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Neuroglial P2Y1 receptor signalling differentially contributes to inflammatory neurodegeneration
Charlotte Schubert1, Ricardo Lopes Fonseca1, Alexandros Hadjilaou1,2,3
1Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Journal of Neuroinflammation
|June 13, 2026
Summary
Extracellular adenosine diphosphate (ADP) and triphosphate (ATP) signal through the P2Y1 receptor, driving astrocyte-mediated neurotoxicity in models of multiple sclerosis (MS). Targeting this pathway reduces neuroinflammation and neuronal loss.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Extracellular adenosine triphosphate (ATP) and diphosphate (ADP) are crucial signaling molecules in the central nervous system (CNS).
- Purinergic receptors mediate neuroinflammatory responses, but their specific roles in inflammation-induced neurodegeneration are not fully understood.
- Astrocytes and neurons undergo significant changes during inflammation.
Purpose of the Study:
- To investigate the role of specific purinergic pathways in neuroinflammation and neurodegeneration.
- To determine the contribution of the ADP/ATP-activated P2Y1 receptor to astrocyte-mediated neurotoxicity in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS).
Main Methods:
- Utilized plasma membrane-targeted luciferase reporter mice to measure extracellular ATP levels during EAE.
- Examined P2ry1 expression in astrocytes and MS lesions.
- Employed pharmacological inhibition and astrocyte-specific/neuron-specific P2Y1 receptor deletion in vivo.
- Investigated astrocytic P2Y1 signaling mechanisms in vitro using cytokine stimulation and analyzed neuronal viability in astrocyte-derived supernatants.
Main Results:
- Extracellular ATP levels and astrocytic P2ry1 expression were elevated during acute EAE and in MS lesions.
- Pharmacological inhibition or astrocyte-specific deletion of P2Y1 significantly reduced EAE severity, astrocytosis, and neuronal loss.
- Astrocytic P2Y1 signaling promoted inflammatory gene expression and metabolic reprogramming, leading to astrocyte-derived neurotoxicity.
- Neuronal P2Y1 signaling contributed to oxidative stress and mitochondrial dysfunction.
Conclusions:
- Astrocytic P2Y1 receptor is a key regulator of neuroinflammatory damage in EAE.
- Targeting astrocytic P2Y1 offers a potential therapeutic strategy for neuroinflammatory diseases like MS.
- Distinct roles for P2Y1 signaling in astrocytes and neurons were identified in the context of neuroinflammation.
