Extracellular ATP is a Key Factor in Promoting Alzheimer’s Disease Neuroinflammation

Alzheimer’s disease (AD) is a neurodegenerative disease caused by poorly known pathogenetic mechanisms and aggravated by delayed therapeutic intervention; it still lacks an effective cure. However, it is clear that some important neurophysiological processes are altered years before the onset of clinical symptoms, offering the possibility of identifying biological markers useful for early diagnosis and implementation of effective therapies. It has become clear over recent years that nonneuronal cells, mainly microglia, are dysfunctional in the AD brain and that inflammation of the brain (neuroinflammation) has a very important pathogenic role.

A key molecule involved in the activation and propagation of inflammation is ATP. ATP is well known for being the fundamental intracellular energy currency; however, we now know that this molecule is also released into the extracellular space when cells are stressed or injured. In inflamed tissue interstitium, extracellular ATP (eATP) is a signal of danger to nearby cells, amplifying a series of reactions linked to the inflammatory response. In our previous research project funded by Cure Alzheimer’s Fund, we engineered novel probes to measure the ATP concentration in the brain interstitium in animal models of AD, making monitoring its concentration during AD progression possible. Furthermore, we have investigated the role of one of the main eATP receptors, P2X7, providing evidence of its pivotal role in supporting neuroinflammation. We also found the concentration of the P2X7 receptor in the blood varies with age and gender, and it is increased in subjects with initial cognitive deterioration (but not in overt AD patients), suggesting that this receptor might be a peripheral biomarker of early cognitive impairment. In the follow-on project, we aim to investigate whether the modulation of both the P2X7 receptor and the concentration of eATP in the brain could halt or delay AD progression. We are confident that these studies focused on extracellular ATP as a mediator of AD neuroinflammation will provide novel information for the design of more effective approaches to early AD diagnosis and treatment.