Geniposide attenuates the level of Aβ1–42 via enhancing leptin signaling in cellular and APP/PS1 transgenic mice

Abstract

An large body of evidence indicates that leptin has protective role against Alzheimer's disease, where it reduces β-amyloid (Aβ) production in both cell culture and animal models. Our previous studies revealed that geniposide could attenuate the production of Aβ and antagonize the neurotoxicity of Aβ in neurons. However, the mechanism that underlies these effects remains to be clarified. To investigate whether leptin signaling is involved in regulating the production of Aβ by geniposide, we treated primary neurons with leptin antagonist (LA), and determined the influence of LA on the activities of leptin signaling molecules and the expressions of secretases associated with the production of Aβ. The finding showed that, accompanied with the inhibition on the level of Aβ in primary neurons and APP/PS1 transgenic mice, geniposide induced the phosphorylation of JAK2 and STAT3, regulated the expression level of α- and β-secretase, and all of these could be prevented by the pre-incubation with LA. The results of this study suggest that geniposide may regulate the production of Aβ via leptin signaling.

Geniposide Alleviates Oxidative Stress of Mice With Depression-Like Behaviors by Upregulating Six3os1

“…In animal experiments, GP was diluted with DMSO to different concentrations of 25, 50, and 100 mg/kg (Cai et al, 2015); meanwhile, a stock solution at the concentration of 10 µM (Liu et al, 2017) was used and stored at −80 • C.…”

“…The CUMS-induced neurons were separately infected with the lentivirus of oe-NC, sh-NC, oe-Fezf1, sh-Fezf1, oe-Six3os1, inhibitor-NC, mimic-NC, miR-511-3p mimic and miR-511-3p inhibitor or in combination for 48 h. Other CUMS-induced neurons were firstly incubated with 10 µM GP for 24 h (Liu et al, 2017) and then separately infected with the lentivirus of sh-NC, sh-Fezf1, sh-Six3os1, mimic-NC, miR-511-3p mimic, miR-511-3p inhibitor, inhibitor-NC, oe-NC and oe-Fezf1 or in combination for 48 h. All lentiviruses were purchased from Shanghai Sangon Biotechnology Co. Ltd. (Shanghai, China), and the primer sequences and plasmids construction were conducted by Shanghai Sangon Biotechnology Co. Ltd. (Shanghai, China). Experiments were performed according to operation instructions.…”

A Review on the Phytochemistry, Pharmacology, Pharmacokinetics and Toxicology of Geniposide, a Natural Product

“…As for the protective mechanism, the iridoid glycoside could induce the phosphorylation of Janus kinase 2 (JAK2) in addition to the signal transducers and activators of transcription 3 (STAT3). Furthermore, this glycoside can regulate the expression level of α- and β-secretase, which may be mediated with leptin signaling [ 170 ]. Furthermore, Aβ accumulation and cholinergic defects are considered to be related with learning and memory impairments.…”

Iridoids and Other Monoterpenes in the Alzheimer’s Brain: Recent Development and Future Prospects

“…The vast arrays of neuroprotective effects of iridoids and some monoterpenes are shown in Table 1 [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 ]. The Aβ formation, aggregation and function have been the major target areas of AD for in vitro experiments.…”

“…By using primary cortical neurons in a culture media, Zhang et al [ 39 ] have demonstrated that geniposide enhance the phosphorylation of peroxisome proliferator-activated receptor γ (PPARγ). The effect of geniposide in the activation of the IDE promoter was also shown to be mediated via the glucagon-like peptide-1 (GLP-1) receptor while other pathways confirmed to be involved by inhibitor studies (see Table 1 ) where phosphatidyl inositol 3-kinase, PI3K, proto-oncogene tyrosine-protein kinase Src (c-Src), PPARγ, protein kinase A (PKA) and epidermal growth factor receptor (EGFR) [ 39 , 40 ]. Furthermore, in the SH-SY5Y cells, geniposide has been shown to ameliorate the cytotoxicity of Aβ along with its oligomer assembly and cytotoxicity [ 41 ].…”