Microglial P2X4 receptors promote ApoE degradation and contribute to memory deficits in Alzheimer disease

Abstract Numerous evidence support that microglia contributes to the progression of Alzheimer’s disease. P2X4 receptors are ATP-gated channels with high calcium permeability, which are de novo expressed in a subset of reactive microglia associated to various pathological contexts, contributing to microglial functions. P2X4 receptors trafficking to the plasma membrane is tightly regulated and are mainly localized in lysosomes. Here, we investigated the role of P2X4 in the context of Alzheimer disease (AD). 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 APPswe/PSEN1dE9 brain. In both human AD brain and APP/PS1 mice, P2X4 and ApoE are almost exclusively expressed in plaque associated microglia. In 12 months old APP/PS1 mice, genetic deletion of p2rx4 reverses topographical and spatial memory impairment and reduces amount of soluble small aggregates of Aß1-42 peptide, while no obvious alteration of plaque associated microglia characteristics is observed. 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 uncover a specific interplay between purinergic signaling, microglial ApoE, sAß species and cognitive deficits associated with AD.