Amnesia induced in mice by centrally administered beta-amyloid peptides involves cholinergic dysfunction.
Substantial evidences suggest that the increased cerebral deposition, and neurotoxic action of the beta-amyloid peptide, the major constituent of senile plaques, may represent the underlying cause of the cognitive deficits observed in Alzheimer's disease. Herein, we attempted to verify this hypothesis by inducing a potential Alzheimer's-type amnesia after direct intracerebroventricular administration of aggregated beta 25-35-amyloid peptide in mice. In this aim, mnesic capacities were evaluated after 6-13 days, using spontaneous alternation in the Y-maze, step-down type passive avoidance and place learning in a water-maze. Pretraining administration of aggregated beta 25-35 peptide induced dose-dependent decreases in both alternation behaviour and passive avoidance, at doses of 3 and 9 nmol/mouse. A reduced but still significant impairment was observed when the peptide was not aggregated, or 'aged', by preincubation for 4 days at 37 degrees C. The beta 1-28 peptide, at 3 nmol/mouse, also induced a marked decrease in step-down latency. Posttraining, but not preretention, administration of beta 25-35 peptide also significantly impaired learning. The beneficial effects of cholinergic agents on beta 25-35-induced amnesia was examined using the cholinesterase inhibitor tacrine (THA, 1.3 and 4.3 mumol/kg i.p.) and the nicotinic receptor agonist (-)-nicotine (NIC, 0.06 and 0.2 mumol/kg i.p.). Both drugs induced a dose-dependent abrogation of the beta 25-35-induced decreases in alternation behaviour and passive avoidance. Furthermore, THA, at 1.3 mumol/kg, and NIC, at 0.2 mumol/kg, also reversed the beta 25-35-induced impairment of place learning and retention in the water-maze. Histological examination of Cresyl violet-stained brain sections indicated a moderate but significant cell loss within the frontoparietal cortex and the hippocampal formation of mice treated with aged beta 25-35 peptide (9 nmol). Examination of Congo red-stained sections in the same animals demonstrated the presence of numerous amyloid deposits throughout these brain areas. These results confirm that the deposition of beta-amyloid peptide in the brain is in some way related to impairment of learning and cholinergic degeneration and suggest that the [25-35] fragment of the beta-amyloid protein, sufficient to induce neuronal death in cultures, also induces an Alzheimer's-type amnesia in mice.
Maurice
T
T
INSERM U336, Développement, Plasticité et Vieillessement du Système Nerveux, Ecole Nationale Supérieure de Chimie, Montpellier, France.
Lockhart
B P
BP
Privat
A
A
D000109:Acetylcholine / Q000502:physiology*; D000544:Alzheimer Disease / Q000188:drug therapy / Q000503:physiopathology*; D000647:Amnesia / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009538:Nicotine / Q000494:pharmacology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors; D013619:Tacrine / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); D013619:Tacrine; D009538:Nicotine; D000109:Acetylcholine