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

Topic: Disease mechanisms in lab and animal studies

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.

Key findings

• 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.
• 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.
• Posttraining, but not preretention, administration of beta 25-35 peptide also significantly impaired learning.
• 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.

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Study details

• Evidence strengthLow

Read the original

• DOI: 10.1016/0006-8993(95)01032-7
• PubMed: 8822355
• Original source →

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@article{maurice1996-8822355,
  author  = {Maurice, T. and Lockhart, B. P. and Privat, A.},
  title   = {{Amnesia induced in mice by centrally administered beta-amyloid peptides involves cholinergic dysfunction}},
  journal = {Brain research},
  year    = {1996},
  doi     = {10.1016/0006-8993(95)01032-7},
  pmid    = {8822355},
  url     = {https://doi.org/10.1016/0006-8993(95)01032-7}
}

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