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

Article type: Research Article

Authors: Schallier, Anneleen^a | Smolders, Ilse^a | Van Dam, Debby^b | Loyens, Ellen^a | De Deyn, Peter Paul^{b; c} | Michotte, Alex^{d; *} | Michotte, Yvette^a | Massie, Ann^a

Affiliations: [a] Research Group Experimental Pharmacology, Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Centre of Pharmaceutical Research, Vrije Universiteit Brussel, Brussel, Belgium | [b] Department of Biomedical Sciences, Laboratory of Neurochemistry & Behaviour>, Institute Born-Bunge, Universiteit Antwerpen, Belgium | [c] Department of Neurology/Memory Clinic, ZNA, Middelheim General Hospital, Antwerp, Belgium | [d] Department of Neurology and Pathology (Neuropathology), Universitair Ziekenhuis Brussel, Brussels, Belgium

Correspondence: [*] Correspondence to: Yvette Michotte, Faculty of Medicine and Pharmacy, Department of Pharmaceutical Chemistry, Drug analysis and Drug Information, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 Brussels, Belgium. Tel.: +32 2 477 47 48; Fax: + 32 2 477 41 13; E-mail: [email protected].

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 xc−, 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.

Keywords: Alzheimer's disease, AβPP23 model, cortex, EAAT, hippocampus, VGLUT, xCT

DOI: 10.3233/JAD-2011-101005

Journal: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 287-300, 2011