A study conducted by Cecile Delarasse and colleagues at ICM shows the deleterious role of P2X7 receptor and the positive effect of its inactivation in a mice model of amyloid plaques, one of the main lesions in Alzheimer’s disease. The results, published in Molecular Psychiatry, open new avenues of research on the potential of this receptor as a therapeutic target.
Alzheimer’s disease is characterized by two types of lesions: amyloid lesions caused by aggregates of Aβ peptides and neurofibrillary tangles linked with the accumulation of aggregated Tau proteins. Their presence leads to chronic inflammatory response in the brain. In case of damages, cells release large quantities of ATP. High concentration of ATP is detected as a danger signal by specific receptors called P2X7.
A dual role for this receptor, both pro-inflammatory and neuroprotective, was reported in Alzheimer’s disease. A study conducted by Cecile Delarasse’s team at the ICM sought to better understand its role in this pathology. To this purpose, they studied the consequences of the inactivation of P2X7 receptor in a mouse model of amyloid lesions.
Through multiple behavioral, electrophysiological, biochemical and histological tests, they showed that the absence of P2X7 receptor was associated with decrease of amyloid lesions and an improvement of cognitive functions and synaptic plasticity, confirming the deleterious effect of the receptor activation during the course of the disease.
« The next step was to understand the underlying mechanisms. What’s going on with this receptor from a cellular and molecular point of view? Why does its absence have a beneficial effect? »
P2X7 receptor is activated in an inflammatory context or in case of lesions, so the researchers looked at the immune consequences of its inactivation.
They did not show any effect on specific activation of innate immune system: microglial cells of the central nervous system or recruitment of macrophages. However, they did show the involvement of the adaptive immune system through T cells.
In absence of P2X7 receptor, they observed a decrease in chemokines, which attract the immune system cells to the inflammatory site, and in consequence a smaller recruitment of T cells in the brain, which have a deleterious effect on the symptoms of the disease.
« These results bring new important elements on the pathological role of P2X7 receptor and the positive effect of its inactivation on amyloid pathology, characteristic of Alzheimer’s disease. They open new avenues of research on the potential of this receptor as a therapeutic target. » concludes Cécile Delarasse
Source : New role of P2X7 receptor in an Alzheimer’s disease mouse model. Elodie Martin, Majid Amar, Carine Dalle, Ihsen Youssef, Céline Boucher, Caroline Le Duigou, Matthias Brückner, Annick Prigent, Véronique Sazdovitch, Annett Halle, Jean M. Kanellopoulos, Bertrand Fontaine, Benoît Delatour, Cécile Delarasse. Molecular Pyschiatry. 2018