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

Abstract

Alzheimer's disease is the most common form of dementia characterized by intracellular aggregates of hyperphosphorylated Tau protein and extracellular accumulation of amyloid β (Aβ) peptides. We previously demonstrated that the purinergic receptor P2X7 (P2X7) plays a major role in Aβ-mediated neurodegeneration but the relationship between P2X7 and Tau remained overlooked. Such a link was supported by cortical upregulation of P2X7 in patients with various type of frontotemporal lobar degeneration, including mutation in the Tau-coding gene, MAPT, as well as in the brain of a Tauopathy mouse model (THY-Tau22). Subsequent phenotype analysis of P2X7-deficient Tau mice revealed the instrumental impact of this purinergic receptor. Indeed, while P2X7-deficiency had a moderate effect on Tau pathology itself, we observed a significant reduction of microglia activation and of Tau-related inflammatory mediators, particularly CCL4. Importantly, P2X7 deletion ultimately rescued synaptic plasticity and memory impairments of Tau mice. Altogether, the present data support a contributory role of P2X7 dysregulation on processes governing Tau-induced brain anomalies. Due to the convergent role of P2X7 blockade in both Aβ and Tau background, P2X7 inhibitors might prove to be ideal candidate drugs to curb the devastating cognitive decline in Alzheimer's disease and Tauopathies.

• Authors: Kevin Carvalho, Elodie Martin, Aurélia Ces, Nadège Sarrazin, Pauline Lagouge-Roussey, Caroline Nous, Leyna Boucherit, Ihsen Youssef, Annick Prigent, Emilie Faivre, Sabiha Eddarkaoui, Thibaut Gauvrit, Didier Vieau, Susana Boluda, Vincent Huin, Bertrand Fontaine, Luc Buée, Benoît Delatour, Patrick Dutar, Florian Sennlaub, Xavier Guillonneau, David Blum, Cécile Delarasse, NeuroCEB Brain Bank
• Journal: Progress in neurobiology (Prog Neurobiol) Vol. 206 Pg. 102139 (11 2021) ISSN: 1873-5118 [Electronic] England
• PMID: 34391810 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021. Published by Elsevier Ltd.

Chemical References

• Amyloid beta-Peptides
• P2rx7 protein, mouse
• Receptors, Purinergic P2X7
• tau Proteins

Topics

• Alzheimer Disease (genetics)
• Amyloid beta-Peptides
• Animals
• Cognition
• Disease Models, Animal
• Humans
• Mice
• Mice, Transgenic
• Receptors, Purinergic P2X7 (deficiency)
• Tauopathies (genetics)
• tau Proteins (genetics)