P2-004: aβ-induced calcium flux is dependent on glutamate and copper
Alzheimers & Dementia(2014)
Abstract
Alzheimer's disease (AD) is characterised by progressive cognitive impairment resulting from synaptic degeneration and neuronal loss. Oligomeric forms of the beta amyloid (Aβ) peptide have been implicated in the aetiology of AD by disrupting calcium homeostasis rendering human neurons vulnerable to calcium flux and excitotoxicity mediated through the NMDA receptor (NMDAr). Recent work has demonstrated Aβ induces excitotoxicity. We sought to determinewhethercopper was involved in enhanced glutamate toxicity caused by Aβ that has previously been reported. Mouse cortical neurons were cultured for 9 days in vitro prior to performing calcium flux and toxicity assays. In order to observe Aβ42-induced calcium flux cortical neurons were loaded with the Flou4 dye (Invitrogen) for 1 hr prior to addition of Aβ42, glutamate or copper or a combination of these components. Neurons were treated for 48 hours with a combination of Aβ42, glutamate and copper prior to measuring cell viability by CCK8 assay based on reduction of the tetrazolium salt, WST-8 (Dojindo). Treatments of neurons with various Aβ42 preparations alone were not sufficient to induce a calcium flux above background. However, co-treatment with glutamate and copper significantly increased calcium flux and this increase was dose-dependent with regard to Aβ42. Cell viability experiments demonstrated that the resulting toxicity from Aβ42, glutamate and copper treatment was mediated via the NMDA receptor. Finally the observed increase in calcium flux was shown to be dependent on metals following treatment with chelators. Here we have demonstrated that Aβ-induced NMDAr-mediated toxicity is irrespective of aggregation and dependent on Aβ42 interacting with glutamate through a metal dependent mechanism. These results support the use of metal complexing agents as potential therapies for AD.
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Key words
dependent on glutamate,calcium,copper
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