Repeated intracerebroventricular administration of beta-amyloid(25-35) to rats decreases muscarinic receptors in cerebral cortex.
The effects of repeated in vivo administration to rats of beta-amyloid(25-35) (betaA(25-35)) on several cholinergic markers have been studied and compared with those of a peptide with a scrambled sequence. Rats received intracerebroventricular injections of betaA(25-35) (5 or 20 microg/day) for 7 days and they were sacrificed at 2 or 3 weeks survival. The density of total muscarinic receptors labeled with [3H]N-methyl-scopolamine was dose-dependently decreased by betaA(25-35) in the cerebral cortex at 3 weeks survival. No changes were observed at 2 weeks survival in cerebral cortex or in the hippocampus, at any time. BetaA(25-35) administration did not modify choline acetyltranferase activity in cerebral cortex. However, in betaA(25-35)-treated rats hypertrophic/hyperactive positive acetylcholinesterase nucleus basalis cholinergic neurons were observed at 2 weeks survival, while the density of acetylcholinesterase-positive fibers of cerebral cortex was increased along with the number of cortical positive neurons at 3 weeks survival. These results suggest that increased cholinergic function may be responsible of muscarinic receptor down-regulation. Given the involvement of cholinergic systems in memory and learning, repeated administration of betaA(25-35) may represent a good approach to explore the role of betaA in Alzheimer's disease and to develop therapeutic strategies relevant to it.
Pavía
J
J
Department of Pharmacology, Faculty of Medicine, University of Málaga, Spain.
Alberch
J
J
Alvárez
I
I
Toledano
A
A
de Ceballos
M L
ML
D000110:Acetylcholinesterase / Q000032:analysis; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D020532:Basal Nucleus of Meynert / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000032:analysis; D002799:Cholinergic Fibers / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007276:Injections, Intraventricular; D007858:Learning / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000187:drug effects* / Q000235:genetics; D009473:Neuronal Plasticity / Q000187:drug effects; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000235:genetics; D017661:Receptors, Presynaptic / Q000187:drug effects
D016229:Amyloid beta-Peptides; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D011976:Receptors, Muscarinic; D017661:Receptors, Presynaptic; C074636:amyloid beta-protein (25-35); D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase