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

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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.