Glucose metabolism in cholinoceptive cortical rat brain regions after basal forebrain cholinergic lesion.
To address the question whether the changes in cortical glucose metabolism observed in patients with Alzheimer's disease are interrelated with, or consequences of, basal forebrain cholinergic cell loss, an experimental approach was employed to produce cortical cholinergic dysfunction in rat brain by administration of the cholinergic immunotoxin 192IgG-saporin. [14C]D-glucose utilization in brain homogenates, D-glucose-displaceable [3H]cytochalasin B binding to glucose transporters (GLUT). Northern and Western analyses, as well as in vivo [14C]2-deoxyglucose autoradiography were used to quantify the regional glucose metabolism. Basal forebrain cholinergic lesion resulted in transient increases in glucose transporter binding in cortical regions displaying reduced acetylcholinesterase activity, already detectable seven days after lesion with peak values around 30 days post lesion. Western analysis revealed that the changes in total glucose transporter binding are mainly due to changes in the GLUT3 subtype only, while the levels of GLUT1 and GLUT3 mRNA (Northern analysis) were not affected by cholinergic lesion. Both immunocytochemistry and in situ hybridization demonstrated preferential localizations of GLUT1 on brain capillaries and GLUT3 on neurons, respectively. A lesion-induced transient decrease in [14C]D-glucose utilization seven days post lesion was detected in the lesion site, whereas cholinoceptive cortical regions were not affected. In vivo [14C]deoxyglucose uptake was transiently increased in cholinoceptive cortical regions and in the lesion site being highest between three to seven days after lesion. The cholinergic lesion-induced transient up-regulation of cortical glucose transporters and deoxyglucose uptake reflects an increased glucose demand in regions depleted by acetylcholine suggesting functional links between cortical cholinergic activity and glucose metabolism in cholinoceptive target regions.
Mehlhorn
G
G
Paul Flechsig Institute for Brain Research, Department of Neurochemistry, University of Leipzig Medical Faculty, Germany.
Löffler
T
T
Apelt
J
J
Rossner
S
S
Urabe
T
T
Hattori
N
N
Nagamatsu
S
S
Bigl
V
V
Schliebs
R
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000633:toxicity*; D001345:Autoradiography; D015152:Blotting, Northern; D015153:Blotting, Western; D018678:Cholinergic Agents / Q000633:toxicity*; D003571:Cytochalasin B / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D000922:Immunotoxins / Q000633:toxicity*; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009699:N-Glycosyl Hydrolases; D016548:Prosencephalon / Q000187:drug effects* / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011950:Receptors, Cholinergic / Q000187:drug effects* / Q000378:metabolism; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins
C085696:192 IgG-saporin; D000911:Antibodies, Monoclonal; D018678:Cholinergic Agents; D000922:Immunotoxins; D009004:Monosaccharide Transport Proteins; D011950:Receptors, Cholinergic; D054789:Ribosome Inactivating Proteins, Type 1; D003571:Cytochalasin B; D009699:N-Glycosyl Hydrolases; D000076985:Saporins; D005947:Glucose