Amyloid-β_1–42Slows Clearance of Synaptically Released Glutamate by Mislocalizing Astrocytic GLT-1

Abstract

GLT-1, the major glutamate transporter in the adult brain, is abundantly expressed in astrocytic processes enveloping synapses. By limiting glutamate escape into the surrounding neuropil, GLT-1 preserves the spatial specificity of synaptic signaling. Here we show that the amyloid-␤ peptide A␤ 1-42 markedly prolongs the extracellular lifetime of synaptically released glutamate by reducing GLT-1 surface expression in mouse astrocytes and that this effect is prevented by the vitamin E derivative Trolox. These findings indicate that astrocytic glutamate transporter dysfunction may play an important role in the pathogenesis of Alzheimer's disease and suggest possible mechanisms by which several current treatment strategies could protect against the disease.

Ceftriaxone ameliorates tau pathology and cognitive decline via restoration of glial glutamate transporter in a mouse model of Alzheimer's disease

“…Recent studies have demonstrated that synthetic oligomeric Ab 1-42 decreased GLT-1 expression or promoted mislocalization of GLT-1 from the cell surface of primary astrocytes, leading to glutamate dyshomeostasis in synapses (Abdul et al, 2009;Scimemi et al, 2013). Our in vivo evidence (Fig.…”

Deriving the Time Course of Glutamate Clearance with a Deconvolution Analysis of Astrocytic Transporter Currents

“…They provide valuable tools that can be used to estimate the lifetime of glutamate in the extracellular space at different stages of development 13 in a variety of animal species 14 and brain regions under physiological and pathological conditions 21 .…”

The Role of the Tripartite Glutamatergic Synapse in the Pathophysiology of Alzheimer’s Disease

“…In cultured astrocytes, surface expression of GLT-1, but not GLAST, is reduced following incubation with Aβ1-42 (500 nM) [133]. In the hippocampus of mice, however, the expression of both GLT-1 and GLAST is reduced following injection of Aβ1-40 (400 pmol/site) [135].…”

“…Another way in which Aβ can increase extracellular concentrations of glutamate is by inhibition of astrocytic uptake, resulting in an increased duration of glutamate in the synaptic cleft [131][132][133][134][135]. In cultured astrocytes, surface expression of GLT-1, but not GLAST, is reduced following incubation with Aβ1-42 (500 nM) [133].…”

“…Similarly, GLT-1 and GLAST uptake activity is inhibited following the administration of either Aβ1-40 (5 µM) or Aβ1-42 (5 µM) to cultured astrocytes [132]; this decrease in transporter activity is due to a decrease in transporter expression resulting from Aβ-mediated phosphorylation/activation of astrocytic mitogenactivated protein (MAP) kinases, including ERK and JNK [132]. Altered activity of MAP kinase cascades results from the oxidative stress conditions induced by Aβ [132], and anti-oxidant pretreatment can prevent the Aβ-mediated decrease in astrocytic uptake of glutamate [133]. The ability of Aβ to almost double the amount of time required to clear synaptically released glutamate suggests Aβ may promote the spread of glutamate from one synaptic domain to the next [133].…”