P2X receptor overexpression induced by soluble oligomers of amyloid beta peptide potentiates synaptic failure and neuronal dyshomeostasis in cellular models of Alzheimer's disease. (January 2018)

• Record Type: Journal Article
• Authors: Sáez-Orellana, Francisco; Fuentes-Fuentes, María C.; Godoy, Pamela A.; Silva-Grecchi, Tiare; Panes, Jessica D.; Guzmán, Leonardo; Yévenes, Gonzalo E; Gavilán, Javiera; Egan, Terrance M.; Aguayo, Luis G.; Fuentealba, Jorge
• Is Part Of: Neuropharmacology. Volume 128(2018)
• Page Start: 366
• Page End: 378
• Publication Date: 2018-01
• Subjects: P2X receptor -- Alzheimer's disease -- Amyloid-β peptide -- Synaptic failure -- ATP; APP Amyloid Precursor Protein -- ATP Adenosine Triphosphate -- BAPTA 1, 2-bis(o-aminophenoxy)ethane-N, N, N′, N′-tetraacetic acid -- CNQX 6-cyano-7-nitroquinoxaline-2, 3-dione -- D-AP5 (2R)-amino-5-phosphonovaleric acid -- DMEM Dulbecco modified Eagle's Minimum Essential Medium -- DMSO Dimethyl Sulfoxide -- DPBS Dulbecco's Phosphate-Buffered Saline -- DPCPX 8-Cyclopentyl-1, 3-dipropylxanthine -- EMCCD Electron-multiplying charge-coupled device -- FCCP Carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone -- GAPDH Glyceraldehyde 3-phosphate dehydrogenase -- GTP Guanosine Triphosphate -- HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid -- HRP Horseradish peroxidase -- LTP Long Term Potentiation -- MAP2 Microtubule Associated Protein 2 -- MEM Minimum Essential Medium -- mEPSC miniature Excitatory Post Synaptic Current -- MTT 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide -- NIH National Institute of Health -- NMDAR N-Methyl-d-Aspartate Receptor -- P2XR Purinergic Ionotropic Receptor -- PPADS PyridoxalPhosphate-6-Azophenyl-2′, 4′-DiSulfonic acid -- PrPC Prion Protein -- PSD95 Postsynaptic Density Protein of 95 kDa -- SEM Standard error of the mean -- SDS-PAGE Sodium dodecyl sulfate polyacrylamide gel electrophoresis -- SV2 Synaptic Vesicle glycoprotein 2 -- TBS-T Tris-Buffered Saline-Tween 20; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2017.10.027
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: The most common cause of dementia is Alzheimer's disease. The etiology of the disease is unknown, although considerable evidence suggests a critical role for the soluble oligomers of amyloid beta peptide (Aβ). Because Aβ increases the expression of purinergic receptors (P2XRs) in vitro and in vivo, we studied the functional correlation between long-term exposure to Aβ and the ability of P2XRs to modulate network synaptic tone. We used electrophysiological recordings and Ca 2+ microfluorimetry to assess the effects of chronic exposure (24 h) to Aβ oligomers (0.5 μM) together with known inhibitors of P2XRs, such as PPADS and apyrase on synaptic function. Changes in the expression of P2XR were quantified using RT-qPCR. We observed changes in the expression of P2X1R, P2X7R and an increase in P2X2R; and also in protein levels in PC12 cells (143%) and hippocampal neurons (120%) with Aβ. In parallel, the reduction on the frequency and amplitude of mEPSCs (72% and 35%, respectively) were prevented by P2XR inhibition using a low PPADS concentration. Additionally, the current amplitude and intracellular Ca 2+ signals evoked by extracellular ATP were increased (70% and 75%, respectively), suggesting an over activation of purinergic neurotransmission in cells pre-treated with Aβ. Taken together, our findings suggest that Aβ disrupts the main components of synaptic transmission at both pre- and post-synaptic sites, and induces changes in the expression of key P2XRs, especially P2X2R; changing the neuromodulator function of the purinergic tone that could involve the P2X2R as a key factor for cytotoxic mechanisms. These results identify novel targets for the treatment of dementia and other diseases characterized by increased purinergic transmission. Highlights: Pharmacological inhibition P2X receptors results in a lower toxicity induced by Aβ. P2XR antagonist/modulators prevent the synaptic alterations of neurons treated with Aβ. P2X2 receptors have a role on mechanism of Aβ toxicity.