Characterization of cognitive deficits in a transgenic mouse model of Alzheimer's disease and effects of donepezil and memantine

被引:46
|
作者
Nagakura, Akira [1 ]
Shitaka, Yoshitsugu [1 ]
Yarimizu, Junko [1 ]
Matsuoka, Nobuya [1 ]
机构
[1] Astellas Pharma Inc, Pharmacol Res Labs, Drug Discovery Res, Tsukuba, Ibaraki 3058585, Japan
关键词
PS1/APP transgenic mice; Morris water maze; Y-maze; Donepezil; Memantine; AMYLOID-PRECURSOR-PROTEIN; NMDA RECEPTOR ANTAGONISTS; CHOLINERGIC NEURONS; IMPROVES COGNITION; MODIFYING EFFICACY; LEARNING-DEFICITS; MICE; PRESENILIN-1; MEMORY; MUTANT;
D O I
10.1016/j.ejphar.2012.12.023
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Alzheimer's disease is characterized by a progressive decline in cognitive function and involves beta-amyloid (A beta) in its pathogenesis. To characterize cognitive deficits associated with A beta 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 A beta 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 A beta 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. (c) 2012 Elsevier B.V. All rights reserved.
引用
收藏
页码:53 / 61
页数:9
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