Molecular Mechanisms Of Geniposide Attenuating The Neurotoxicity Of β-Amyloid And Regulating Its Metabolism In Vitro And In Vivo

Alzheimer’s disease(AD) is the most common cause of dementia amongst in the elderly older people, which are characterized by abnormal protein processing, and two prominent pathological features of AD which are the presence of elevated levels of extracellular senile plaques and intracellular neurofibrillary tangles(NFTs). Because the causes of AD remain unclear and under much debate, there is no efficient strategy for the treatment of AD.The increasing evidence shows that activation of glucagon-like peptide 1 receptor(GLP-1R) is becoming increasingly important in the field of AD treatment for its neurotrophic and neuroprotective effects. Our previous work demonstrated that geniposide was a novel selective agonist for GLP-1R, which showed neurotrophic effects to accelerate the release of c AMP and induced the neuronal differention of PC12 cells with the activation of GLP-1R, and neuroprotective effects to prevent the oxidative damage through PI3 K signal pathway. But unfortunately, the role of geniposide on the neurotoxicity of Aβ and the moecular mechanisms keeps to be explored, and it is not clear whether geniposide regulates the metabolism of Aβ and tau phosphorylation.In this study, we designed to explore the neuroprotection of geniposide in Aβ1-42 treated primary cultured cortical neurons and its molecular mechanisms. Our data suggested that preincubation with geniposide could attenuate the neurotoxicity of Aβ1-42, and this effect was associated with the expression of insulin-degrading enzyme with activation of GLP-1R in primary cultured cortical neurons. And then, we analyzed the progress of cell signaling transduction and molecular mechanisms by which geniposide induces the expression of IDE in primary cortical neurons. The current study revealed that LY294002(an inhibitor for phosphatidyl inositol 3-kinase, PI3K), PP1(inhibitor for c-Src), GW9662(antagonist for peroxisome proliferator-activated receptor γ, PPARγ), H89(an inhibitor for protein kinase A, PKA) and AG1478(an antagonist for epidermal growth factor receptor, EGFR) prohibited the up-regul`ation of IDE induced by geniposide in primary cortical neurons. And geniposide also enhanced the phosphorylation of PPARγ and accelerated the release of phosphorylated Fox O1(forkhead box O1) from nuclear fraction to the cytosol. Additionally, geniposide directly activated the activity of IDE promoter in PC12 cells, which confirmed the presence of the GLP-1 receptor. All these data show that geniposide upregulating IDE expression through the activation of GLP-1 receptor plays an important role on its neuroprotection to antagonize the neurotoxicity of Aβ1-42 in primary cortical neurons.After that,we continued to investigate the role of geniposide on the metabolism of Aβ and phosphorylation of tau in vitro and in vivo. We administered streptozotocin(STZ) to induce insulin-deficiency in an AD transgenic mouse model. The results demonstrated that administration of geniposide significantly decreased the concentrations of cerebral β-amyloid peptides and the level of phosphorylated tau in STZ-treated AD mice, and this effect may be related with affecting the expression level of β-secretase via enchancing insulin signal. Further, we continued to explore the cell signaling transduction and molecular mechanisms by which geniposide regulate the metabolism of Aβ and phosphorylation of tau in primary cortical neurons. Experimental data showed that geniposide reduced Aβ1-42 levels by enhancing the effects of insulin via PI3 K signaling pathway, up-regulated the levels of β-site APP cleaving enzyme(BACE1), and decreased the protein levels of ADAM10. Meanwhile, inhibited tau phosphorylation via GSK-3β phosphorylation in primary cultured cortical neurons.Taken together, our findings reveal for the first time the cell signaling transduction pathway of geniposide regulating the expression of IDE to attenuate the neurotoxicity of Aβ1-42 in neurons. Meanwhile, our findings also clarify the molecular mechanisms of geniposide regulating Aβ metabolim and tau phosphorylation via potentiating insulin signal, which is consistent with the notion that geniposide might play an essential role on APP processing via enhancing insulin signaling and may convey a therapeutic benefit in AD.