This is an intriguing study showing that exogenous ATP acting through P2 receptors can attenuate deleterious actions of Aβ42 on neuronal properties, including reductions in spine density, synaptic protein expression, and synaptic plasticity. Because ATP is known to be a gliotransmitter released from astrocytes, and since the authors show, at least in culture, that Aβ42 stimulates astrocytic ATP release, they suggest that astrocyte-derived ATP may protect against Aβ42-induced impairments in synaptic plasticity. This observation will need to be verified in more intact systems, and it will be necessary to selectively inhibit ATP release from astrocytes and determine consequences on the progression of the neuronal and synaptic impairments in Alzheimer’s mouse models.

View all comments by Philip Haydon

Alzheimer’s disease (AD) is characterized by irreversible neuronal damage as a result of a direct effect of Aβ on neurons, as well as a profound subversion of neuron-glia interactions.

The paper by Sun Jung and coworkers describes a novel mechanism by which neuron-glia, or rather glia-neuron, interaction might modulate the neurotoxic effect of Aβ. They identify ATP as the astrocyte-derived messenger that attenuates Aβ’s injurious effects. The finding that Aβ triggers ATP release from astrocytes is not novel per se, but the observation that co-stimulation with ATP protects neurons from the damaging effect of β amyloid is. The role of ATP as a neuro- and gliotransmitter is long known. More recently, a trophic activity for ATP has also been described. This paper reports a good example of this neuroprotective activity.

However, it should be stressed that ATP released in the central nervous system is likely to have a dual role: as a neurotrophic factor and a proinflammatory mediator. Whether ATP acts as the former or the latter depends on the concentration, the glial cell type...  Read more

Alzheimer’s disease (AD) is characterized by irreversible neuronal damage as a result of a direct effect of Aβ on neurons, as well as a profound subversion of neuron-glia interactions.

The paper by Sun Jung and coworkers describes a novel mechanism by which neuron-glia, or rather glia-neuron, interaction might modulate the neurotoxic effect of Aβ. They identify ATP as the astrocyte-derived messenger that attenuates Aβ’s injurious effects. The finding that Aβ triggers ATP release from astrocytes is not novel per se, but the observation that co-stimulation with ATP protects neurons from the damaging effect of β amyloid is. The role of ATP as a neuro- and gliotransmitter is long known. More recently, a trophic activity for ATP has also been described. This paper reports a good example of this neuroprotective activity.

However, it should be stressed that ATP released in the central nervous system is likely to have a dual role: as a neurotrophic factor and a proinflammatory mediator. Whether ATP acts as the former or the latter depends on the concentration, the glial cell type involved, and the P2 receptor activated. In order to place the paper by Sun Jung et al. in the proper context, we should keep in mind that Aβ can also trigger ATP release from microglia, but in this case, rather than having a protective effect, ATP aggravates Aβ neurotoxicity by triggering IL-1 release and thus inducing inflammation. In this respect, a key piece of information missing from this paper is the lack of identification of the P2 receptor subtypes responsible for the neuroprotective effect. They use PPADS as an inhibitor, but this molecule has a broad selectivity and does not allow identification of the receptor(s) involved. This is crucial in my opinion because, if one wishes to take inspiration from these observations to develop an innovative pharmacological treatment, identification of the P2 receptor(s) is mandatory. Furthermore, these findings raise obvious questions: If Aβ triggers a protective ATP release, why is this not sufficient to prevent Aβ neurotoxicity? Is this protective effect relevant in vivo? Finally, a better model to check for the protective ATP effect would be neuron-astrocyte co-cultures. This experimental system allows one to explore astrocyte-neuron interactions in a more physiological setting.

View all comments by Francesco Di Virgilio