P2X7 receptor blockade reduces tau induced toxicity, therapeutic implications in tauopathies

Lauro, Caterina Di; Bianchi, Carolina; Sebastián-Serrano, Álvaro; Soria-Tobar, Lucía; Álvarez-Castelao, Beatriz; Nicke, Annette; Dı́az-Hernández, Miguel

doi:10.1016/j.pneurobio.2021.102173

Cited by 27 publications

(44 citation statements)

References 54 publications

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“…In vivo studies have shown that P2X7R antagonism reduces the amyloid load in the brain, rescues cognitive deficits, and improves synaptic plasticity [183,184], demonstrating its therapeutic potential. More recent data also show that P2X7R antagonism protects against tau-induced pathology, both at a molecular and behavioural level [185][186][187]. While the mechanisms explaining how P2X7R activation leads to an AD-like phenotype are still to be determined, several pathways have been proposed to be regulated via P2X7R during AD and tauopathies, including phosphorylation of the tau kinase glycogen synthase 3β (GSK-3β), leading thereby to the hyperphosphorylation of tau [183,186] and inflammatory pathways, including a pathogenic CD8 + T cell recruitment [184].…”

Section: P2x7rs and Other Common Co-morbidities Associated With Epilepsymentioning

confidence: 97%

“…More recent data also show that P2X7R antagonism protects against tau-induced pathology, both at a molecular and behavioural level [185][186][187]. While the mechanisms explaining how P2X7R activation leads to an AD-like phenotype are still to be determined, several pathways have been proposed to be regulated via P2X7R during AD and tauopathies, including phosphorylation of the tau kinase glycogen synthase 3β (GSK-3β), leading thereby to the hyperphosphorylation of tau [183,186] and inflammatory pathways, including a pathogenic CD8 + T cell recruitment [184]. Further in line with P2X7R contributing to tauopathies via driving inflammation, P2X7Rs were found to be highly expressed on microglia in mice overexpressing tau and in patients with tauopathies and P2X7R deficiency, reduced tau-related neuroinflammation, and microglia activation [186,187].…”

Section: P2x7rs and Other Common Co-morbidities Associated With Epilepsymentioning

confidence: 97%

“…While the mechanisms explaining how P2X7R activation leads to an AD-like phenotype are still to be determined, several pathways have been proposed to be regulated via P2X7R during AD and tauopathies, including phosphorylation of the tau kinase glycogen synthase 3β (GSK-3β), leading thereby to the hyperphosphorylation of tau [183,186] and inflammatory pathways, including a pathogenic CD8 + T cell recruitment [184]. Further in line with P2X7R contributing to tauopathies via driving inflammation, P2X7Rs were found to be highly expressed on microglia in mice overexpressing tau and in patients with tauopathies and P2X7R deficiency, reduced tau-related neuroinflammation, and microglia activation [186,187]. Nevertheless, regardless of how the P2X7R contributes to AD, these results strongly suggest that P2X7R is involved in memory loss and, consequently, identify the P2X7R as a possible therapeutic target to counteract cognitive decline seen, for example, in epilepsy [188].…”

Section: P2x7rs and Other Common Co-morbidities Associated With Epilepsymentioning

confidence: 99%

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Beyond Seizure Control: Treating Comorbidities in Epilepsy via Targeting of the P2X7 Receptor

Gil

Smith

Tang

et al. 2022

IJMS

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Epilepsy is one of the most common chronic diseases of the central nervous system (CNS). Treatment of epilepsy remains, however, a clinical challenge with over 30% of patients not responding to current pharmacological interventions. Complicating management of treatment, epilepsy comes with multiple comorbidities, thereby further reducing the quality of life of patients. Increasing evidence suggests purinergic signalling via extracellularly released ATP as shared pathological mechanisms across numerous brain diseases. Once released, ATP activates specific purinergic receptors, including the ionotropic P2X7 receptor (P2X7R). Among brain diseases, the P2X7R has attracted particular attention as a therapeutic target. The P2X7R is an important driver of inflammation, and its activation requires high levels of extracellular ATP to be reached under pathological conditions. Suggesting the therapeutic potential of drugs targeting the P2X7R for epilepsy, P2X7R expression increases following status epilepticus and during epilepsy, and P2X7R antagonism modulates seizure severity and epilepsy development. P2X7R antagonism has, however, also been shown to be effective in treating conditions most commonly associated with epilepsy such as psychiatric disorders and cognitive deficits, which suggests that P2X7R antagonisms may provide benefits beyond seizure control. This review summarizes the evidence suggesting drugs targeting the P2X7R as a novel treatment strategy for epilepsy with a particular focus of its potential impact on epilepsy-associated comorbidities.

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Section: P2x7rs and Other Common Co-morbidities Associated With Epilepsymentioning

confidence: 97%

Section: P2x7rs and Other Common Co-morbidities Associated With Epilepsymentioning

confidence: 97%

Section: P2x7rs and Other Common Co-morbidities Associated With Epilepsymentioning

confidence: 99%

See 1 more Smart Citation

Beyond Seizure Control: Treating Comorbidities in Epilepsy via Targeting of the P2X7 Receptor

Gil

Smith

Tang

et al. 2022

IJMS

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“…Another interesting factor linked to inflammation and GSK3 is the P2X7 receptor (P2X7-R) which is known to promote chronic neuroinflammation and neurodegenerative brain diseases [ 156 ]. In AD mouse models, P2X7-R inhibition was shown to have a protective effect through GSK3 inhibition [ 157 , 158 ]. P2X7-R is expressed in the retina and the RPE, and during retinal degeneration its expression increases [ 159 ].…”

Section: Gsk3 and Retinal Inflammationmentioning

confidence: 99%

GSK3 Is a Central Player in Retinal Degenerative Diseases but a Challenging Therapeutic Target

Hottin

Perron

Roger

2022

Cells

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Glycogen synthase kinase 3 (GSK3) is a key regulator of many cellular signaling processes and performs a wide range of biological functions in the nervous system. Due to its central role in numerous cellular processes involved in cell degeneration, a rising number of studies have highlighted the interest in developing therapeutics targeting GSK3 to treat neurodegenerative diseases. Although recent works strongly suggest that inhibiting GSK3 might also be a promising therapeutic approach for retinal degenerative diseases, its full potential is still under-evaluated. In this review, we summarize the literature on the role of GSK3 on the main cellular functions reported as deregulated during retinal degeneration, such as glucose homeostasis which is critical for photoreceptor survival, or oxidative stress, a major component of retinal degeneration. We also discuss the interest in targeting GSK3 for its beneficial effects on inflammation, for reducing neovascularization that occurs in some retinal dystrophies, or for cell-based therapy by enhancing Müller glia cell proliferation in diseased retina. Together, although GSK3 inhibitors hold promise as therapeutic agents, we highlight the complexity of targeting such a multitasked kinase and the need to increase our knowledge of the impact of reducing GSK3 activity on these multiple cellular pathways and biological processes.

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“…P2X7R protein expression has been found to be up-regulated in the brain of patients with different neurological diseases and P2X7R antagonism has shown bene ts in multiple animal models of brain diseases (e.g. epilepsy, schizophrenia, depression) [17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Functional expression of the ATP-gated P2X7 receptor in human iPSC-derived astrocytes

Kesavan

Watters

Diego-García

et al. 2023

Preprint

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The P2X7 receptor (P2X7R) is a cation-permeable ionotropic receptor activated by extracellular adenosine 5’-triphosphate (ATP) which has been implicated in numerous diseases of the CNS, including epilepsy. Activation of the P2X7R can trigger diverse responses including the release of pro-inflammatory cytokines, modulation of neurotransmission, cell proliferation or cell death. There have been conflicting reports on the cellular identity of P2X7R-expressing cells in the brain. Expression of P2X7Rs is well documented on microglia and oligodendrocytes but the presence of P2X7Rs on astrocytes remains debated. Furthermore, most functional studies on P2X7R responses have used cells from rodents or immortalised cell lines expressing human P2X7Rs. To assess the endogenous and functional expression of P2X7Rs in human astrocytes, we differentiated human-induced pluripotent stem cells (hiPSCs) into GFAP and S100 β-expressing astrocytes. Immunostaining revealed prominent punctate P2X7R staining on hiPSC-derived astrocytes and P2X7R protein expression was also confirmed by Western blot analysis. Importantly, stimulation with the potent nonselective P2X7R agonist BzATP or endogenous agonist ATP induced robust calcium rises in hiPSC-derived astrocytes which were blocked by the selective P2X7R antagonists AFC-5128 or JNJ-47965567. Our findings provide evidence for the functional expression of P2X7Rs in hiPSC-derived astrocytes and support their in vitro utility in investigating the role of the P2X7R and drug screening in disorders of the CNS.

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P2X7 receptor blockade reduces tau induced toxicity, therapeutic implications in tauopathies

Cited by 27 publications

References 54 publications

Beyond Seizure Control: Treating Comorbidities in Epilepsy via Targeting of the P2X7 Receptor

Beyond Seizure Control: Treating Comorbidities in Epilepsy via Targeting of the P2X7 Receptor

GSK3 Is a Central Player in Retinal Degenerative Diseases but a Challenging Therapeutic Target

Functional expression of the ATP-gated P2X7 receptor in human iPSC-derived astrocytes

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