Activation of microglia by secreted amyloid precursor protein evokes release of glutamate by cystine exchange and attenuates synaptic function


  • Steven W. Barger,

    1. Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
    2. Department of Anatomy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
    3. Geriatric Research Education and Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA
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  • Anthony S. Basile

    1. Laboratory of Neuroscience, National Institute of Digestive Disorders and Kidney, Bethesda, Maryland, USA
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Address correspondence and reprint requests to Steven W. Barger Department of Geriatrics, Slot 807, University of Arkansas for Medical Sciences, 629 S. Elm St, Little Rock, AR 72205, USA. E-mail:


Microglial activation as part of a chronic inflammatory response is a prominent component of Alzheimer's disease. Secreted forms of the β-amyloid precursor protein (sAPP) previously were found to activate microglia, elevating their neurotoxic potential. To explore neurotoxic mechanisms, we analyzed microglia-conditioned medium for agents that could activate glutamate receptors. Conditioned medium from primary rat microglia activated by sAPP caused a calcium elevation in hippocampal neurons, whereas medium from untreated microglia did not. This response was sensitive to the NMDA receptor antagonist, aminophosphonovaleric acid. Analysis of microglia-conditioned by HPLC revealed dramatically higher concentrations of glutamate in cultures exposed to sAPP. Indeed, the glutamate levels in sAPP-treated cultures were substantially higher than those in cultures treated with amyloid β-peptide. This sAPP-evoked glutamate release was completely blocked by inhibition of the cystine–glutamate antiporter by α-aminoadipate or use of cystine-free medium. Furthermore, a sublethal concentration of sAPP compromised synaptic density in microglia–neuron cocultures, as evidenced by neuronal connectivity assay. Finally, the neurotoxicity evoked by sAPP in microglia-neuron cocultures was attenuated by inhibitors of either the neuronal nitric oxide synthase (NG-propyl-l-arginine) or inducible nitric oxide synthase (1400 W). Together, these data indicate a scenario by which microglia activated by sAPP release excitotoxic levels of glutamate, probably as a consequence of autoprotective antioxidant glutathione production within the microglia, ultimately causing synaptic degeneration and neuronal death.