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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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Summary: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.
Main Authors:Figueiredo, Catarina Martins de
Subject:Cell Competition Alzheimer’s Disease Glutamate Neuronal Hyperactivity Drosophila melanogaster
Year:2021
Country:Portugal
Document type:master thesis
Access type:open access
Associated institution:Universidade Nova de Lisboa
Language:English
Origin:Repositório Institucional da UNL

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