FIGURE 1.

Glutamate-mediated neurodegeneration in MS and AD. Schematic showing possible glutamate-mediated neurodegenerative mechanisms in MS and AD. Under healthy conditions, perisynaptic glutamate levels are maintained through the glutamate cap provided by astrocytes in close proximity of the synapse. Under neuroinflammatory conditions, glutamate spill-over can occur due to downregulation of glutamate transporters, leading to activation of extrasynaptic NMDARs and subsequent neurodegeneration. This downregulation is driven by several effectors including actions of TNFα released by activated microglia or amyloid-beta accumulation. In MS, oligodendrocytes are also sensitive to glutamate excitotoxicity, with glutamate also deriving from activated microglia. Glutamate export is mediated via the cysteine/glutamate antiporter xc^–, and is driven in part by a TNFα-mediated autocrine mechanism. Th17 cells have also been shown to release glutamate through the formation of an immuno-neuronal synapse. In AD, amyloid beta can stimulate microglia to produce proinflammatory cytokines such as TNFα, and through interaction with NMDARs, drives AMPAR downregulation (affecting synaptic communication), synapse loss and neuronal degeneration.