De Deyn, Peter Paul

Loyens, Ellen

Massie, Ann

Michotte, Alex

Michotte, Yvette

Schallier, Anneleen

Smolders, Ilse

Van Dam, Debby

Abstract: Using 8- and 18-month-old A\u3b2PP23 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 xc-, in Alzheimers 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 A\u3b2PP23 mice, despite decreased GLAST and GLT-1 expression, and resulted in status epilepticus in all A\u3b2PP23 mice, contrary to wildtype littermates. In hippocampus of 8-month-old A\u3b2PP23 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 A\u3b2PP23 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

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Region- and age-specific changes in glutamate transport in the <tex>A\beta PP23$</tex> mouse model for Alzheimers disease

Region- and age-specific changes in glutamate transport in the <tex>A\beta PP23$</tex> mouse model for Alzheimers disease

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Institutional Repository Universiteit Antwerpen