Microglial P2X4 receptors promote ApoE degradation and cognitive deficits in Alzheimer disease

Numerous evidence support that microglia contributes to the progression of Alzheimer’s disease. P2X4 receptors are ATP-gated channels, which are de novo expressed in a subset of reactive microglia associated to various pathological contexts, contributing to microglial functions. Here, we investigated the role of P2X4 in the context of Alzheimer disease (AD). In both human AD brain and APPswe/PSEN1dE9 mice, P2X4 is almost exclusively expressed in plaque associated microglia. Genetic deletion of P2rx4 results in the reversal of cognitive declines and in a lower amount of soluble Aß1 −42 in 12 months old APP/PS1 mice, while no obvious alteration of plaque associated microglia characteristics is observed. Using proteomic, we identified ApoE as a specific P2X4 interacting protein. We found that P2X4 regulates lysosomal cathepsin B activity promoting ApoE degradation; P2rx4 deletion results in higher amount of intracellular and secreted ApoE in both BMDM and microglia from APP/PS1 brain. Our results support that microglial P2X4 promotes lysosomal ApoE degradation, indirectly altering Aß peptide clearance, which in turn might promote synaptic dysfunctions and cognitive deficits. Our findings also uncover a specific interplay between purinergic signaling, microglial ApoE, sAß species and cognitive deficits associated with AD. ### Competing Interest Statement The authors have declared no competing interest.