Amnesia induced in mice by centrally administered β-amyloid peptides involves cholinergic dysfunction

Substantial evidences suggest that the increased cerebral deposition, and neurotoxic action of the β-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 aggregatedβ25–35-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 aggregatedβ25–35 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°C. Theβ1–28 peptide, at 3 nmol/mouse, also induced a marked decrease in step-down latency. Posttraining, but not preretention, administration of25–35 peptide also significantly impaired learning. The beneficial effects of cholinergic agents onβ25–35-induced amnesia was examined using the cholinesterase inhibitor tacrine (THA, 1.3 and 4.3 μmol/kg i.p.) and the nicotinic receptor agonist (−)-nicotine (NIC, 0.06 and 0.2 μmol/kg i.p.). Both drugs induced a dose-dependent abrogation of theβ25–35-induced decreases in alternation behaviour and passive avoidance. Furthermore, THA, at 1.3 μmol/kg, and NIC, at 0.2 μmol/kg, also reversed theβ25–31-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 agedβ25–35 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 β-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 β-amyloid protein, sufficient to induce neuronal death in cultures, also induces an Alzheimer's-type amnesia in mice.