Abstract
Neuronal insulin resistance is a significant feature of Alzheimer’s disease (AD). Accumulated evidence has revealed the possible neuroprotective mechanisms of antidiabetic drugs in AD. Liraglutide, a glucagon-like peptide-1 (GLP-1) analog and an antidiabetic agent, has a benefit in improving a peripheral insulin resistance. However, the neuronal effect of liraglutide on the model of neuronal insulin resistance with Alzheimer’s formation has not been thoroughly investigated. The present study discovered that liraglutide alleviated neuronal insulin resistance and reduced beta-amyloid formation and tau hyperphosphorylation in a human neuroblostoma cell line, SH-SY5Y. Liraglutide could effectively reverse deleterious effects of insulin overstimulation. In particular, the drug reversed the phosphorylation status of insulin receptors and its major downstream signaling molecules including insulin receptor substrate 1 (IRS-1), protein kinase B (AKT), and glycogen synthase kinase 3 beta (GSK-3β). Moreover, liraglutide reduced the activity of beta secretase 1 (BACE-1) enzyme, which then decreased the formation of beta-amyloid in insulin-resistant cells. This indicated that liraglutide can reverse the defect of phosphorylation status of insulin signal transduction but also inhibit the formation of pathogenic Alzheimer’s proteins like Aβ in neuronal cells. We herein provided the possibility that the liraglutide-based therapy may be able to reduce such deleterious effects caused by insulin resistance. In view of the beneficial effects of liraglutide administration, these findings suggest that the use of liraglutide may be a promising therapy for AD with insulin-resistant condition.
Highlights
Insulin resistance is defined as an inefficient response of tissue to normal plasma insulin levels [1]
The control cells showed a normal response to insulin stimulation observed by the phosphorylations of insulin receptors (IRs) (Tyr1162/1163), pIRS-1(Tyr)/insulin receptor substrate 1 (IRS-1), and AKT/PKB (Ser473), while the insulin resistant-cells significantly decreased those of phosphorylations (Figure 2A–C compared C+/C to I+/I)
These findings indicated that 48 h treatment of 100 nM insulin administration was enough to induce neuronal insulin resistance
Summary
Insulin resistance is defined as an inefficient response of tissue to normal plasma insulin levels [1]. It is well known that insulin signaling is associated with the regulation of tau protein, and deregulation of brain insulin signaling is linked to AD [12]. Systemic insulin resistance results in tau hyperphosphorylation detected in cerebrospinal fluid [13]. A defect in insulin pathway results in Aβ accumulation. This statement is supported by a study reporting that induction of insulin resistance in Tg2576 mice reduced the amount and activity of insulin-degrading enzyme (IDE), contributing to an increase in Aβ levels in the hippocampus and cerebral cortex [17]. The defined mechanism of tau phosphorylation has been reported to be due to the glycogen synthase kinase 3 beta (GSK-3β), a Tau kinase regulated by insulin via the protein kinase B (AKT) pathway [18]. The newly identified category of AD as type 3 diabetes [11] has encouraged researchers to focus on antidiabetic drugs as a new strategy for treating AD associated with insulin resistance
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