Abstract
Background:
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. However, during chronic neurodegeneration, such as that seen in prion diseases, microglia transition from process-based surveillance to extensive body-to-body interactions, enveloping neuronal somata. Despite its widespread use as a homeostatic marker, the functional role of P2Y12 in chronic neurodegenerative contexts remains largely unexplored.
Methods:
We investigated how genetic deletion of P2Y12 affects microglial morphology and microglia-neuron interactions in both healthy and prion-infected adult mice. In parallel, we assessed the impact of P2Y12 loss on prion disease progression and associated neuropathology.
Results:
In healthy adult mice, deletion of P2Y12 significantly disrupted canonical process-to-soma contacts, while paradoxically promoting increased microglia-neuron body-to-body interactions. This finding uncovers a previously unrecognized, P2Y12-independent mode of microglial engagement with neurons. Strikingly, in prion-infected mice, P2Y12 loss significantly increased the prevalence of neuronal envelopment by reactive microglia, and accelerated disease progression. Notably, this acceleration occurred without affecting prion accumulation or hippocampal neuronal loss, implicating altered microglia-neuron interactions - specifically excessive envelopment - as a key driver of disease exacerbation.
Conclusions:
This study redefines P2Y12 not as a passive marker of homeostasis but as an active regulator of neuroimmune dynamics. We demonstrate that P2Y12 is essential for maintaining balanced microglia-neuron communication under physiological conditions and for restraining maladaptive microglial behavior during chronic neurodegeneration associated with prion disease. These findings uncover a novel mechanism by which microglia contribute to disease progression and position P2Y12 as a potential therapeutic target for modulating microglial responses in neurodegenerative disorders.