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Donepezil improves the cognitive impairment in a tree shrew model of Alzheimer’s disease induced by amyloid-β1–40 via activating the BDNF/TrkB signal pathway

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Abstract

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder which can contribute to memory loss and cognitive damage in the elderly; moreover, evidence from clinical and animal studies demonstrated that AD always exhibit severe cognitive deficits. However, the effects of donepezil medications on cognition are controversial. Additionally, it is unclear whether donepezil can protect neurons to improve cognitive function through the brain-derived neurotropic factor (BDNF)/tyrosine receptor kinase B (TrkB) signalling pathway in the tree shrew (TS), which has a closer evolutionary relationship to primates than rodents. Here, we designed a study on an amyloid-β1–40 (Aβ1–40)-induced TS model of AD and investigated the molecular mechanism by which donepezil protects neurons and improves cognitive function through activating the BDNF/TrkB signalling pathway. The results showed that donepezil could rescue Aβ1–40-induced spatial cognition deficits, and reverse Aβ1–40-induced temporal horn along with ADC enlargement in the TS brain. Meanwhile, it suppressed Aβ1–40-induced neuronal damage and loss of body weight. Intriguingly, donepezil could increase the choline acetyl transferase (ChAT) expression level and reduce the fibrillary acid protein (GFAP) expression level in the hippocampus and cortex of TS. Additionally, donepezil significantly upregulated the expression level of BDNF, as well as the phosphorylated level of TrkB. These results suggested that donepezil could protect neurocytes from senility and ameliorate learning and memory impairment in the TS model of AD, which appeared to be through regulating the cholinergic system and inhibiting the BDNF/TrkB-dependent signalling pathway. Moreover, the study underlines the potency of TS to be a novel animal model for research on AD, and it deserves intensive attention.

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Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (81460647) and the CAMS Initiative for Innovative Medicine (2016-I2M-2-006).

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Authors and Affiliations

  1. Department of Laboratory Animal Science, Kunming Medical University, Kunming, 650500, China

    Hong Zheng

  2. Department of Biochemistry and Molecular Biology, School of Basic Medicine, Kunming Medical University, Kunming, 650500, China

    Shiwei Niu & Shude Li

  3. Department of Emergency Medicine, the First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China

    Hongbin Zhao

  4. Technology Transfer Center, Kunming Medical University, Kunming, 650031, China

    Jianlin Jiao

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  1. Hong Zheng
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  2. Shiwei Niu
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Correspondence to Shude Li or Jianlin Jiao.

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Zheng, H., Niu, S., Zhao, H. et al. Donepezil improves the cognitive impairment in a tree shrew model of Alzheimer’s disease induced by amyloid-β1–40 via activating the BDNF/TrkB signal pathway. Metab Brain Dis 33, 1961–1974 (2018). https://doi.org/10.1007/s11011-018-0303-6

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