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.