Identifying a new drug target for the treatment of Alzheimer's disease

炎症有助于阿尔茨海默病（AD）的进展，并且正在进行的研究正在将NLRP 3-炎性体复合物确立为AD中最重要的炎症调节剂之一。NLRP 3炎性体在小胶质细胞内形成分子平台，催化蛋白酶caspase-1的活化。半胱天冬酶-1负责将有效的促炎细胞因子白细胞介素-1 β（IL-1 β）从非活性分泌形式转化为活性分泌形式，其被认为是许多不同疾病和关键治疗靶点的主要贡献者。活跃的caspase-1存在于AD患者的大脑中，这表明NLRP 3可能有助于人类疾病。NLRP 3也是AD小鼠模型中炎症、病理学和记忆缺陷发展的核心。抗IL-1药物，如生物制剂canakinumab和anakinra，不容易穿透大脑，并且在临床使用中没有已知直接靶向NLRP 3的分子。我们已经确定了体积调节阴离子通道（VRAC），质膜中的Cl-通道，作为NLRP 3炎性体的重要调节剂，以及限制NLRP 3依赖性炎症的潜在靶点。在这里，我们假设VRAC有助于支撑AD病理过程的炎症，因此旨在将VRAC确立为AD的治疗靶点。

Inflammation contributes to the progression of Alzheimer's disease (AD) and on-going research is establishing the NLRP3-inflammasome complex as one of the most important regulators of inflammation in AD. The NLRP3 inflammasome forms a molecular platform inside microglial cells, catalysing the activation of the protease caspase-1. Caspase-1 is responsible for converting the potent pro-inflammatory cytokine interleukin-1beta (IL-1beta) from an inactive to an active secreted form, which is recognised as a major contributor to a number of diverse diseases and key therapeutic target. Active caspase-1 is present in the brains of humans with AD, suggesting that NLRP3 may contribute to the human condition. NLRP3 is also central to the development of inflammation, pathology and memory deficits in a mouse model of AD. Anti-IL-1 drugs, such as the biologicals canakinumab and anakinra, do not easily penetrate the brain and there are no molecules known to directly target NLRP3 in clinical use. We have identified the volume regulated anion channel (VRAC), a Cl- channel in the plasma membrane, as an important regulator of the NLRP3 inflammasome, and a potential target to limit NLRP3-dependent inflammation. Here we hypothesise that VRAC contributes to the inflammation that underpins the pathological process of AD and therefore aim to establish VRAC as a therapeutic target for AD.