Alzheimer and Purinergic Signaling: Just a Matter of Inflammation?

Merighi, Stefania; Poloni, Tino Emanuele; Terrazzan, Anna; Moretti, Eva; Gessi, Stefania; Ferrari, Davide

doi:10.3390/cells10051267

Cited by 18 publications

(9 citation statements)

References 192 publications

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“…Once on the extracellular side of the membrane, ATP either follows a degradative pathway or stimulates P2 receptors [ 63 ]. Under normal conditions, cytosolic concentrations of ATP range from 3 mM to 10 mM, whereas the amount of extracellular ATP vary widely from picomoles to micromoles with cells and tissue types [ 64 ]. Injured cells can release ATP through the cytomembrane in different ways.…”

Section: Discussionmentioning

confidence: 99%

Targeted P2X7/NLRP3 signaling pathway against inflammation, apoptosis, and pyroptosis of retinal endothelial cells in diabetic retinopathy

et al. 2022

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Retinal endothelial cells (RECs) are the primary target cells for diabetes-induced vascular damage. The P2X7/NLRP3 pathway plays an essential role in amplifying inflammation via an ATP feedback loop, promoting the inflammatory response, pyroptosis, and apoptosis of RECs in the early stages of diabetic retinopathy induced by hyperglycemia and inflammation. 3TC, a type of nucleoside reverse transcriptase inhibitor, is effective against inflammation, as it can targeting formation of the P2X7 large pore formation. Hence, our aim was to evaluated the anti-inflammatory effects and potential mechanisms of action of 3TC in vitro in retinal microvascular endothelial cells treated with high-glucose (HG) and lipopolysaccharide (LPS), as well as in vivo in the retinas of C57BL/6J male mice with streptozotocin-induced diabetes. The expression of inflammasome-related proteins P2X7 and NLRP3, and apoptosis in the retinas of 3TC-treated diabetic mice were compared to those of untreated diabetic mice. Furthermore, the anti-inflammatory, anti-apoptotic, and anti-pyroptotic effects of 3TC were evaluated in vitro in cultured mice retinal endothelial cells. Co-application of HG and LPS significantly increased the secretion of IL-6, IL-1β, and TNF-α, and ATP levels, whereas 3TC decreased cell inflammation, apoptosis, and pyroptosis. Inhibition of P2X7R and NLRP3 inflammasome activation decreased NLRP3 inflammasome-mediated injury. 3TC prevented cytokine and ATP release following co-application of HG and LPS/BzATP. Our findings provide new insights regarding the mechanisms of action of 3TC in diabetic environment-induced retinal injury, including apoptosis and pyroptosis.

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Section: Discussionmentioning

confidence: 99%

Targeted P2X7/NLRP3 signaling pathway against inflammation, apoptosis, and pyroptosis of retinal endothelial cells in diabetic retinopathy

et al. 2022

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“…The modulation of neuroinflammation by ARs makes them an attractive pharmacological target for neurodegenerative diseases that share chronic brain inflammation as a ubiquitous common feature, including Alzheimer’s disease [ 176 , 177 ], Parkinson’s disease [ 178 , 179 ], multiple sclerosis [ 180 , 181 ], and Huntington’s disease [ 182 ]. Remarkably, an alteration of A 2A ARs was found in the brain and peripheral blood cells of patients affected by such neurodegenerative diseases [ 183 , 184 , 185 , 186 , 187 , 188 ].…”

Section: Neuroinflammationmentioning

confidence: 99%

Adenosine and Inflammation: Here, There and Everywhere

Pasquini

Contri

Borea

et al. 2021

IJMS

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Adenosine is a ubiquitous endogenous modulator with the main function of maintaining cellular and tissue homeostasis in pathological and stress conditions. It exerts its effect through the interaction with four G protein-coupled receptor (GPCR) subtypes referred as A1, A2A, A2B, and A3 adenosine receptors (ARs), each of which has a unique pharmacological profile and tissue distribution. Adenosine is a potent modulator of inflammation, and for this reason the adenosinergic system represents an excellent pharmacological target for the myriad of diseases in which inflammation represents a cause, a pathogenetic mechanism, a consequence, a manifestation, or a protective factor. The omnipresence of ARs in every cell of the immune system as well as in almost all cells in the body represents both an opportunity and an obstacle to the clinical use of AR ligands. This review offers an overview of the cardinal role of adenosine in the modulation of inflammation, showing how the stimulation or blocking of its receptors or agents capable of regulating its extracellular concentration can represent promising therapeutic strategies for the treatment of chronic inflammatory pathologies, neurodegenerative diseases, and cancer.

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“…Regarding these events, it was found that a reduced P2X 7 R expression or the administration of P2X 7 R antagonists increased alpha-secretase activity through the inhibition of glycogen synthase kinase-3β (GSK-3β) and decreased the number of amyloid plaques [ 134 , 135 , 136 ]. However, single nucleotide polymorphisms of these receptors have been reported in neurological disorders including AD (reviewed in [ 137 ]). Thus, P2X 7 R effects seem to depend on different factors, also including the amount of available APP and multi-factorial-dependent unbalance between alpha- and beta/gamma-secretases.…”

Section: Influence Of the Purinergic Signaling On The Main Functions ...mentioning

confidence: 99%

Bidirectional Control between Cholesterol Shuttle and Purine Signal at the Central Nervous System

Passarella

Ronci

Liberto

et al. 2022

IJMS

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Recent studies have highlighted the mechanisms controlling the formation of cerebral cholesterol, which is synthesized in situ primarily by astrocytes, where it is loaded onto apolipoproteins and delivered to neurons and oligodendrocytes through interactions with specific lipoprotein receptors. The “cholesterol shuttle” is influenced by numerous proteins or carbohydrates, which mainly modulate the lipoprotein receptor activity, function and signaling. These molecules, provided with enzymatic/proteolytic activity leading to the formation of peptide fragments of different sizes and specific sequences, could be also responsible for machinery malfunctions, which are associated with neurological, neurodegenerative and neurodevelopmental disorders. In this context, we have pointed out that purines, ancestral molecules acting as signal molecules and neuromodulators at the central nervous system, can influence the homeostatic machinery of the cerebral cholesterol turnover and vice versa. Evidence gathered so far indicates that purine receptors, mainly the subtypes P2Y2, P2X7 and A2A, are involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer’s and Niemann–Pick C diseases, by controlling the brain cholesterol homeostasis; in addition, alterations in cholesterol turnover can hinder the purine receptor function. Although the precise mechanisms of these interactions are currently poorly understood, the results here collected on cholesterol–purine reciprocal control could hopefully promote further research.

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Alzheimer and Purinergic Signaling: Just a Matter of Inflammation?

Cited by 18 publications

References 192 publications

Targeted P2X7/NLRP3 signaling pathway against inflammation, apoptosis, and pyroptosis of retinal endothelial cells in diabetic retinopathy

Targeted P2X7/NLRP3 signaling pathway against inflammation, apoptosis, and pyroptosis of retinal endothelial cells in diabetic retinopathy

Adenosine and Inflammation: Here, There and Everywhere

Bidirectional Control between Cholesterol Shuttle and Purine Signal at the Central Nervous System

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