Investigating P2X7R‐mediated inflammatory signalling in Alzheimer's disease

Abstract

AbstractBackgroundGlial function is altered in Alzheimer’s disease (AD) in response to danger‐associated molecular patterns in the local environment such as the binding of Aβ species to toll‐like and purinergic receptors, including P2X7R. These interactions activate pro‐inflammatory pathways and lead to the release of cytokines and chemokines that participate in damaging inter‐cellular cascades. In vivo AD models have shown beneficial effects following P2X7R inhibition via mechanisms that could prevent pathological tau changes. However, the effects of P2X7R activation and downstream inflammatory signalling on tau‐mediated neurodegeneration in AD remains unknown.MethodWe have used biochemical and immunohistochemical methods in post‐mortem control and AD BA9 prefrontal cortex to examine changes in P2X7R expression, determine the spatial pattern of P2X7R activation relative to Aβ and pathological tau accumulation and evaluate the association between P2X7R and local inflammatory responses. Primaryglial and organotypic slice culturesare being used to model glial responses to physiological Aβ species and the downstream consequences on neurons.ResultWe found elevated levels of P2X7R from Braak stage II relative to controls associated with an increased plaque burden, mislocalization of tau to the synapses and astrocyte reactivity. P2X7R was markedly expressed in astrocytes surrounding AD hallmarks and also in disease‐associated microglia neighbouring Aβ plaques. Investigation of inflammatory mediators linked with P2X7R‐positive glia revealed higher activation of the NLRP3 inflammasome and NFκB pathways with disease progression. Preliminary in vitro and ex vivo models suggest that pathological changes in tau following Aβ stimulation are related to P2X7R‐inflammatory activity.ConclusionThese data suggest that P2X7 receptor expression and activation is altered in the early stages of AD, prior to marked synapse loss. Ongoing studies are aimed at determining if blockade of P2X7R‐mediated inflammatory changes in has benefit in models of AD.