Region- and Age-Specific Changes in Glutamate Transport in the AβPP23 Mouse Model for Alzheimer's Disease

Abstract

Using 8- and 18-month-old AβPP23 mice, we investigated the involvement of high-affinity glutamate transporters (GLAST, GLT-1, EAAC1), vesicular glutamate transporters (VGLUT1-3) and xCT, the specific subunit of system x(c)⁻, in Alzheimer's disease (AD) pathogenesis. Transporter expression was studied in cortical and hippocampal tissue and linked to extracellular glutamate and glutamate reuptake activity as measured using in vivo microdialysis. In 8-month-old animals, we could not observe plaque formation or gliosis. Yet, in hippocampus as well as cortex GLAST and GLT-1 expression was decreased. Whereas in cortex this was accompanied by upregulated VGLUT1 expression, extracellular glutamate concentrations were decreased. Surprisingly, inhibiting glutamate reuptake with TBOA revealed increased glutamate reuptake activity in cortex of AβPP23 mice, despite decreased GLAST and GLT-1 expression, and resulted in status epilepticus in all AβPP23 mice, contrary to wildtype littermates. In hippocampus of 8-month-old AβPP23 mice, we observed increased EAAC1 expression besides the decrease in GLAST and GLT-1. Yet, glutamate reuptake activity was drastically decreased according to the decreased GLAST and GLT-1 expression. In 18-month-old AβPP23 mice, plaque formation and gliosis in cortex and hippocampus were accompanied by decreased GLT-1 expression. We also showed, for the first time, increased cortical expression of VGLUT3 and xCT together with a strong tendency towards increased cortical extracellular glutamate levels. VGLUT2 expression remained unaltered in all conditions. The present findings support the hypothesis that alterations in transport of glutamate, and more particular via GLT-1, may be involved in AD pathogenesis.

Altered vesicular glutamate transporter expression in human temporal lobe epilepsy with hippocampal sclerosis

“…Interestingly, we recently showed increased xCT levels in the same human sclerotic hippocampal samples compared to autopsy controls [17]. Moreover, we already reported the joint upregulation of xCT and VGLUT3 in the cortex of 18-month-old A␤PP23 mice, a model for Alzheimer's disease marked by plaque formation and gliosis, coupled with a strong tendency toward increased cortical extracellular glutamate levels [24]. These findings suggest an important role of both glial transporters in neurological diseases involving gliosis and glutamate excitotoxicity.…”

Amyloid Beta A4 Precursor Protein-binding Family B Member 1 (FE65) Interactomics Revealed Synaptic Vesicle Glycoprotein 2A (SV2A) and Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase 2 (SERCA2) as New Binding Proteins in the Human Brain

“…The association of SV2A with AD has not been described, but some disorientation in AD is associated with epileptiform activity and might be prevented with antiepileptic drugs (62). In contrast, VGLUT1, the vesicular glutamate transporter in neurons, has been found to be differentially expressed in different AD mouse models (63,64). The observation that FE65 is associated with synaptic plasticity (65) might in part be due to the interaction of FE65 with SV2A and VGLUT1.…”

The Cystine/Glutamate Antiporter System xc−in Health and Disease: From Molecular Mechanisms to Novel Therapeutic Opportunities

“…Significantly, increased xCT gene expression is seen in adult mouse hippocampus after an injection of Ab and in activated microglia in the cerebral cortex of Thy1-APP 751 transgenic mice (211). In the cortex of aged APP23 mice, xCT overexpression is accompanied by reduced glutamate uptake and increased extracellular glutamate levels (238). With regard to models of PD, an ipsilateral increase in striatal xCT protein levels occurred in 6-hydroxydopamine (6-OHDA)-lesioned hemi-Parkinson rats 3 weeks after an injection (176).…”