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Liraglutide Ameliorates Hyperhomocysteinemia-Induced Alzheimer-Like Pathology and Memory Deficits in Rats via Multi-molecular Targeting

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Abstract

Hyperhomocysteinemia (Hhcy) is an independent risk factor for Alzheimer’s disease (AD), and insulin-resistance is commonly seen in patients with Hhcy. Liraglutide (Lir), a glucagon-like peptide that increases the secretion and sensitivity of insulin, has a neurotrophic or neuroprotective effect. However, it is not known whether Lir ameliorates the AD-like pathology and memory deficit induced by Hhcy. By vena caudalis injection of homocysteine to produce the Hhcy model in rats, we found here that simultaneous administration of Lir for 2 weeks ameliorated the Hhcy-induced memory deficit, along with increased density of dendritic spines and up-regulation of synaptic proteins. Lir also attenuated the Hhcy-induced tau hyperphosphorylation and Aβ overproduction, and the molecular mechanisms involved the restoration of protein phosphatase-2A activity and inhibition of β- and γ-secretases. Phosphorylated insulin receptor substrate-1 also decreased after treatment with Lir. Our data reveal that Lir improves the Hhcy-induced AD-like spatial memory deficit and the mechanisms involve the modulation of insulin-resistance and the pathways generating abnormal tau and Aβ.

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Acknowledgements

This work was supported by the National Key R&D Program of China, National Basic Research Development Program of the Ministry of Science and Technology of China (2016YFC1305800), the National Natural Science Foundation of China (31730035, 91632305, and 81721005), and the Integrated Innovation Team for Major Human Disease Program of Tongji Medical College, Huazhong University of Science and Technology, China.

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  1. Yao Zhang and Jia-Zhao Xie have contributed equally to this work.

Authors and Affiliations

  1. Endocrinology Department of Liyuan Hospital and Key Laboratory of the Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430077, China

    Yao Zhang

  2. Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of the Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Jia-Zhao Xie & Jian-Zhi Wang

  3. Endocrinology Department, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430077, China

    Jun Hu, Teng Xu, Si Jin & Shao-Juan Yang

  4. Radiology Department, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430077, China

    Xiang-Yang Xu

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  1. Yao Zhang
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Zhang, Y., Xie, JZ., Xu, XY. et al. Liraglutide Ameliorates Hyperhomocysteinemia-Induced Alzheimer-Like Pathology and Memory Deficits in Rats via Multi-molecular Targeting. Neurosci. Bull. 35, 724–734 (2019). https://doi.org/10.1007/s12264-018-00336-7

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