The role of adenosine A2A receptors in Alzheimer?s disease and tauopathies

Adenosine signals through four distinct G protein-coupled receptors that are located at various synapses, cell types and brain areas. Through them, adenosine regulates neuromodulation, neuronal signaling, learning and cognition as well as the sleep-wake cycle, all strongly impacted in neurogenerative disorders, among which Alzheimer's Disease (AD). AD is a complex form of cognitive deficits characterized by two pathological hallmarks: extracellular deposits of aggregated beta-amyloid peptides and intraneuronal fibrillar aggregates of hyperand abnormally phosphorylated Tau proteins. Both lesions contribute to the early dysfunction and loss of synapses which are strongly associated to the development of cognitive decline in AD patients. The present review focuses on the pathophysiological impact of the A2ARs dysregulation observed in cognitive area from AD patients. We are reviewing not only evidence of the cellular changes in A2AR levels in pathological conditions but also describe what is currently known about their consequences in term of synaptic plasticity, neuro-glial miscommunication and memory abilities. We finally summarize the proof-of-concept studies that support A2AR as credible targets and the clinical interest to repurpose adenosine drugs for the treatment of AD and related disorders.This article is part of the Special Issue on "Purinergic Signaling: 50 years".