Jung ES, An K, Hong HS, Kim JH, Mook-Jung I.
Astrocyte-originated ATP protects Aβ(1-42)-induced impairment of synaptic plasticity.
J Neurosci. 2012 Feb 29;32(9):3081-7.
PubMed.
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.
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.
Comments
Tufts University School of Medicine
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.
University of Ferrara
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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