title: Characterization of cognitive deficits in a transgenic mouse model of Alzheimer's disease and effects of donepezil and memantine.
abstract: Alzheimer's disease is characterized by a progressive decline in cognitive function and involves β-amyloid (Aβ) in its pathogenesis. To characterize cognitive deficits associated with Aβ accumulation, we analyzed PS1/APP mice overexpressing mutant presenilin-1 (PS1, M146L; line 6.2) and amyloid precursor protein (APP, K670N/M671L; line Tg2576), a mouse model of Alzheimer's disease with accelerated Aβ production. Age-dependent changes in working and spatial memory behaviors were investigated using Y-maze and Morris water maze tasks, respectively, in female PS1/APP mice at ages of 2, 4, 6, and 12 months. Significant deficits in working and spatial memory were observed from 4 and 6 months of age, respectively. Acute single-dose administrations of memantine, a low-to-moderate-affinity N-methyl-d-aspartate (NMDA) antagonist, showed improvements in working memory deficits at 4 months of age, whereas donepezil, an acetylcholinesterase (AChE) inhibitor, did not. However, both drugs improved spatial memory dysfunction at 6 months of age at therapeutically relevant doses. No age-related dramatic changes were observed in expression levels of several proteins relating to memory dysfunction and also the mechanisms of donepezil and memantine in the cerebral cortex of PS1/APP mice until 6 months of age. Taken together, these results suggest dysfunctions in cholinergic and/or glutamatergic transmissions may be involved in the cognitive deficits associated with Aβ toxicity. Since donepezil and memantine have been widely used for treating patients of Alzheimer's disease, these results also suggest that cognitive deficits in PS1/APP mice assessed in the Y-maze and Morris water maze tasks are a useful animal model for evaluating novel Alzheimer's disease therapeutics.
authors.affiliation: Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 305-8585, Japan. akira.nagakura@astellas.com
authors.forename: Akira
authors.initials: A
authors.lastname: Nagakura
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Shitaka
authors.forename: Junko
authors.initials: J
authors.lastname: Yarimizu
authors.forename: Nobuya
authors.initials: N
authors.lastname: Matsuoka
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D000077265:Donepezil; D005260:Female; D007189:Indans / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D018782:Maze Learning; D008559:Memantine / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D008568:Memory / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D018697:Nootropic Agents / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D010880:Piperidines / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D018091:Receptors, AMPA / Q000378:metabolism
chemical_list: D002800:Cholinesterase Inhibitors; D017362:Cyclic AMP Response Element-Binding Protein; D000077265:Donepezil; D007189:Indans; D008559:Memantine; D018697:Nootropic Agents; D010880:Piperidines; D018091:Receptors, AMPA; C492004:Creb1 protein, mouse