Amyloid-beta peptide decreases glutamate uptake in cultured astrocytes: Involvement of oxidative stress and mitogen-activated protein kinase cascades

Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss

“…Inflammatory cells, including microglia and astrocytes, are thought to contribute to damage in AD, in part via glutamate excitotoxicity (2,12). For example, exposure to oligomeric Aβ or conditioned medium from microglial cultures incubated with Aβ has been reported to decrease glutamate reuptake from astrocytes in brain slices and cultures (13)(14)(15)(16), but whether Aβ also induces local release of toxic glutamate levels onto neurons remains unknown. To study this question, we used a FRET-based…”

Glutamate system, amyloid β peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology

“…High levels of glutamate in astrocytes lead to the risk of glutamate being returned to the synaptic cleft if mitochon drial membranes are depolarized, a process that is thought to occur in Alzheimer disease because of reduced energy supplies. 73,74 Taken together, these changes in glutamate transport and conversion to glutamine can lead to increased concentrations of glutamate at the synapse, which can subsequently trigger excitotoxic cell death via NMDA receptor-mediated increase of intracellular Ca 2+ concentrations. 75,76 Elevated Ca 2+ levels lead to neuronal death through a number of known pathways, including increased activation of calpain, 77 release of reactive oxygen species and de polarization of the mitochondrial membrane, which leads to reduced energy metabolism and cytochrome c release.…”

Astrocytes in Alzheimer's Disease

“…173 In contrast, A␤ was reported to decrease expression and capacity of glutamate-aspartate transporter and glutamate transporter-1 mediated glutamate uptake in cultured astrocytes. 174 The activated astrocytes are intimately involved in the neuro-inflammatory component of the AD through the release of cytokines, proinflammatory factors, and nitric oxide/reactive oxygen species neurotoxicity. 124 At the early stages of the AD pathology in the tripletransgenic mice (3xTg-AD), harboring the mutant genes for amyloid precursor protein (APP Swe ), presenilin 1PS1 M146V , and tau P301L 175 ), the reduction in the morphological presence of astrocytes, indicative of astroglial degeneration/atrophy, was discovered.…”