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


OBJECTIVE
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.


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.


CONCLUSIONS
This is the first study reporting disease-modifying efficacy of donepezil at the level of cognitive performance in transgenic mice modeling Alzheimer's disease.
Van Dam
Debby
D
Department of Biomedical Sciences, Laboratory of Neurochemistry and Behaviour, Institute Born-Bunge, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.
Coen
Katrien
K
De Deyn
Peter Paul
PP
D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004924:Escape Reaction / Q000187:drug effects; D005838:Genotype; D007189:Indans / Q000494:pharmacology*; D015918:Infusion Pumps, Implantable; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D018697:Nootropic Agents / Q000494:pharmacology*; D009949:Orientation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D011930:Reaction Time / Q000187:drug effects; D012153:Retention, Psychology / Q000187:drug effects; D016896:Treatment Outcome
D016564:Amyloid beta-Protein Precursor; C078201:Aplp1 protein, mouse; D007189:Indans; D018697:Nootropic Agents; D010880:Piperidines; D000077265:Donepezil