Alteration of glial-neuronal metabolic interactions in a mouse model of Alexander disease.
Alexander disease is a rare and usually fatal neurological disorder characterized by the abundant presence of protein aggregates in astrocytes. Most cases result from dominant missense de novo mutations in the gene encoding glial fibrillary acidic protein (GFAP), but how these mutations lead to aggregate formation and compromise function is not known. A transgenic mouse line (Tg73.7) over-expressing human GFAP produces astrocytic aggregates indistinguishable from those seen in the human disease, making them a model of this disorder. To investigate possible metabolic changes associated with Alexander disease Tg73.7 mice and controls were injected simultaneously with [1-(13)C]glucose to analyze neuronal metabolism and [1,2-(13)C]acetate to monitor astrocytic metabolism. Brain extracts were analyzed by (1)H magnetic resonance spectroscopy (MRS) to quantify amounts of several key metabolites, and by (13)C MRS to analyze amino acid neurotransmitter metabolism. In the cerebral cortex, reduced utilization of [1,2-(13)C]acetate was observed for synthesis of glutamine, glutamate, and GABA, and the concentration of the marker for neuronal mitochondrial metabolism, N-acetylaspartate (NAA) was decreased. This indicates impaired astrocytic and neuronal metabolism and decreased transfer of glutamine from astrocytes to neurons compared with control mice. In the cerebellum, glutamine and GABA content and labeling from [1-(13)C]glucose were increased. Evidence for brain edema was found in the increased amount of water and of the osmoregulators myo-inositol and taurine. It can be concluded that astrocyte-neuronal interactions were altered differently in distinct regions.
Meisingset
Tore Wergeland
TW
Department of Neuroscience, Norwegian University of Science and Technology (NTNU), N-7489 Trondheim, Norway.
Risa
Øystein
Ø
Brenner
Michael
M
Messing
Albee
A
Sonnewald
Ursula
U
D038261:Alexander Disease / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D001929:Brain Edema / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008959:Models, Neurological; D009457:Neuroglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*
D005904:Glial Fibrillary Acidic Protein