Qing Dong1, Shuai-Wen Teng2, Yue Wang2, Feng Qin3, Yue Li4, Lu-Lu Ai5, Hui Yu6. 1. Department of Neurology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510630, People's Republic of China. Electronic address: dongqing2009tracy@163.com. 2. Shandong Provincial Key Laboratory of Mental Disorders, Department of Cell and Neurobiology, School of Basic Medicine, Shandong University, Jinan, Shandong, 250012, People's Republic of China. 3. Department of Neurosurgery, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510630, People's Republic of China. 4. Department of Traditional Chinese Medicine, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510630, People's Republic of China. 5. Department of Neurology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510630, People's Republic of China. 6. Shandong Provincial Key Laboratory of Mental Disorders, Department of Cell and Neurobiology, School of Basic Medicine, Shandong University, Jinan, Shandong, 250012, People's Republic of China. Electronic address: yuhuicn@sdu.edu.cn.
Abstract
BACKGROUND: Sitagliptin is an anti-diabetic drug and its effects on Alzheimer's disease (AD) remain controversial. This study aimed to investigate the protective effect of sitagliptin on the cognition in AD and its underlying molecular mechanism. METHODS: The APP/PS1 (a model of AD) mice received daily gastric gavage administration of sitagliptin (20 mg/kg) for 8 weeks. Then animals were subjected to behavioral experiment or sacrificed to histological staining and protein level analysis. RESULTS: The MWM test showed that sitagliptin treatment significantly reduced the escape latency times in APP/PS1 mice in the learning phase (day 3-5) and elongated the time spent in the target quadrant in the probe test. Sitagliptin significantly reduced amyloid plaque deposition and elevated the spine density and the protein levels of synaptoneurosome GluA1- and GluA2-containing AMPA receptor (GluA1R and GluA2R) in the brain of the APP/PS1 mice. Sitagliptin treatment significantly up-regulated the brain BNDF protein and phosphorylation of tyrosine receptor kinase B (TrkB). Furthermore, exendin-(9-39) (a glucagon-like peptide-1 [GLP-1] receptor antagonist) and K252a (a Trk tyrosine kinase inhibitor) treatment significantly abolished the cognitive protective effect of sitagliptin in the MWM test. CONCLUSION: Sitagliptin treatment effectively protected the cognition function of the AD mice by regulating synaptic plasticity, at least partially, through activating GLP-1 and BDNF-TrkB signalings.
BACKGROUND:Sitagliptin is an anti-diabetic drug and its effects on Alzheimer's disease (AD) remain controversial. This study aimed to investigate the protective effect of sitagliptin on the cognition in AD and its underlying molecular mechanism. METHODS: The APP/PS1 (a model of AD) mice received daily gastric gavage administration of sitagliptin (20 mg/kg) for 8 weeks. Then animals were subjected to behavioral experiment or sacrificed to histological staining and protein level analysis. RESULTS: The MWM test showed that sitagliptin treatment significantly reduced the escape latency times in APP/PS1mice in the learning phase (day 3-5) and elongated the time spent in the target quadrant in the probe test. Sitagliptin significantly reduced amyloid plaque deposition and elevated the spine density and the protein levels of synaptoneurosome GluA1- and GluA2-containing AMPA receptor (GluA1R and GluA2R) in the brain of the APP/PS1mice. Sitagliptin treatment significantly up-regulated the brain BNDF protein and phosphorylation of tyrosine receptor kinase B (TrkB). Furthermore, exendin-(9-39) (a glucagon-like peptide-1 [GLP-1] receptor antagonist) and K252a (a Trk tyrosine kinase inhibitor) treatment significantly abolished the cognitive protective effect of sitagliptin in the MWM test. CONCLUSION:Sitagliptin treatment effectively protected the cognition function of the ADmice by regulating synaptic plasticity, at least partially, through activating GLP-1 and BDNF-TrkB signalings.
Authors: Laura Poupon-Bejuit; Eridan Rocha-Ferreira; Claire Thornton; Henrik Hagberg; Ahad A Rahim Journal: Front Cell Neurosci Date: 2020-05-06 Impact factor: 5.505