Numerous evidences 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 with various pathological contexts, contributing to microglial functions. P2X4 receptors are mainly localized in lysosomes and trafficking to the plasma membrane is tightly regulated. Here, we investigated the role of P2X4 in the context of
Alzheimer's disease (AD). Using proteomics, we identified
Apolipoprotein E (
ApoE) as a specific P2X4 interacting
protein. We found that P2X4 regulates lysosomal
cathepsin B (CatB) activity promoting
ApoE degradation; P2rX4 deletion results in higher amounts of intracellular and secreted
ApoE in both bone-marrow-derived macrophage (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-month-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 promotes synaptic dysfunctions and cognitive deficits. Our findings uncover a specific interplay between purinergic signaling, microglial
ApoE, soluble Aß (sAß) species and cognitive deficits associated with AD.