Sitagliptin protects the cognition function of the Alzheimer’s disease mice through activating glucagon-like peptide-1 and BDNF-TrkB signalings

Abstract Background Sitagliptinis an anti-diabetic drug and its effects on Alzheimer’s disease (AD) remain controversial. This study aimed to investigate the protective effect of sitagliptinon 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 sitagliptintreatment 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. Sitagliptinsignificantly 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. Sitagliptintreatment 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 sitagliptinin the MWM test. Conclusion Sitagliptintreatment effectively protected the cognition function of the AD mice by regulating synaptic plasticity, at least partially, through activating GLP-1 and BDNF-TrkB signalings.