期刊
PROGRESS IN NEUROBIOLOGY
卷 206, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pneurobio.2021.102139
关键词
Purinergic receptor; P2X7; Tauopathies; Frontotemporal lobar degeneration; Alzheimer's disease; Chemokines
资金
- INSERM, Sorbonne University, Agence Nationale pour la Recherche [ANR-12-MALZ-0003-02-P2X7RAD]
- Programme Investissements d'Avenir IHU FOReSIGHT [ANR-18-IAHU-01]
- Hauts-de-France (PARTEN-AIRR, COGNADORA) , ANR (ADORASTrAU to DB) , CoEN [5008]
- Programs d'Investissements d'Avenir LabEx (excellence laboratory) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease)
- Fondation pour la Recherche Medicale
- France Alzheimer/Fondation de France,
- FHU VasCog research network (Lille, France)
- Fondation Vaincre Alzheimer
- Fondation Plan Alzheimer as well as Inserm
- CNRS
- Universite Lille
- Lille Metropole Communaute Urbaine
- 2 Investissements d'avenir [ANR-10-IAIHU-06, ANR-11-INBS-0011-NeurATRIS]
- Fondation pour la Recherche Medicale. Neuro-CEB
- ARSLA
- CSC
- France DFT
- Fondation ARSEP
The purinergic receptor P2X7 plays a crucial role in Alzheimer's disease and Tauopathies, with deletion of P2X7 having significant effects on inflammatory mediators and memory function in Tau pathology. P2X7 inhibitors may be ideal drugs for treating these neurodegenerative diseases.
Alzheimer's disease is the most common form of dementia characterized by intracellular aggregates of hyperphosphorylated Tau protein and extracellular accumulation of amyloid beta (A beta) peptides. We previously demonstrated that the purinergic receptor P2X7 (P2X7) plays a major role in A beta-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 P2X7deficiency 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 A beta and Tau background, P2X7 inhibitors might prove to be ideal candidate drugs to curb the devastating cognitive decline in Alzheimer's disease and Tauopathies.
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