Liraglutide Suppresses Tau Hyperphosphorylation, Amyloid Beta Accumulation through Regulating Neuronal Insulin Signaling and BACE-1 Activity

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.

Insulin Resistance and Diabetes Mellitus in Alzheimer’s Disease

“…Genetic studies have shown that presenilin-1 mutations, due to their role in lysosome acidification and activation of the lysosomal cathepsin protease, trigger defective lysosomal turnover of Aβ [ 400 ]. In summary, all of these results evidence that autophagy is a critical process for maintaining neuronal cytoplasmic homeostasis, supported by many studies using other autophagy enhancers for improving neuronal clearance in AD models [ 401 , 402 ]. Among these compounds, resveratrol has been widely used for AD damage treatment and may be a future therapeutic candidate [ 403 , 404 , 405 ].…”

Repurposing of Anti-Diabetic Agents as a New Opportunity to Alleviate Cognitive Impairment in Neurodegenerative and Neuropsychiatric Disorders

“…In preclinical studies, GLP-1 receptor agonists protected PC12 cells from apoptosis involving EGFR transactivation and subsequent activation of the PI3K/Akt/mTOR signaling pathway( Kimura et al, 2013 ), and glucose metabolic aberration involving Sirt1-dependent deacetylation and Akt-dependent phosphorylation of Forkhead box O (FoxO) 1( Chen et al, 2019a ). Liraglutide could reverse deleterious effects of insulin resistance in neuronal cells by improving the phosphorylation status of insulin receptor, IRS-1 and Akt( Jantrapirom et al, 2020 ). Exendine-4, a long-acting GLP-1 receptor agonist, inhibited glucose-induced apoptosis and oxidative stress in neurons( Chen et al, 2012 ), and ameliorated cognitive impairment( Chen et al, 2012 ) involving its metabolic, anti-inflammatory and anti-oxidant effects( Solmaz et al, 2015 ; Abdelwahed et al, 2018 ).…”

Liraglutide improves cognitive function by reducing amyloid-beta peptide accumulation and inhibiting inflammation in 5×FAD mice

“…In addition, treatment with GLP-1 was shown to improve learning and memory de cits in type 2 diabetic rats and decrease the mRNA expression of APP and BACE1 [23]. Liraglutide was also found to reduce the activity of BACE1, in turn decreasing the formation of Aβ in insulin-resistant cells [24]. Conclusively, these observations have indicated that liraglutide might be an effective pathway for improving the cognitive function of patients with AD by reducing the expression of BACE1 and Aβ.…”