Microglial purinergic signaling in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease. The prevalent features of AD pathogenesis are the appearance of β-amyloid (Aβ) plaques and neurofibrillary tangles, which cause microglial activation, synaptic deficiency, and neuronal loss. Microglia accompanies AD pathological processes and is also linked to cognitive deficits. Purinergic signaling has been shown to play a complex and tight interplay with the chemotaxis, phagocytosis, and production of pro-inflammatory factors in microglia, which is an important mechanism for regulating microglia activation. Here, we review recent evidence for interactions between AD, microglia, and purinergic signaling and find that the purinergic P2 receptors pertinently expressed on microglia are the ionotropic receptors P2X4 and P2X7, and the subtypes of P2YRs expressed by microglia are metabotropic receptors P2Y₂, P2Y₆, P2Y₁₂, and P2Y₁₃. The adenosine P1 receptors expressed in microglia include A₁R, A_2AR, and A_2BR. Among them, the activation of P2X4, P2X7, and adenosine A₁, A_2A receptors expressed in microglia can aggravate the pathological process of AD, whereas P2Y₂, P2Y₆, P2Y₁₂, and P2Y₁₃ receptors expressed by microglia can induce neuroprotective effects. However, A₁R activation also has a strong neuroprotective effect and has a significant anti-inflammatory effect in chronic neuroinflammation. These receptors regulate a variety of pathophysiological processes in AD, including APP processing, Aβ production, tau phosphorylation, neuroinflammation, synaptic dysfunction, and mitochondrial dysfunction. This review also provides key pharmacological advances in purinergic signaling receptors.