title: ATP leakage induces P2XR activation and contributes to acute synaptic excitotoxicity induced by soluble oligomers of β-amyloid peptide in hippocampal neurons.
abstract: Recent studies suggest that the toxic effects of Aβ can be attributed to its capability to insert in membranes and form pore-like structures, which are permeable to cations and molecules such as ATP. Our working hypothesis is that Aβ increases extracellular ATP causing activation of P2X receptors and potentiating excitatory synaptic activity. We found that soluble oligomers of β-amyloid peptide increased cytosolic Ca(2+) 4-fold above control (415 ± 28% of control). Also, ATP leakage (157 ± 10% of control) was independent of extracellular Ca(2+), suggesting that ATP traveled from the cytosol through an Aβ pore-mediated efflux and not from exocytotic mechanisms. The subsequent activation of P2XR by ATP can contribute to the cytosolic Ca(2+) increase observed with Aβ. Additionally, we found that β-amyloid oligomers bind preferentially to excitatory neurons inducing an increase in excitatory synaptic current frequency (248.1 ± 32.7%) that was blocked by the use of P2XR antagonists such as PPADS (Aβ + PPADS: 110.9 ± 18.35%) or Apyrase plus DPCPX (Aβ + inhibitors: 98.97 ± 17.4%). Taken together, we suggest that Aβ induces excitotoxicity by binding preferentially to excitatory neuron membranes forming a non-selective pore and by increasing intracellular calcium by itself and through P2XR activation by extracellular ATP leading to an augmention in mEPSC activity. All these effects were blocked with a non-specific P2XR antagonist, indicating that part of the neurotoxicity of Aβ is mediated by P2XR activation and facilitation of excitatory neurotransmitter release. These findings suggest that P2XR can be considered as a potential new target for the development of drugs or pharmacological tools to treat Alzheimer's disease. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'.
authors.affiliation: Laboratory of Screening of Neuroactive Compound, Physiology Department, Faculty of Biological Sciences, Universidad de Concepción, Concepción, Chile.
authors.forename: F
authors.initials: F
authors.lastname: Sáez-Orellana
authors.affiliation: Laboratory of Screening of Neuroactive Compound, Physiology Department, Faculty of Biological Sciences, Universidad de Concepción, Concepción, Chile.
authors.forename: P A
authors.initials: PA
authors.lastname: Godoy
authors.affiliation: Laboratory of Screening of Neuroactive Compound, Physiology Department, Faculty of Biological Sciences, Universidad de Concepción, Concepción, Chile.
authors.forename: C Y
authors.initials: CY
authors.lastname: Bastidas
authors.affiliation: Laboratory of Screening of Neuroactive Compound, Physiology Department, Faculty of Biological Sciences, Universidad de Concepción, Concepción, Chile.
authors.forename: T
authors.initials: T
authors.lastname: Silva-Grecchi
authors.affiliation: Neurophysiology Laboratory, Physiology Department, Faculty of Biological Sciences, Universidad de Concepción, Concepción, Chile.
authors.forename: L
authors.initials: L
authors.lastname: Guzmán
authors.affiliation: Neurophysiology Laboratory, Physiology Department, Faculty of Biological Sciences, Universidad de Concepción, Concepción, Chile.
authors.forename: L G
authors.initials: LG
authors.lastname: Aguayo
authors.affiliation: Laboratory of Screening of Neuroactive Compound, Physiology Department, Faculty of Biological Sciences, Universidad de Concepción, Concepción, Chile; Center for Advanced Research on Biomedicine (CIAB-UdeC), Physiology Department, Faculty of Biological Sciences, Universidad de Concepción, Concepción, Chile. Electronic address: jorgefuentealba@udec.cl.
authors.forename: J
authors.initials: J
authors.lastname: Fuentealba
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D058469:Receptors, Purinergic P2X / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D058469:Receptors, Purinergic P2X; D000255:Adenosine Triphosphate; D002118:Calcium
keywords: ATP; Alzheimer's disease; Aβ peptide oligomer; P2X receptors