Abstract
The association of Alzheimer disease (AD) and Diabetes (DM) is less clear. Accumulation of beta amyloid (Aβ) and presence of hyperphosphorylated tau (p-tau) are hallmarks of AD, spreading in the region where insulin receptors are also found. Aβ exerts neuron toxicity, and could disturb insulin signaling of phosphatidylinositol 3-kinase (PI3K), glycogen synthase kinase (GSK)-3β and AMP-activated protein kinase (AMPK), but increase IRS-1-Ser307 phosphorylation which is viewed as insulin resistance marker. Previously we reported dipeptidyl peptidase-4 (DPP-4) mediate insulin resistance signals, and Abelmoschus esculentus (AE) subfractions F1 (rich in quercetin glucosides and triterpene ester) and F2 (containing large amount of polysaccharides) attenuate DPP-4-mediated apoptosis. In the present study, we aim to investigate if Aβ induce neuron death by regulating DPP-4 and insulin resistance signals, and the putative effect of F1 and F2. By MTT, microscopy, and Western blotting, we demonstrate treatment of appropriate doses of AE subfractions prevent Aβ-induced neuron apoptosis. F1 attenuate Aβ-induced caspase 3 expression especially at 25 μg/mL, while F2 attenuate caspase 3 activation even at the low dose of 1 μg/mL. Both AE subfractions decrease Aβ-enhanced DPP-4, but increase Aβ-reduced p-AMPK and p-PI3K. The activity analysis reveals that F2 is more valid than F1 to reduce DPP-4 activity. The inhibition of DPP-4 demonstrates it plays the pivotal role in Aβ-induced neuron apoptosis. Moreover, although both F1 and F2 are effective to inhibit p-IRS-1-Ser307, F2 takes advantage to reduce p-Tau while F1 is superior to enhance p-GSK-3β. This implies AE subfractions act on different targets, and could be developed respectively. In conclusion, we demonstrate AE is potential to prevent Aβ-induced neuron damage by regulating DPP-4 and the insulin resistance cascades. AE could be an adjuvant to protect neuron degenerative disease related to Aβ and insulin resistance.
Highlights
The worldwide increasing prevalence of diabetes (DM), characterized by insulin secretion defect, insulin resistance or both, burdens the public health
We demonstrated that the treatment of appropriate dose of Abelmoschus esculentus (AE) subfractions inhibit Aβ-induced apoptosis of neurons (Fig 7)
Treatment of F1 attenuates Aβ-induced cleavage of caspase 3, while F2 attenuates the activation of caspase 3 even at the low dose of 1 μg/mL. Both AE subfractions decrease Aβ-enhanced expression of dipeptidyl peptidase-4 (DPP-4), but increase Aβreduced expression of phosphorylation of AMPK (p-AMPK) and p-phosphatidylinositol 3-kinase (PI3K). Both F1 and F2 inhibit the expressions of p-insulin receptor substrates (IRS)-1-Ser307, F2 takes advantage to reduce p-Tau, and F1 is superior to enhance p-glycogen synthase kinase (GSK)-3β
Summary
The worldwide increasing prevalence of diabetes (DM), characterized by insulin secretion defect, insulin resistance or both, burdens the public health. Our previous study have shown that DPP-4 mediate the insulin resistance signals and the downstream cascades [11]. Aβ induced insulin resistance through the downregulation of IRS [13]. In the present study, we aim to investigate if Aβ-induced neuron death by regulating GLP-1/DPP-4 and the insulin resistance-signals, and the putative action of F1 and F2. Membranes were blocked with 5% nonfat milk powder with 0.1% Tween-20 in TBS, and incubated with the primary antibody at 4 ̊C overnight against the following targets: AE attenuate Aβ-induced neuron apoptosis cleaved caspase 3 (1:500), procaspase 3 (1:200), GLP-1R (1:1000), DPP4 (1:5000), pPI3K (1:200), PI3K (1:200), pAMPK (1:1000), AMPK (1:200), p-IRS-1-Ser307 (1:1000), p-Tau (1:1000) and p-GSK3 (1:1000). One-way ANOVA was performed (p < 0.05), while Bonferroni’s multiple comparison was used for post-test
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