Knockout of P2Y12 receptor facilitates microglia-neuron body-to-body interactions and accelerates prion disease.

Microglia continuously monitor neuronal health through somatic purinergic junctions, where microglial processes establish dynamic contacts with neuronal cell bodies. The P2Y12 receptor is a key component of these junctions, essential for intercellular communication between ramified microglia and neurons under homeostatic conditions. While P2Y12 has long been considered a marker of homeostatic microglia, its potential role in reactive microglia during neurodegenerative disease remains largely unexplored. In this study, we demonstrate that P2Y12 deletion significantly reduces microglia-neuron process-to-body contacts in adult mice, consistent with previous findings. However, unexpectedly, P2Y12 loss markedly increases microglia-neuron body-to-body contacts, revealing an alternative mode of microglia-neuron communication independent of P2Y12. In prion-infected mice, P2Y12 expression persists in reactive, amoeboid microglia during advanced disease stages, including those engaging in extensive neuronal envelopment. Notably, P2Y12 loss increases the prevalence of envelopment events and accelerates disease progression. These findings redefine the role of P2Y12 in neurodegeneration, suggesting that its progressive decline lowers the threshold for microglia-neuron body-to-body interactions, ultimately influencing disease trajectory.