P2X7-deficiency improves plasticity and cognitive abilities in a mouse model of Tauopathy

Carvalho, Kevin; Martin, Elodie; Cès, Aurélia; Sarrazin, Nadège; Lagouge-Roussey, Pauline; Nous, Caroline; Boucherit, Leyna; Youssef, Ihsen; Prigent, Annick; Faivre, Émilie; Eddarkaoui, Sabiha; Gauvrit, Thibaut; Vieau, Didier; Boluda, Susana; Huin, Vincent; Fontaine, Bertrand; Buée, Luc; Delatour, Benoı̂t; Dutar, P.; Sennlaub, Florian; Guillonneau, Xavier; Blum, David; Delarasse, Cécile; Bank, NeuroCEB Brain

doi:10.1016/j.pneurobio.2021.102139

Cited by 32 publications

(53 citation statements)

References 45 publications

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“…73 In a tau mouse model with P2RX7 deleted, spatial memory and synaptic plasticity were rescued. 74 A deeper understanding of P2RX7's role in microglia immunomodulation is necessary to interpret how the receptor contributes to AD risk.…”

Section: Discussionmentioning

confidence: 99%

IL-1RA Disrupts ATP Activation of P2RX7 in Human Monocyte-Derived Microglia-like Cells

Heavener,

Kabra,

Yidenk

et al. 2024

Preprint

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The immune system has a dynamic role in neurodegenerative diseases, and purinergic receptors allow immune cells to recognize neuronal signaling, cell injury, or stress. Purinergic Receptor 7 (P2RX7) can modulate inflammatory cascades and its expression is upregulated in Alzheimer′s disease (AD) brain tissue. P2RX7 expression is enriched in microglia, and elevated levels are found in microglia surrounding amyloid-beta plaques in the brain. While P2RX7 is thought to play a role in neurodegenerative diseases, how it modulates pathology and disease progression is not well understood. Here, we utilize a human monocyte-derived microglia-like cell (MDMi) model to interrogate P2RX7 activation and downstream consequences on microglia function. By using MDMi derived from human donors, we can examine how human donor variation impacts microglia function. We assessed P2RX7-driven IL1β and IL18 production and amyloid-beta peptide 1-42 (Aβ1-42) uptake levels. Our results show that ATP-stimulation of MDMi triggers upregulation of IL1β and IL18 expression. This upregulation of cytokine gene expression is blocked with the A740003 P2RX7 antagonist. We find that high extracellular ATP conditions also reduced MDMi capacity for Aβ1-42 uptake, and this loss of function is prevented through A740003 inhibition of P2RX7. In addition, pretreatment of MDMi with IL-1RA limited ATP-driven IL1β and IL18 gene expression upregulation, indicating that ATP immunomodulation of P2RX7 is IL-1R dependent. Aβ1-42 uptake was higher with IL-1RA pretreatment compared to ATP treatment alone, suggesting P2RX7 regulates phagocytic engulfment through IL-1 signaling. Overall, our results demonstrate that P2RX7 is a key response protein for high extracellular ATP in human microglia-like cells, and its function can be modulated by IL-1 signaling. This work opens the door to future studies examining anti-IL-1 biologics to increase the clearance of amyloid-beta.

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Section: Discussionmentioning

confidence: 99%

IL-1RA Disrupts ATP Activation of P2RX7 in Human Monocyte-Derived Microglia-like Cells

Heavener,

Kabra,

Yidenk

et al. 2024

Preprint

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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: 95%

“…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: 97%

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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“…These include tracers for purinergic P2Y12 receptor [[ 11 C]AZD1283], for organic anion-transporting polypeptide 1c1 [[ 18 F]2B-SRF101], and for neutrophil infiltration [( 68 Ga) PEG-cFLFLFK] ( Kreimerman et al, 2019 ; Kong et al, 2020 ; Maeda et al, 2021 ). P2X7 deficiency has been shown to improve plasticity and cognitive abilities in THY-Tau22 mice ( Carvalho et al, 2021 ). Maeda et al (2021) showed a distinct response of P2Y12 receptor to tau deposits using [ 11 C]AZD1283 by ex vivo autoradiography and immunohistochemical staining in rTg4510 and PS19 tau mice.…”

Section: Neuroinflammation Imagingmentioning

confidence: 99%

Positron Emission Tomography in Animal Models of Tauopathies

Cao

Kong

et al. 2022

Front. Aging Neurosci.

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The microtubule-associated protein tau (MAPT) plays an important role in Alzheimer’s disease and primary tauopathy diseases. The abnormal accumulation of tau contributes to the development of neurotoxicity, inflammation, neurodegeneration, and cognitive deficits in tauopathy diseases. Tau synergically interacts with amyloid-beta in Alzheimer’s disease leading to detrimental consequence. Thus, tau has been an important target for therapeutics development for Alzheimer’s disease and primary tauopathy diseases. Tauopathy animal models recapitulating the tauopathy such as transgenic, knock-in mouse and rat models have been developed and greatly facilitated the understanding of disease mechanisms. The advance in PET and imaging tracers have enabled non-invasive detection of the accumulation and spread of tau, the associated microglia activation, metabolic, and neurotransmitter receptor alterations in disease animal models. In vivo microPET studies on mouse or rat models of tauopathy have provided significant insights into the phenotypes and time course of pathophysiology of these models and allowed the monitoring of treatment targeting at tau. In this study, we discuss the utilities of PET and recently developed tracers for evaluating the pathophysiology in tauopathy animal models. We point out the outstanding challenges and propose future outlook in visualizing tau-related pathophysiological changes in brain of tauopathy disease animal models.

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P2X7-deficiency improves plasticity and cognitive abilities in a mouse model of Tauopathy

Cited by 32 publications

References 45 publications

IL-1RA Disrupts ATP Activation of P2RX7 in Human Monocyte-Derived Microglia-like Cells

IL-1RA Disrupts ATP Activation of P2RX7 in Human Monocyte-Derived Microglia-like Cells

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

Positron Emission Tomography in Animal Models of Tauopathies

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