A2A Adenosine Receptor: A Possible Therapeutic Target for Alzheimer’s Disease by Regulating NLRP3 Inflammasome Activity?

Abstract

The A2A adenosine receptor, a member of the P1 purinergic receptor family, plays a crucial role in the pathophysiology of different neurodegenerative illnesses, including Alzheimer’s disease (AD). It regulates both neurons and glial cells, thus modulating synaptic transmission and neuroinflammation. AD is a complex, progressive neurological condition that is the leading cause of dementia in the world’s old population (>65 years of age). Amyloid peptide-β extracellular accumulation and neurofibrillary tangles constitute the principal etiologic tracts, resulting in apoptosis, brain shrinkage, and neuroinflammation. Interestingly, a growing body of evidence suggests a role of NLRP3 inflammasome as a target to treat neurodegenerative diseases. It represents a tripartite multiprotein complex including NLRP3, ASC, and procaspase-1. Its activation requires two steps that lead with IL-1β and IL-18 release through caspase-1 activation. NLRP3 inhibition provides neuroprotection, and in recent years adenosine, through the A2A receptor, has been reported to modulate NLRP3 functions to reduce organ damage. In this review, we describe the role of NLRP3 in AD pathogenesis, both alone and in connection to A2A receptor regulation, in order to highlight a novel approach to address treatment of AD.

Adenosine receptor signalling in Alzheimer’s disease

“…Indeed, additional studies support the importance of glial cells, with A 2A R being upregulated in microglia and astrocytes after treatment with Aβ o [228] and conditional genetic ablation of astroglial A 2A R enhancing long-term memory in young and in ageing mice [229]. Targeting the NLRP3 (nucleotidebinding oligomerisation domain-, leucine-rich repeat-, and pyrin domain-containing 3) inflammasome to modulate AD pathology has increasing interest as a therapeutic strategy [230], with emerging evidence of A 2A R in microglia offers an upstream therapeutic target [231]. A 2A R activation stimulates sustained NLRP3 inflammasome activity and the production of proinflammatory cytokines (e.g.…”

Therapeutic Potential of Allicin and Aged Garlic Extract in Alzheimer’s Disease

“…However, these studies are derived from cellular or mouse models, while clinical trials concerning these compounds and AD are not present, suggesting that this evidence should be confirmed in human studies before the beneficial effects of compounds contained in garlic might be translated into therapy. Finally, the importance of the NLRP3 inflammasome pathway in neuroinflammation and neurodegenerative diseases, such as AD, has been established [125], and very recent data on its modulation via allicin have been reported, whereas no evidence has been shown for AGE, implying the need for further characterization.…”

Mitochondrial Damage-Associated Molecular Patterns Content in Extracellular Vesicles Promotes Early Inflammation in Neurodegenerative Disorders

“…The modulation of NLRP3-mediated inflammasome activation has been presented as a potential therapeutic approach in AD [ 159 , 160 ], PD [ 161 ], HD [ 162 ] and ALS [ 163 ]. Although the relationship between NLRP3 and extracellular cardiolipin has not been assessed in these neurodegenerative diseases, it seems legitimate to believe in the involvement of cardiolipin as a mtDAMP in neurodegeneration progression.…”