title: 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.
authors.affiliation: Research Group Experimental Pharmacology, Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Centre of Pharmaceutical Research, Vrije Universiteit Brussel, Brussel, Belgium.
authors.forename: Anneleen
authors.initials: A
authors.lastname: Schallier
authors.forename: Ilse
authors.initials: I
authors.lastname: Smolders
authors.forename: Debby
authors.initials: D
authors.lastname: Van Dam
authors.forename: Ellen
authors.initials: E
authors.lastname: Loyens
authors.forename: Peter Paul
authors.initials: PP
authors.lastname: De Deyn
authors.forename: Alex
authors.initials: A
authors.lastname: Michotte
authors.forename: Yvette
authors.initials: Y
authors.lastname: Michotte
authors.forename: Ann
authors.initials: A
authors.lastname: Massie
mesh_terms: D000375:Aging; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D027322:Amino Acid Transport System X-AG / Q000145:classification / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D018698:Glutamic Acid; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics
chemical_list: D027322:Amino Acid Transport System X-AG; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D027342:Excitatory Amino Acid Transporter 2; C493396:Slc1a2 protein, mouse; D018698:Glutamic Acid