RT Journal Article
T1 P2X7 receptor blockade reduces tau induced toxicity, therapeutic implications in tauopathies
A1 Di Lauro, Caterina
A1 Bianchi, Carolina
A1 Sebastián Serrano, Álvaro
A1 Soria Tobar, Lucía
A1 Álvarez Castelao, Beatriz
A1 Nicke, Annette
A1 Díaz Hernández, Miguel
AB 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.
PB Elsevier
SN 0301-0082
YR 2022
FD 2022-09-10
LK https://hdl.handle.net/20.500.14352/72456
UL https://hdl.handle.net/20.500.14352/72456
LA eng
NO CRUE-CSIC (Acuerdos Transformativos 2021)
NO Unión Europea. Horizonte 2020
NO Ministerio de Economía y Competitividad (MINECO)
NO Ministerio de Ciencia e Innovación (MICINN)
NO Universidad Complutense de Madrid/Banco de Santander
NO Comunidad de Madrid
DS Docta Complutense
RD 7 abr 2025