. Astrocyte-originated ATP protects Aβ(1-42)-induced impairment of synaptic plasticity. J Neurosci. 2012 Feb 29;32(9):3081-7. PubMed.

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  1. 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.

  2. 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.

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