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Donepezil improves learning and memory deficits in APP/PS1 mice by inhibition of microglial activation.
Neuroscience. 2015 Apr 02; 290:530-42.N

Abstract

Donepezil, a cholinesterase inhibitor, is a representative symptomatic therapy for Alzheimer's disease (AD). Recent studies have reported the anti-inflammatory effects of donepezil. However, limited studies that investigate its anti-inflammatory effect in AD have been reported. Considering the role of proinflammatory molecules and microglial activation in the pathogenesis of AD, the current study aimed to elucidate the effects of donepezil on microglial activation induced by amyloid deposition in transgenic mice. Our results showed that chronic treatment with donepezil significantly improved the cognitive function in the novel object recognition test and Morris water maze test in amyloid precursor protein (APP)/presenilin-1 (PS1) transgenic mice. We further demonstrated that these cognitive enhancements were related to the anti-inflammatory effect of donepezil. We found that donepezil could inhibit the expression of CD68, a specific marker of microglial activation, and reduce the release of proinflammatory cytokines including tumor necrosis factor-α and interleukin-1β. Immunohistochemistry and Congo red co-staining revealed that congophilic amyloid and activated microglia around plaques were also reduced by donepezil treatment. Enzyme-linked immunosorbent assay (ELISA) analysis showed that donepezil decreased insoluble Aβ40/Aβ42 and soluble Aβ40 levels. Moreover, donepezil reversed the impaired expression of insulin-degrading enzyme in the hippocampus of APP/PS1 mice. Our findings indicated that donepezil improves cognitive deficits in APP/PS1 mice by a mechanism that may be associated with its inhibition of microglial activation and release of proinflammatory cytokines.

Authors+Show Affiliations

Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: jpx@smu.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25662507

Citation

Guo, H B., et al. "Donepezil Improves Learning and Memory Deficits in APP/PS1 Mice By Inhibition of Microglial Activation." Neuroscience, vol. 290, 2015, pp. 530-42.
Guo HB, Cheng YF, Wu JG, et al. Donepezil improves learning and memory deficits in APP/PS1 mice by inhibition of microglial activation. Neuroscience. 2015;290:530-42.
Guo, H. B., Cheng, Y. F., Wu, J. G., Wang, C. M., Wang, H. T., Zhang, C., Qiu, Z. K., & Xu, J. P. (2015). Donepezil improves learning and memory deficits in APP/PS1 mice by inhibition of microglial activation. Neuroscience, 290, 530-42. https://doi.org/10.1016/j.neuroscience.2015.01.058
Guo HB, et al. Donepezil Improves Learning and Memory Deficits in APP/PS1 Mice By Inhibition of Microglial Activation. Neuroscience. 2015 Apr 2;290:530-42. PubMed PMID: 25662507.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Donepezil improves learning and memory deficits in APP/PS1 mice by inhibition of microglial activation. AU - Guo,H B, AU - Cheng,Y F, AU - Wu,J G, AU - Wang,C M, AU - Wang,H T, AU - Zhang,C, AU - Qiu,Z K, AU - Xu,J P, Y1 - 2015/02/04/ PY - 2014/10/24/received PY - 2014/12/26/revised PY - 2015/01/25/accepted PY - 2015/2/10/entrez PY - 2015/2/11/pubmed PY - 2015/12/17/medline KW - Alzheimer’s disease KW - amyloid-β KW - donepezil KW - insulin-degrading enzyme KW - microglia KW - neuroinflammation SP - 530 EP - 42 JF - Neuroscience JO - Neuroscience VL - 290 N2 - Donepezil, a cholinesterase inhibitor, is a representative symptomatic therapy for Alzheimer's disease (AD). Recent studies have reported the anti-inflammatory effects of donepezil. However, limited studies that investigate its anti-inflammatory effect in AD have been reported. Considering the role of proinflammatory molecules and microglial activation in the pathogenesis of AD, the current study aimed to elucidate the effects of donepezil on microglial activation induced by amyloid deposition in transgenic mice. Our results showed that chronic treatment with donepezil significantly improved the cognitive function in the novel object recognition test and Morris water maze test in amyloid precursor protein (APP)/presenilin-1 (PS1) transgenic mice. We further demonstrated that these cognitive enhancements were related to the anti-inflammatory effect of donepezil. We found that donepezil could inhibit the expression of CD68, a specific marker of microglial activation, and reduce the release of proinflammatory cytokines including tumor necrosis factor-α and interleukin-1β. Immunohistochemistry and Congo red co-staining revealed that congophilic amyloid and activated microglia around plaques were also reduced by donepezil treatment. Enzyme-linked immunosorbent assay (ELISA) analysis showed that donepezil decreased insoluble Aβ40/Aβ42 and soluble Aβ40 levels. Moreover, donepezil reversed the impaired expression of insulin-degrading enzyme in the hippocampus of APP/PS1 mice. Our findings indicated that donepezil improves cognitive deficits in APP/PS1 mice by a mechanism that may be associated with its inhibition of microglial activation and release of proinflammatory cytokines. SN - 1873-7544 UR - https://www.unboundmedicine.com/medline/citation/25662507/Donepezil_improves_learning_and_memory_deficits_in_APP/PS1_mice_by_inhibition_of_microglial_activation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-4522(15)00116-5 DB - PRIME DP - Unbound Medicine ER -