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Characterization of cognitive deficits in a transgenic mouse model of Alzheimer's disease and effects of donepezil and memantine.
Eur J Pharmacol. 2013 Mar 05; 703(1-3):53-61.EJ

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+Show Affiliations

Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 305-8585, Japan. akira.nagakura@astellas.comNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

23276665

Citation

Nagakura, Akira, et al. "Characterization of Cognitive Deficits in a Transgenic Mouse Model of Alzheimer's Disease and Effects of Donepezil and Memantine." European Journal of Pharmacology, vol. 703, no. 1-3, 2013, pp. 53-61.
Nagakura A, Shitaka Y, Yarimizu J, et al. Characterization of cognitive deficits in a transgenic mouse model of Alzheimer's disease and effects of donepezil and memantine. Eur J Pharmacol. 2013;703(1-3):53-61.
Nagakura, A., Shitaka, Y., Yarimizu, J., & Matsuoka, N. (2013). Characterization of cognitive deficits in a transgenic mouse model of Alzheimer's disease and effects of donepezil and memantine. European Journal of Pharmacology, 703(1-3), 53-61. https://doi.org/10.1016/j.ejphar.2012.12.023
Nagakura A, et al. Characterization of Cognitive Deficits in a Transgenic Mouse Model of Alzheimer's Disease and Effects of Donepezil and Memantine. Eur J Pharmacol. 2013 Mar 5;703(1-3):53-61. PubMed PMID: 23276665.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Characterization of cognitive deficits in a transgenic mouse model of Alzheimer's disease and effects of donepezil and memantine. AU - Nagakura,Akira, AU - Shitaka,Yoshitsugu, AU - Yarimizu,Junko, AU - Matsuoka,Nobuya, Y1 - 2012/12/28/ PY - 2012/06/25/received PY - 2012/12/07/revised PY - 2012/12/18/accepted PY - 2013/1/2/entrez PY - 2013/1/2/pubmed PY - 2013/9/24/medline SP - 53 EP - 61 JF - European journal of pharmacology JO - Eur. J. Pharmacol. VL - 703 IS - 1-3 N2 - 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. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/23276665/Characterization_of_cognitive_deficits_in_a_transgenic_mouse_model_of_Alzheimer's_disease_and_effects_of_donepezil_and_memantine_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(12)01040-0 DB - PRIME DP - Unbound Medicine ER -