Glucagon-like peptide-1 protects hippocampal neurons against advanced glycation end product-induced tau hyperphosphorylation

Abstract

We have previously demonstrated that glucagon-like peptide-1 (GLP-1) receptor agonist ameliorated neurodegenerative changes in rat models of diabetes-related Alzheimer's disease (AD), and protected neurons from glucose toxicity in vitro. Herein, we investigated the effects of GLP-1 receptor mediates on cell toxicity and tau hyperphosphorylation induced by advanced glycation end products (AGEs), which are associated with glucose toxicity, and the molecular mechanism in PC12 cells and the primary hippocampal neurons. Our study demonstrated that the similar protection effects of GLP-1 existed in PC12 cells treated with glucose-bovine serum albumin (BSA) in hyperglycemic conditions or with glycoaldehyde-BSA alone. Additionally, glucose-BSA alone did not induce significant cytotoxicity in PC12 cells, but resulted in tau hyperphosphorylation in primary hippocampal neurons in 24h. And we found that GLP-1 could reduce cell tau phosphorylation induced by high glucose or glucose-BSA. Furthermore, our data in the present study suggested that GLP-1 regulated tau phosphorylation induced by AGEs through a signaling pathway involving glycogen synthase kinase 3β (GSK-3β), similarly to the GSK-3β inhibitor, lithium chloride. Our findings suggest that GLP-1 can protect neurons from diabetes-associated AGE insults in vitro, and provide new evidence for a potential therapeutic value of GLP-1 receptor agonist in the treatment of AD especially diabetes-related AD.

Keywords: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide; AD; AGEs; APP; Alzheimer’s disease; Aβ; BSA; DM; DMSO; DPP-IV; Ex-4; FBS; GLP-1; GLP-1R; GLP-1RA; GSK-3β; HG; ICV-STZ; MTT; NFTs; PBS; PHF; PI3-K; RAGE; advanced glycation end products; amyloid precursor protein; amyloid β-peptide; bovine serum albumin; diabetes mellitus; diabetes-related Alzheimer’s disease; dimethyl sulfoxide; dipeptidyl peptidase IV; exendin-4; fetal bovine serum; glucagon-like peptide-1; glucagon-like peptide-1 receptor; glucagon-like peptide-1 receptor agonist; glycogen synthase kinase 3β; glycogen synthase kinase-3β; high glucose; intracerebroventricular-streptozotocin; neurofibrillary tangles; paired helical filament; phosphate buffer saline; phosphatidyl inositol 3 kinase; receptor for advanced glycation end products; tau.