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

Sáez-Orellana, Francisco; Godoy, Pamela A.; Bastidas, Camila Y.; Silva-Grecchi, Tiare; Guzmán, Leonardo; Aguayo, Luis G.; Fuentealba, Jorge

doi:10.1016/j.neuropharm.2015.04.005

Cited by 46 publications

(46 citation statements)

References 67 publications

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“…As calcium ions enter the cell, there will also be leakage of ATP from the cell into solution by the same mechanism. ATP leakage has been observed in other experiments at much higher acute oligomer concentrations34, and may affect neighbouring cells leading to the release of pro-inflammatory cytokines. The amount of calcium influx occurring as the oligomer crosses will potentially depend on the oligomer size.…”

Section: Discussionsupporting

confidence: 54%

Individual aggregates of amyloid beta induce temporary calcium influx through the cell membrane of neuronal cells

Drews

Flint

Shivji

et al. 2016

Sci Rep

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Local delivery of amyloid beta oligomers from the tip of a nanopipette, controlled over the cell surface, has been used to deliver physiological picomolar oligomer concentrations to primary astrocytes or neurons. Calcium influx was observed when as few as 2000 oligomers were delivered to the cell surface. When the dosing of oligomers was stopped the intracellular calcium returned to basal levels or below. Calcium influx was prevented by the presence in the pipette of the extracellular chaperone clusterin, which is known to selectively bind oligomers, and by the presence a specific nanobody to amyloid beta. These data are consistent with individual oligomers larger than trimers inducing calcium entry as they cross the cell membrane, a result supported by imaging experiments in bilayers, and suggest that the initial molecular event that leads to neuronal damage does not involve any cellular receptors, in contrast to work performed at much higher oligomer concentrations.

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Section: Discussionsupporting

confidence: 54%

Individual aggregates of amyloid beta induce temporary calcium influx through the cell membrane of neuronal cells

Drews

Flint

Shivji

et al. 2016

Sci Rep

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“…Abnormal ATP release to the extracellular medium in neuronal cultures exposed to A␤Os may be an important mediator of neurotoxicity via activation of purinergic receptors in AD brains. Indeed, a recent report demonstrated that A␤O-induced ATP leakage activates P2X receptors to cause excitotoxicity (53). Furthermore, adenosine resulting from extracellular ATP degradation could also serve as a messenger mediating communication between neurons and glia, likely via activation of glial purinergic receptors, to exacerbate brain and memory dysfunction, as suggested (54 -57).…”

Section: Discussionmentioning

confidence: 94%

Amyloid-β oligomers transiently inhibit AMP-activated kinase and cause metabolic defects in hippocampal neurons

Silva¹,

Melo²,

Lourenco

et al. 2017

Journal of Biological Chemistry

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AMP-activated kinase (AMPK) is a key player in energy sensing and metabolic reprogramming under cellular energy restriction. Several studies have linked impaired AMPK function to peripheral metabolic diseases such as diabetes. However, the impact of neurological disorders, such as Alzheimer disease (AD), on AMPK function and downstream effects of altered AMPK activity on neuronal metabolism have been investigated only recently. Here, we report the impact of Aβ oligomers (AβOs), synaptotoxins that accumulate in AD brains, on neuronal AMPK activity. Short-term exposure of cultured rat hippocampal neurons or human cortical slices to AβOs transiently decreased intracellular ATP levels and AMPK activity, as evaluated by its phosphorylation at threonine residue 172 (AMPK-Thr(P)). The AβO-dependent reduction in AMPK-Thr(P) levels was mediated by glutamate receptors of the -methyl-d-aspartate (NMDA) subtype and resulted in removal of glucose transporters (GLUTs) from the surfaces of dendritic processes in hippocampal neurons. Importantly, insulin prevented the AβO-induced inhibition of AMPK. Our results establish a novel toxic impact of AβOs on neuronal metabolism and suggest that AβO-induced, NMDA receptor-mediated AMPK inhibition may play a key role in early brain metabolic defects in AD.

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“…This has received support in recent reviews [20,[22][23][24]. It has be reported that β-amyloid increases release of ATP which, via P2X receptors, potentiates excitatory synaptic activity; these effects were blocked by P2X antagonists [25]. It has been claimed that adenosine A3 receptor agonists suppress amyloid- protein precursor internalization and amyloid- generation [26].…”

Section: Alzheimer's Diseasementioning

confidence: 96%

Purinergic Signalling and Neurological Diseases: An Update

Burnstock

2017

CNSNDDT

107

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Purinergic signalling, i.e. ATP as an extracellular signalling molecule and cotransmitter in both peripheral and central neurons, is involved in the physiology of neurotransmission and neuromodulation. Receptors for purines have been cloned and characterised, including 4 subtypes of the P1(adenosine) receptor family, 7 subtypes of the P2X ion channel nucleotide receptor family and 8 subtypes of the P2Y G protein-coupled nucleotide receptor family. The roles of purinergic signalling in diseases of the central nervous system and the potential use of purinergic compounds for their treatment are attracting increasing attention. In this review, the focus is on the findings reported in recent papers and reviews to update knowledge in this field about the involvement of purinergic signalling in Alzheimer's, Parkinson's and Huntington's diseases, multiple sclerosis, amyotrophic lateral sclerosis, degeneration and regeneration after brain injury, stroke, ischaemia, inflammation, migraine, epilepsy, psychiatric disorders, schizophrenia, bipolar disorder, autism, addiction, sleep disorders and brain tumours. The use in particular of P2X7 receptor antagonists for the treatment of neurodegenerative diseases, cancer, depression, stroke and ischaemia, A2A receptor antagonists for Parkinson's disease and agonists for brain injury and depression and P2X3 receptor antagonists for migraine and seizures has been recommended. P2Y receptors have also been claimed to be involved in some central nervous disorders.

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

Cited by 46 publications

References 67 publications

Individual aggregates of amyloid beta induce temporary calcium influx through the cell membrane of neuronal cells

Individual aggregates of amyloid beta induce temporary calcium influx through the cell membrane of neuronal cells

Amyloid-β oligomers transiently inhibit AMP-activated kinase and cause metabolic defects in hippocampal neurons

Purinergic Signalling and Neurological Diseases: An Update

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