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

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Di Lauro, Caterina and Bianchi, Carolina and Sebastián Serrano, Álvaro and Soria Tobar, Lucía and Álvarez Castelao, Beatriz and Nicke, Annette and Díaz Hernández, Miguel (2022) P2X7 receptor blockade reduces tau induced toxicity, therapeutic implications in tauopathies. Progress in Neurobiology, 208 . p. 102173. ISSN 0301-0082

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Official URL: https://doi.org/10.1016/j.pneurobio.2021.102173



Abstract

Tauopathies are neurodegenerative diseases characterized by the presence of aberrant intraneuronal aggregates of hyperphosphorylated Tau protein. Recent studies suggest that associated chronic neuroinflammation may contribute to the pathological Tau dissemination. However, the underlying molecular mechanisms remain unknown. Since purinergic P2X7 receptors (P2X7) can sense the rise of extracellular ATP levels associated with neuroinflammation, its involvement in neurodegeneration-associated inflammation was suggested. We found a P2X7 upregulation in patients diagnosed with different tauopathies and in a tauopathy mouse model, P301S mice. In vivo pharmacological or genetic blockade of P2X7 reverted microglial activation in P301S mice leading to a reduction in microglial migratory, secretory, and proliferative capacities, and promoting phagocytic function. Furthermore, it reduced the intraneuronal phosphorylated Tau levels in a GSK3-dependent way and increased extracellular phosphorylated Tau levels by reducing the expression of ectoenzyme TNAP. Accordingly, pharmacological or genetic blockade of P2X7 improved the cellular survival, motor and memory deficits and anxiolytic profile in P301S mice. Contrary, P2X7 overexpression caused a significant worsening of Tauinduced toxicity and aggravated the deteriorated motor and memory deficits in P301S mice. Our results indicate that P2X7 plays a deleterious role in tauopathies and suggest that its blockade may be a promising approach to treat Tauopathies.


Item Type:Article
Additional Information:

CRUE-CSIC (Acuerdos Transformativos 2021)

Uncontrolled Keywords:Alzheimer disease, Pick disease, Neuroinflammation, ATP, P2X7
Subjects:Medical sciences > Medicine > Neurosciences
ID Code:69607
Deposited On:17 Jan 2022 15:57
Last Modified:03 Mar 2022 15:00

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