Purinergic checkpoints in neuroinflammation and Alzheimer’s disease: extracellular ATP and the P2X7 receptor as main drivers of neurodegeneration

Despite strenuous investigation, aetiology and pathogenesis of Alzheimer’s disease (AD) are still unclear. Extracellular amyloid β (Aβ) plaques and intracellular aggregates of hyperphosphorylated tau protein are thought to be main causes of AD thus spurring a thorough investigation of their role, yet this research effort generated an enormous mass of data but no cures.

Inflammation is central in AD. Identification of novel inflammatory biomarkers and clarification of their pathogenetic role might facilitate early diagnosis of AD and promote drug discovery. Inflammation is ignited and amplified by release of factors of endogenous (DAMPs, damage-associated molecular patterns) or exogenous (PAMPs, pathogen-associated molecular patterns) origin. Among DAMPs, a major role is played by extracellular ATP (eATP). Extracellular ATP is present in low concentrations (nanomolar range) in healthy tissues but reaches tens or even hundreds of micromoles/liter at sites of trauma, tumour or inflammation, AD brain included. In diseased conditions, eATP can leak passively, following cell injury or cell death, but frequently is released via as plasma membrane (PM) channels and transporters, or exocytosis. In the extracellular space, eATP acts as a pro-inflammatory agent acting at P2Y and P2X receptors (the P2X7 receptor, P2X7R, being most frequently involved in inflammation), and as a precursor of adenosine (ADO), a powerful anti-inflammatory agent, thus behaving as a versatile immunomodulator that promotes or dampens (via ADO) inflammation. Thus, P2X7R is increasingly considered an “inflammatory checkpoint” since its activation is a fundamental prerequisite for ignition of inflammation. Furthermore, the P2X7R is also a conduit for the release of eATP. Activation of the P2X7R can be tuned by modulating the eATP concentration [eATP] by targeting non-lytic release pathways, such as pannexins and connexins (or the P2X7R itself), or PM ecto-nucleotidases (CD39 and CD73).Microglia, a main target of eATP in the brain, has a key role in AD, not only as an inflammatory cell type but also as a homeostatic agent, crucial for the control of neuronal activity.

In this proposal, we will investigate the role played by eATP and microglia in the pathogenesis of AD based on the following hypotheses: a) different agents and insults ignite inflammation in the brain (neuroinflammation) by releasing eATP; b) eATP activates microglia P2Y and P2X receptors; c) activated microglia loses its homeostatic function and releases neurotoxic molecules, among which Aβ; d) CD39 and CD73 activity is downregulated in activated glia; e) eATP levels are increased and ADO generation is inhibited in the AD brain; f) eATP synergizes with Aβ at microglia mainly via P2X7R to amplify inflammation and further promote microglia dysfunction. Should our hypothesis be verified, eATP/P2X7R targeting might be an innovative approach for AD therapy