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 pro-inflammatory 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.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the formation of neurofibrillary tangles, composed of intraneuronal aggregates of hyperphosphorylated tau protein, and senile plaques, composed of Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Biochemistry Biophysics and Structural Biology, Université ParisSud, 91405 Orsay, France 5 Present address: German Center for Neurodegenerative Diseases, 53127 Bonn, Germany extracellular aggregates of amyloid β (Aβ) peptides
The cell types expressing P2X7 receptor (P2X7R) have not been clearly established in AD, we analyzed P2X7R expression further with double immunostaining for P2X7R and GFAP, an astrocyte marker, or Iba1, a microglia marker
We investigated whether the lack of P2X7R promoted or prevented pathology in mouse model of AD
Summary
Biochemistry Biophysics and Structural Biology, Université ParisSud, 91405 Orsay, France 5 Present address: German Center for Neurodegenerative Diseases, 53127 Bonn, Germany extracellular aggregates of amyloid β (Aβ) peptides. These neuropathological accumulations are accompanied by a neuroinflammatory response [1, 2]. Activated microglia and astrocytes surround Aβ lesions, and we recently showed that the immune response in murine cerebral amyloidosis models was characterized by the continuous production of several pro-inflammatory cytokines [7]. Damaged neurons [8, 9], as well as microglia and astrocytes can release ATP in response to extracellular particles, such as Aβ peptides [10,11,12,13]. Purinergic receptors have various properties in the central nervous system; they contribute to neurotransmission and neuromodulation and to neuronal injury depending on the physiological or pathological environment, the ATP concentration, the purinergic receptor subtype and the cell type that harbors these receptors [9, 15]
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