Amyloid beta-peptide 25-35 reduces [3H]acetylcholine release in retinal neurons. Involvement of metabolic dysfunction.
Cholinergic pathways serve important functions in learning and memory processes. The loss of basal forebrain cholinergic neurons and the presence of senile plaques composed by amyloid beta-peptide (A beta) are found in post-mortem brains of Alzheimer's disease (AD) patients. However, the role of A beta in the cholinergic dysfunction observed in AD is not yet clarified. In this study, we observed that the release of [3H]acetylcholine evoked by K(+)-depolarization was significantly lower in cells treated with A beta 25-35 peptide, than in untreated cells or in cells exposed to the reverse sequence peptide A beta 35-25. The levels of pyruvate, the substrate for pyruvate dehydrogenase, the enzyme involved in acetyl coenzyme A synthesis in the brain, which is rate-limiting for the synthesis of acetylcholine, were significantly decreased, about 40%, in A beta treated cells. A beta 25-35 did not affect choline acetyltransferase activity or [3H]choline uptake. 2-[3H]-deoxyglucose uptake was decreased when cells were exposed to A beta 25-35 or to A beta 1-40. Taken together these data suggest that an impairment of glycolysis, and the consequent decrease in pyruvate levels, may be responsible for the decrement of acetylcholine release observed in A beta treated cells, thus sustaining the hypothesis that the cholinergic dysfunction, observed in AD patients, might be associated with extracellular A beta accumulation.
Melo
Joana Barbosa
JB
Center for Neurosciences of Coimbra, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal.
Agostinho
Paula
P
Oliveira
Catarina Resende
CR
D000109:Acetylcholine / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D002642:Chick Embryo; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000502:physiology*; D012160:Retina / Q000166:cytology / Q000378:metabolism*; D014316:Tritium
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); D014316:Tritium; D000109:Acetylcholine