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The effect of excessive glutamate release on neuronal fitness, hyperactivity, and locomotor performance in a Drosophila model of Alzheimer’s Disease
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Recent studies have shown that ectopic expression of the human Aβ42 (amyloid beta peptide)
induces cell competition in the brain of a Drosophila model of Alzheimer’s Disease. Neurons that
are less fit upregulate low fitness markers such as azot and FlowerLoseB, activating pathways that
culminate in their death, which has surprisingly positive effects. These unfit neurons correspond
at least in part to Aβ42-induced hyperactive neurons which localize to brain areas exhibiting large
amounts of glutamate, issues that are also common in the brains of patients but remain not well
understood.
In this project, our aim was to uncover the relationship between glutamate accumulation and
aberrant neuronal activity and to understand if neuronal silencing could rescue impaired
locomotor activity seen in Aβ-expressing flies. We also aimed to understand if excess glutamate
induces the upregulation of azot and FlowerLoseB in this context, since it is known that glutamate
excitotoxicity contributes to neuronal death.
We could not find an effective strategy for neuronal silencing that improves the locomotor
performance of flies, nor establish a reliable model for the relationship between hyperactivity and
excessive glutamate. Silencing hyperactive neurons through different strategies did not result in
changes in glutamate levels and downregulating glutamate signalling with different RNAi lines
against DVGLUT showed signs of increased hyperactivity, which would go against what is
predicted in literature, but was not a reliable outcome.
However, by treating AD model flies with memantine, a glutamate antagonist, we found an
upregulation in azot and FlowerLoseB expression, which points to a role of excessive glutamate in
modulating cell fitness in neurons and could provide further insights for the mechanisms of action
behind the success of this drug in patients.
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Cell Competition Alzheimer’s Disease Glutamate Neuronal Hyperactivity Drosophila melanogaster