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

Abstract

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 proinflammatory cytokine, IL-1β; however, P2X7R also induces cleavage of the amyloid precursor protein generating Aβ peptides or the neuroprotective fragment sAPPα. We thus explored in detail the functions of P2X7R in AD transgenic mice. Here, we show that P2X7R deficiency reduced Aβ lesions, rescued cognitive deficits and improved synaptic plasticity in AD mice. However, the lack of P2X7R did not significantly affect the release of IL-1β or the levels of non-amyloidogenic fragment, sAPPα, in AD mice. Instead, our results show that P2X7R plays a critical role in Aβ 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.

Pathological ATPergic Signaling in Major Depression and Bipolar Disorder

“…Similar findings were reported for the cerebral cortex of spontaneously hypertensive rats, where the occlusion of the medial cerebral artery led to the upregulation of P2X7Rs in the penumbra surrounding the necrotic region (Franke et al, 2004). Thus, it was concluded that P2X7Rs induce proliferation of astrocytes upon their stimulation by ATP possibly released from the nearby, massively damaged CNS tissue (Franke et al, 2012;Franke and Illes, 2014;Martin et al, 2019).…”

“…A particularly intensively discussed issue is the transition of the cationic channel to a large membrane pore, because it appears to be essential for cytokine production and secretion (Illes et al, 2019;Martin et al, 2019). Originally, it was suggested based on equilibrium potential (V rev ) measurements with the whole-cell patch-clamp technique that the ion conducting pathway shows progressive dilation (Virginio et al, 1999).…”

“…The preferential location of P2X7Rs in the CNS is on the microglia, the resident macrophages of the brain (Bhattacharya and Jones, 2018). Microglia are equipped with a battery of pattern recognition receptors that stereotypically detect pathogenassociated molecules (PAMPs) such as lipopolysaccharide (LPS) from bacterial infection or danger-associated molecular patterns (DAMPs), such as ATP (Figure 1; Shao et al, 2015;Young and Górecki, 2018;Illes et al, 2019;Martin et al, 2019). Activation of microglia stimulates the release of interleukin-1β (IL-1β) in a two-step process: the first being the stimulation of toll-like receptor 4 (TLR4) by LPS, leading to accumulation of cytoplasmic pro-IL-1β, and the second being the ATP-dependent stimulation of P2X7Rs, promoting nucleotidebinding, leucine-rich repeat, pyrin domain containing 3 (NLRP3) inflammasome-mediated caspase-1 activation and secretion of IL-1β (Perregaux and Gabel, 1998;Ferrari et al, 2006).…”

P2X7 receptor inhibition ameliorates dendritic spine pathology and social behavioral deficits in Rett syndrome mice

“…Other possible pro-inflammatory pathways downstream of P2X7R activation include calcium-dependent PGE2 release, which has been implicated in sickness behavior 65 . In an Alzheimer's disease mouse model, P2X7Rs mediate beta-amyloid-induced chemokine release and lack of P2X7Rs reduces beta-amyloid deposition and improves synaptic plasticity and memory 66 . Furthermore, activation of P2X7Rs leads to the opening of accessory channels such as Pannexin1 (hemi)channels, which mediates ATP release and supports P2X7R activation within an inflammatory microenvironment 21 .…”

Le récepteur P2X7, une nouvelle cible thérapeutique dans la maladie d’Alzheimer

“…Effet/impact de l'invalidation de P2X7R sur le développement de la MA Nous avons tout d'abord mis en évidence que, dans le cerveau de patients atteints de MA et dans un modèle murin développant des lésions amyloïdes (les souris transgéniques TgAPP/PS1 3 ), les cellules qui expriment fortement P2X7R étaient principalement les astrocytes et les cellules microgliales. Afin de déterminer le rôle de P2X7R dans la MA, nous avons donc évalué l'effet de l'invalidation génétique de P2X7R chez ces souris TgAPP/PS1 [7]. Nous avons montré dans ce modèle que la déficience en P2X7R diminuait la patho-…”