ATP leakage induces P2XR activation and contributes to acute synaptic excitotoxiciw induced by soluble oligomers of β-amyloid peptide in hippocampal neurons

Recent studies suggest that the toxic effects of A beta 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 A beta increases extracellular ATP causing activation of P2X receptors and potentiating excitatory synaptic activity. We found that soluble oligomers of beta-amyloid peptide increased cytosolic Ca2+ 4-fold above control (415 +/- 28% of control). Also, ATP leakage (157 +/- 10% of control) was independent of extracellular Ca2+, suggesting that ATP traveled from the cytosol through an A beta poremediated efflux and not from exocytotic mechanisms. The subsequent activation of P2XR by ATP can contribute to the cytosolic Ca2+ increase observed with A beta. Additionally, we found that beta-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 (A beta + PPADS: 110.9 +/- 1835%) or Apyrase plus DPCPX (A beta + inhibitors: 98.97 +/- 17.4%). Taken together, we suggest that A beta 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 extra-cellular 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 A beta 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'. (C) 2015 Elsevier Ltd. All rights reserved.