Changes in cortical acetyl-CoA metabolism after selective basal forebrain cholinergic degeneration by 192IgG-saporin.
The aim of the present study was to reveal whether reduced cortical cholinergic input affects the acetyl-CoA metabolism in cholinoceptive cortical target regions which may play a causative role for the deficits in cerebral glucose metabolism observed in Alzheimer's disease. The effect of cortical cholinergic denervation produced by a single intracerebroventricular application of the cholinergic immunotoxin 192IgG-saporin, on activities of pyruvate dehydrogenase and adenosine triphosphate (ATP)-citrate lyase as well as on the level of synaptoplasmic and mitochondrial acetyl-CoA and acetylcholine release in cortical target regions was studied. Cholinergic lesion produced 83%, 72% and 32% decreases in the activities of choline acetyltransferase, acetylcholinesterase and ATP-citrate lyase in nerve terminals isolated from rat brain cortex, respectively, but no change in pyruvate dehydrogenase activity. Spontaneous and Ca2+-evoked acetylcholine release from synaptosomes was inhibited by 76% and 73%, respectively, following immunolesion. The lesion-induced 39% decrease of acetyl-CoA level in synaptosomal mitochondria was accompanied by 74% increase in synaptoplasmic fraction. Levels of acetyl-CoA and CoASH assayed in fraction of whole brain mitochondria from lesioned cortex were 61% and 48%, respectively, higher as compared to controls. The data suggest a preferential localization of ATP-citrate lyase in cholinergic nerve terminals, where it may contribute to the transport of acetyl-CoA from the mitochondrial to the cytoplasmic compartment. They provide evidence on differential distribution of acetyl-CoA in subcellular compartments of cholinergic and non-cholinergic nerve terminals. There are also indications that cholinergic activity affects acetyl-CoA level and its intracellular distribution in glial and other non-cholinergic cortical cells.
D000105:Acetyl Coenzyme A / Q000378:metabolism*; D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal; D001923:Brain Chemistry; D002540:Cerebral Cortex / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D018678:Cholinergic Agents; D003714:Denervation / Q000379:methods; D000922:Immunotoxins; D008297:Male; D008928:Mitochondria / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D009699:N-Glycosyl Hydrolases; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000378:metabolism*; D016548:Prosencephalon / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D013574:Synaptosomes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism
C085696:192 IgG-saporin; D000911:Antibodies, Monoclonal; D018678:Cholinergic Agents; D000922:Immunotoxins; D054789:Ribosome Inactivating Proteins, Type 1; D000105:Acetyl Coenzyme A; D009699:N-Glycosyl Hydrolases; D000076985:Saporins; D000109:Acetylcholine