界人口的约1%。目前，用于AD的五种药物治疗中有四种是乙酰胆碱酯酶抑制剂，旨在增加大脑中乙酰胆碱的量，第五种是N-甲基-D-天冬氨酸（NMDA）受体拮抗剂。这些治疗纯粹是对症的，很明显它们对预防或延缓疾病进展没有显著作用。由于缺乏有效的药物干预和这种疾病的衰弱性质，社会在心理社会治疗和护理方面的成本越来越高。据估计，仅在英国，AD每年的经济成本为230亿英镑（ARUK，2012），随着人口老龄化，如果没有有效的管理或预防，这一数字只会增加。淀粉样蛋白级联假说表明，在家族性和散发性AD中，淀粉样蛋白β（AB肽）在脑中的积累是驱动AD病理学的主要原因。这种假设已经驱动了AD的药物开发数十年，没有真实的转化为对患者有益的治疗（Karran和哈代，2014，Ann Neurol; 76（2）：185-205）。由于最近大量的基于淀粉样蛋白级联假说的II/III期试验失败，人们越来越多地努力确定治疗AD的新治疗策略。最近，电压门控钾通道Kv3.4亚基，其基础的快速失活的K+电流（IA），已被认为是相关的AD的发病机制，并正在成为一个新的候选目标AD。越来越多的证据表明，Kv3.4，像Kv3.3，也可能在细胞命运中发挥作用。发现Kv3.4蛋白在AD早期患者的死后大脑中过表达;在更晚期的阶段，Kv3.4以高水平存在于退化的结构中。在携带人APP基因突变的AD的Tg 2576转基因小鼠模型中也观察到Kv3.4的类似上调（Angulo等人，2004，J Neurochem; 91（3）：547-57）。最近，据报道Kv3.4通道在暴露于AB寡聚体的星形胶质细胞和Tg 2576小鼠的星形胶质细胞中上调（Boscia等人，2017，Neurobiology of Aging; doi：10.1016/j.neurobiolaging.2017.03.008）.在当前的项目中，我们将利用炎症体外测定，临床前体内模型和人类死后组织来研究Kv3.4在与AD相关的神经退行性通路中的作用，目的是为测试靶向该受体的新药提供平台。

Alzheimer's disease (AD) accounts for almost 2/3 of the cases of dementia, and affects approxiamately 1% of the world's population. Currently four out of the five pharmacological treatments used for AD are acetylcholinesterase inhibitors aimed at boosting the amount of acetylcholine in the brain, with the fifth being an N-methyl-D-aspartate (NMDA) receptor antagonist. These treatments are purely symptomatic and it is clear they have no significant effect on the prevention or delay of disease progression. Due to the lack of effective pharmaceutical intervention and the debilitating nature of the disease, there is an increasing cost to society in the form of psychosocial therapy and care giving. It is estimated that in the UK alone, AD costs the economy £23 billion a year (ARUK, 2012) and with an aging population, this figure is only going to increase without effective management or prevention. The Amyloid Cascade hypothesis suggests that in both familial and sporadic AD, amyloid beta (AB peptide) accumulation in the brain is the primary culprit in driving AD pathology. This hypothesis has driven drug development for AD for decades with no real translation to a beneficial treatment for patients (Karran & Hardy, 2014, Ann Neurol; 76(2):185-205). Due to a number of recent large Phase II/III failures based around the Amyloid Cascade hypothesis there is an increasing effort to identify novel therapeutic strategies for treating AD. Recently, the voltage gated potassium channel Kv3.4 subunit, which underlies the fast-inactivating K+ currents (IA), has been recognized to be relevant for AD pathogenesis and is emerging as a new target candidate for AD.Accumulating evidence suggests that Kv3.4, like Kv3.3, may also play a role in cell fate. Kv3.4 protein was found to be overexpressed in post-mortem brain from patients in the early stages of AD; in more advanced stages, Kv3.4 was present at high levels in degenerated structures. A similar up-regulation of Kv3.4 was also observed in the Tg2576 transgenic mouse model of AD which carries a human APP gene mutation (Angulo et al., 2004, J Neurochem; 91(3):547-57). More recently Kv3.4 channels were reported to be up-regulated in astrocytes exposed to AB oligomers and in astrocytes of Tg2576 mice (Boscia et al., 2017, Neurobiology of Aging; doi: 10.1016/j.neurobiolaging.2017.03.008).In the current project we will utilise inflammatory in vitro assays, preclinical in vivo models and human post-mortem tissue to investigate the role of Kv3.4 in neurodegenerative pathways of relevance to AD with the goal to provide a platform for testing novel drugs targeting this receptor.