The Role of P2X7 Receptor in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease characterized by a progressive cognitive decline associated with global brain damage. Initially, intracellular paired helical filaments composed by hyperphosphorylated tau and extracellular deposits of amyloid-β (Aβ) were postulated as the causing factors of the synaptic dysfunction, neuroinflammation, oxidative stress, and neuronal death, detected in AD patients. Therefore, the vast majority of clinical trials were focused on targeting Aβ and tau directly, but no effective treatment has been reported so far. Consequently, only palliative treatments are currently available for AD patients. Over recent years, several studies have suggested the involvement of the purinergic receptor P2X7 (P2X7R), a plasma membrane ionotropic ATP-gated receptor, in the AD brain pathology. In this line, altered expression levels and function of P2X7R were found both in AD patients and AD mouse models. Consequently, genetic depletion or pharmacological inhibition of P2X7R ameliorated the hallmarks and symptoms of different AD mouse models. In this review, we provide an overview of the current knowledge about the role of the P2X7R in AD.

Keywords: amyloidogenic processing; induced pluripotent stem cells; inflammation; microglia; oxidative stress; synaptopathy.

FIGURE 1

Schematic illustration summarizing the pieces of evidence accumulated over the past years indicating that P2X7R plays a central role in the different physiopathological processes associated with Alzheimer’s disease. The outer circular arrows illustrate a chain of interconnected and mutually influenced pathological processes associated with AD. Inner arrows represent the relationships found between P2X7R and these pathological processes, summarizing the studies discussed in the present review. Briefly, P2X7R modulates amyloid APP processing, and it is postulated as a neuroinflammation triggering factor. Upregulated P2X7R expression in AD patients and different AD and neuroinflammation mouse models give it a key role in disease progression. Besides, P2X7R also contributes to neuronal loss and synaptic alterations, oxidative stress; inflammasome assembling; and altered microglial function, being all of them processes contributing to AD progression, as described in the present review.