Dataset Information

New role of P2X7 receptor in an Alzheimer's disease mouse model.

ABSTRACT: Extracellular aggregates of amyloid ? (A?) peptides, which are characteristic of Alzheimer's disease (AD), act as an essential trigger for glial cell activation and the release of ATP, leading to the stimulation of purinergic receptors, especially the P2X7 receptor (P2X7R). However, the involvement of P2X7R in the development of AD is still ill-defined regarding the dual properties of this receptor. Particularly, P2X7R activates the NLRP3 inflammasome leading to the release of the pro-inflammatory cytokine, IL-1?; however, P2X7R also induces cleavage of the amyloid precursor protein generating A? peptides or the neuroprotective fragment sAPP?. We thus explored in detail the functions of P2X7R in AD transgenic mice. Here, we show that P2X7R deficiency reduced A? lesions, rescued cognitive deficits and improved synaptic plasticity in AD mice. However, the lack of P2X7R did not significantly affect the release of IL-1? or the levels of non-amyloidogenic fragment, sAPP?, in AD mice. Instead, our results show that P2X7R plays a critical role in A? peptide-mediated release of chemokines, particularly CCL3, which is associated with pathogenic CD8+ T cell recruitment. In conclusion, our study highlights a novel detrimental function of P2X7R in chemokine release and supports the notion that P2X7R may be a promising therapeutic target for AD.

SUBMITTER: Martin E

PROVIDER: S-EPMC6756107 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

New role of P2X7 receptor in an Alzheimer's disease mouse model.

Martin Elodie E Amar Majid M Dalle Carine C Youssef Ihsen I Boucher Céline C Le Duigou Caroline C Brückner Matthias M Prigent Annick A Sazdovitch Véronique V Halle Annett A Kanellopoulos Jean M JM Fontaine Bertrand B Delatour Benoît B Delarasse Cécile C

Molecular psychiatry 20180622 1

Extracellular aggregates of amyloid β (Aβ) peptides, which are characteristic of Alzheimer's disease (AD), act as an essential trigger for glial cell activation and the release of ATP, leading to the stimulation of purinergic receptors, especially the P2X7 receptor (P2X7R). However, the involvement of P2X7R in the development of AD is still ill-defined regarding the dual properties of this receptor. Particularly, P2X7R activates the NLRP3 inflammasome leading to the release of the pro-inflammato ...[more]

PMID: 29934546

Similar Datasets

Project description:BackgroundOver recent years, increasing evidence suggests a causal relationship between neurofibrillary tangles (NFTs) formation, the main histopathological hallmark of tauopathies, including Alzheimer's disease (AD), and the ubiquitin-proteasome system (UPS) dysfunction detected in these patients. Nevertheless, the mechanisms underlying UPS failure and the factors involved remain poorly understood. Given that AD and tauopathies are associated with chronic neuroinflammation, here, we explore if ATP, one of the danger-associated molecules patterns (DAMPs) associated with neuroinflammation, impacts on AD-associated UPS dysfunction.MethodsTo evaluate if ATP may modulate the UPS via its selective P2X7 receptor, we combined in vitro and in vivo approaches using both pharmacological and genetic tools. We analyze postmortem samples from human AD patients and P301S mice, a mouse model that mimics pathology observed in AD patients, and those from the new transgenic mouse lines generated, such as P301S mice expressing the UPS reporter UbG76V-YFP or P301S deficient of P2X7R.ResultsWe describe for the first time that extracellular ATP-induced activation of the purinergic P2X7 receptor (P2X7R) downregulates the transcription of β5 and β1 proteasomal catalytic subunits via the PI3K/Akt/GSK3/Nfr2 pathway, leading to their deficient assembly into the 20S core proteasomal complex, resulting in a reduced proteasomal chymotrypsin-like and postglutamyl-like activities. Using UPS-reported mice (UbGFP mice), we identified neurons and microglial cells as the most sensitive cell linages to a P2X7R-mediated UPS regulation. In vivo pharmacological or genetic P2X7R blockade reverted the proteasomal impairment developed by P301S mice, which mimics that were detected in AD patients. Finally, the generation of P301S;UbGFP mice allowed us to identify those hippocampal cells more sensitive to UPS impairment and demonstrate that the pharmacological or genetic blockade of P2X7R promotes their survival.ConclusionsOur work demonstrates the sustained and aberrant activation of P2X7R caused by Tau-induced neuroinflammation contributes to the UPS dysfunction and subsequent neuronal death associated with AD, especially in the hippocampus.

Dataset Information

New role of P2X7 receptor in an Alzheimer's disease mouse model.

Publications

New role of P2X7 receptor in an Alzheimer's disease mouse model.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets