Liraglutide Ameliorates Hyperhomocysteinemia-Induced Alzheimer-Like Pathology and Memory Deficits in Rats via Multi-molecular Targeting
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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.
KeywordsLiraglutide Hyperhomocysteinemia Glucagon-like peptide-1 receptor Tau β-Amyloid
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.
Conflict of interest
The authors claim that there are no conflicts of interest.
- 9.Li B, Xi X, Roane DS, Ryan DH, Martin RJ. Distribution of glucokinase, glucose transporter GLUT2, sulfonylurea receptor-1, glucagon-like peptide-1 receptor and neuropeptide Y messenger RNAs in rat brain by quantitative real time RT-PCR. Brain Res Mol Brain Res 2003, 113: 139–142.CrossRefGoogle Scholar
- 20.Ahren B, Pacini G. Dose-related effects of GLP-1 on insulin secretion, insulin sensitivity, and glucose effectiveness in mice. Am J Physiol 1999, 277: E996–E1004.Google Scholar
- 27.Hoyer S, Muller D, Plaschke K. Desensitization of brain insulin receptor. Effect on glucose/energy and related metabolism. J Neural Transm Suppl 1994, 44: 259–268.Google Scholar
- 39.Qi L, Chen Z, Wang Y, Liu X, Liu X, Ke L, et al. Subcutaneous liraglutide ameliorates methylglyoxal-induced Alzheimer-like tau pathology and cognitive impairment by modulating tau hyperphosphorylation and glycogen synthase kinase-3beta. Am J Transl Res 2017, 9: 247–260.Google Scholar