One of the most studied receptors in this family is the P2Y2R, with a wide distribution in all cells in human body and particularly in immune cells.258 In the brain, P2Y2 receptor is expressed on neurons, microglia, and astrocytes.12,259 Under normal brain conditions, there is a low expression of P2Y2R on neurons, but it can be upregulated to exert neuroprotective effects against the release of pro-inflammatory cytokine IL-1β as a result of P2X7R expression on activated microglia.260 In the AD mouse model TgCRND8, genetic deletion of P2Y2 receptor has shown to enhance early AD pathology, while activation of the receptor enhanced phagocytosis and degradation of the Aβ peptide.261 Furthermore, activation of P2Y2R has proven to result in degradation of amyloid precursor protein by α-secretase, yielding to soluble APPα peptide that prevented production and accumulation of the neurotoxic Aβ1-42. 262,263 In studies that compared brain neocortex and parietal cortex of postmortem patients with AD to those of the normal aged controls, the low level of P2Y2R expression was associated with neuropathology and synapse loss in patients with AD,263 presenting additional support
