Towards Improved P2X7R Cellular Models for Alzheimer’s Disease Drug Discovery

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with no disease-modifying therapeutics. The P2X7 receptor (P2X7R) presents as a promising target for AD drug discovery due to its pathogenic role in the onset and progression of neuroinflammation, a hallmark pathology of AD. There has been extensive pre-clinical work on the development of P2X7R antagonists, but there is yet to be a therapeutic that has progressed for further clinical evaluation in Alzheimer’s disease. To accelerate the discovery and translation of P2X7R antagonists for AD, better in vitro screening models are needed. Current models such as immortalized cell lines fail to replicate the complexity of physiological disease, and animal models present hurdles due to poor translatability, and low accuracy in predicting safety and efficacy of therapeutics. However, induced pluripotent stem cells (iPSCs) may allow bridging of the gap between preclinical screening methods and human disease. These patient-derived cells allow the genetic material of donors to be harvested, better recapitulating the multifaceted aspects of disease. iPSC-derived neurons and glia may facilitate the creation of more successful disease modelling and drug screening platforms, allowing for a greater understanding of the underlying disease pathology. Current work in the central nervous system (CNS) drug discovery space has demonstrated that the P2X7R is functional in disease-relevant iPSC models, supporting their suitability for pharmacological investigation. More importantly, they provide a robust platform that may drive the development of P2X7R antagonists from pre-clinical studies into a clinical setting.