title: Geniposide attenuates insulin-deficiency-induced acceleration of β-amyloidosis in an APP/PS1 transgenic model of Alzheimer's disease.
abstract: Our previous studies have shown that geniposide plays an essential role in glucose-stimulated insulin secretion from pancreatic β cells and also antagonizesAβ1-42-induced cytotoxicity examined using a primary cortical neuron assay. However, the mechanism by which geniposide appears to regulate insulin signaling in the brain is presently not well understood. In this study, we administered streptozotocin (STZ) to induce insulin-deficiency in an AD transgenic mouse model, and investigated the effects of geniposide on the β-amyloidogenic processing of amyloid precursor protein (APP) using in vitro and in vivo models. Our results indicate that treatment with STZ (90 mg/kg, i.p., once daily for two consecutive days) induced significant reduction in peripheral and brain insulin levels in both wild-type and APP/PS1 transgenic mice. Administration of geniposide for 4 weeks significantly decreased the concentrations of cerebral β-amyloid peptides (Aβ1-40 and Aβ1-42) in STZ-treated AD mice. Further experiments showed that geniposide up-regulated the protein levels of β-site APP cleaving enzyme (BACE1) and insulin-degrading enzyme (IDE), and decreased the protein levels of ADAM10 when examined using a primary cultured cortical neuron assay and in STZ-induced AD mice. Meanwhile, geniposide also directly enhanced the effects of insulin by reducing Aβ1-42 levels in primary cultured cortical neurons. Taken together, our findings provide a mechanistic link between diabetes and AD, and is consistent with the notion that geniposide might play an important role on APP processing via enhancing insulin signaling and may convey a therapeutic benefit in AD.
authors.affiliation: College of Chemistry and Chemical Engineering, Chongqing University, Chongqing, 400030, China; College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054, China.
authors.forename: Yonglan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054, China; Chongqing Key Lab of Catalysis & Functional Organic Molecules, Chongqing Technology and Business University, Chongqing, 400067, China. Electronic address: fyin@cqut.edu.cn.
authors.forename: Fei
authors.initials: F
authors.lastname: Yin
authors.affiliation: College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054, China; Chongqing Key Lab of Catalysis & Functional Organic Molecules, Chongqing Technology and Business University, Chongqing, 400067, China.
authors.forename: Jianhui
authors.initials: J
authors.lastname: Liu
authors.affiliation: Chongqing Key Lab of Catalysis & Functional Organic Molecules, Chongqing Technology and Business University, Chongqing, 400067, China.
authors.forename: Zixuan
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Chongqing Key Lab of Catalysis & Functional Organic Molecules, Chongqing Technology and Business University, Chongqing, 400067, China.
authors.forename: Lixia
authors.initials: L
authors.lastname: Guo
authors.affiliation: College of Chemistry and Chemical Engineering, Chongqing University, Chongqing, 400030, China.
authors.forename: Zhining
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, University of Calgary, Calgary, AB, Canada.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Zidichouski
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007328:Insulin / Q000172:deficiency*; D039823:Iridoids / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007328:Insulin; D039823:Iridoids; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); C007835:geniposide
keywords: Alzheimer’s disease (AD); Diabetes; Geniposide; Insulin signaling; Secretase; β-amyloid (Aβ)