Region- and age-specific changes in glutamate transport in the APP23 mouse model

Anneleen Schallier, Ilse Julia Smolders, Debby Van Dam, Ellen Loyens, Peter De Deyn, Alex Michotte, Yvette Michotte, Ann Massie

Onderzoeksoutput: Conference paper


Introduction: Alzheimer's disease (AD) is an irreversible neurodegenerative disorder causing dementia and is characterized by neuronal loss as well as the formation of amyloid plaques and neurofibrillary tangles. To date, few drugs are available and they can only alleviate the symptoms of the disease. In the search for new therapies that could halt or slow down the progression of the disease, it is important to study the mechanisms underlying the pathology of AD. Glutamate, the most important excitatory neurotransmitter in the mammalian central nervous system, plays major roles in normal brain functioning [1]. We here used the APP23 mouse model to investigate the possible involvement of high-affinity Na+/K+-dependent glutamate transporters (GLAST, GLT-1 and EAAC1) as well as vesicular glutamate transporters (vGLUT1-3) in the pathogenesis of AD.

Methods: Distribution patterns and expression levels of the above described glutamate transporters were examined in 8 (mature) and 18 (aged) month old APP23 mice and their WT littermates by means of immunohistochemistry and Western blotting. Moreover, using in vivo microdialysis and a specific inhibitor of the excitatory amino acid transporters, we investigated the functional relevance of these changes in protein expression by measuring extracellular glutamate levels as well as glutamate reuptake activity in hippocampus and frontal cortex.

Results and discussion: Whereas GLAST expression was only decreased in cortical and hippocampal samples of mature APP23 mice, GLT-1 downregulation was age-independent (8 and 18-month-old mice). In all conditions this downregulated expression in glial reuptake transporters could be linked to a decreased in vivo reuptake activity, except for frontal cortex of mature APP23 mice. In this brain region, status epilepticus was induced when glutamate reuptake was inhibited, because of the increased cortical expression of vGLUT1.
In frontal cortex of aged APP23 mice, the decreased reuptake activity for glutamate together with the increased expression level of vGLUT3 resulted in increased basal glutamate levels.
Even though in hippocampus of mature APP23 mice glutamate reuptake activity was strongly diminished, we could not detect an effect on extracellular glutamate concentrations, suggesting a deficiency in glutamate release. This finding points towards an important role of vGLUT3, which showed a decreased expression in hippocampal tissue of APP23 mice, in determining extracellular glutamate levels.
The present findings support the hypothesis that alterations in transport of glutamate may be involved in the pathogenesis of AD. However, more profound research is needed to point towards the most promising target for the development of new therapeutic strategies.

[1] Walton H.S., Dodd P.R. (2007). Glutamate-glutamine cycling in Alzheimer's disease. Neurochem. Int. 50, 1052-1066
Originele taal-2English
Titel13th International Conference on In Vivo Methods
StatusPublished - 7 sep 2010
EvenementUnknown -
Duur: 7 sep 2010 → …


Periode7/09/10 → …


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