Cognitive evaluation of disease-modifying efficacy of donepezil in the APP23 mouse model for Alzheimer's disease

Psychopharmacology (Berl). 2008 Mar;197(1):37-43. doi: 10.1007/s00213-007-1010-x. Epub 2007 Nov 16.

Abstract

Rationale: The interest for acetylcholinesterase inhibitors in the treatment of Alzheimer's disease has been greatly renewed owing to the discovery of a broad range of additional cholinergic and non-cholinergic effects, exploitable to maximize the efficacy of these drugs beyond merely improving intellectual functions at the symptomatic level.

Objectives: The age-dependent cognitive decline in the valid APP23 transgenic mouse model for Alzheimer's disease was employed to evaluate disease-modifying efficacy of chronic treatment with donepezil.

Materials and methods: At age 6 weeks, heterozygous APP23 mice and control littermates were subcutaneously implanted with osmotic pumps delivering saline or donepezil (0.27 or 0.58 mg/kg per day). After 2 months of treatment, a 3-week wash-out period was allowed to prevent bias from sustained symptomatic effects before cognitive evaluation in the Morris water maze commenced.

Results: Donepezil (0.27 mg/kg per day)-treated APP23 mice performed significantly better than their sham-treated counterparts during the Morris water maze acquisition phase and the subsequent probe or retention trial. Chronic donepezil (0.27 mg/kg per day) treatment improved spatial accuracy in APP23 mice as to reach the same level of performance as wild-type control animals on this complex visual-spatial learning task.

Conclusion: This is the first study reporting disease-modifying efficacy of donepezil at the level of cognitive performance in transgenic mice modeling Alzheimer's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Protein Precursor / genetics*
  • Animals
  • Cognition / drug effects*
  • Disease Models, Animal*
  • Donepezil
  • Dose-Response Relationship, Drug
  • Escape Reaction / drug effects
  • Genotype
  • Indans / pharmacology*
  • Infusion Pumps, Implantable
  • Male
  • Maze Learning / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Transgenic
  • Nootropic Agents / pharmacology*
  • Orientation / drug effects
  • Piperidines / pharmacology*
  • Reaction Time / drug effects
  • Retention, Psychology / drug effects
  • Treatment Outcome

Substances

  • Amyloid beta-Protein Precursor
  • Aplp1 protein, mouse
  • Indans
  • Nootropic Agents
  • Piperidines
  • Donepezil