Glycation exacerbates the neuronal toxicity of β-amyloid

• Published in: Cell death & disease 2013-06, Vol.4 (6), p.e673-e673
• Main Authors: Li, X-H, Du, L-L, Cheng, X-S, Jiang, X, Zhang, Y, Lv, B-L, Liu, R, Wang, J-Z, Zhou, X-W
• Format: Article
• Language: English
• Subjects: 631/378/1689/1283; 631/80/221; 631/80/86; Alzheimer Disease - metabolism; Alzheimer Disease - psychology; Amyloid beta-Peptides - metabolism; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cells, Cultured; Glycation End Products, Advanced - metabolism; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Glycosylation; Hippocampus - metabolism; Hippocampus - pathology; Humans; Immunology; Life Sciences; Maze Learning; Memory; Mice; Mice, Transgenic; Neurons - metabolism; Original; original-article; Phosphorylation; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt - metabolism; Receptor for Advanced Glycation End Products; Receptors, Immunologic - metabolism; Up-Regulation
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2013.180

Accumulation evidence shows that β -amyloid (A β ) is a neurotoxic and accumulation of A β is responsible for the pathology of Alzheimer’s disease (AD). However, it is currently not fully understood what makes A β toxic and accumulated. Previous studies demonstrate that A β is a suitable substrate for glycation, producing one form of the advanced glycation endproducts (AGEs). We speculated that A β -AGE formation may exacerbate the neurotoxicity. To explore whether the A β -AGE is more toxic than the authentic A β and to understand the molecular mechanisms, we synthesized glycated A β by incubating A β with methylglyoxal (MG) in vitro and identified the formation of glycated A β by fluorescence spectrophotometer. Then, we treated the primary hippocampal neurons cultured 8 days in vitro with A β -AGE or A β for 24 h. We observed that glycation exacerbated neurotoxicity of A β with upregulation of receptor for AGE (RAGE) and activation of glycogen synthase kinase-3 (GSK-3), whereas simultaneous application of RAGE antibody or GSK-3 inhibitor reversed the neuronal damages aggravated by glycated A β . Thereafter, we found that A β is also glycated with an age-dependent elevation of AGEs in Tg2576 mice, whereas inhibition of A β -AGE formation by subcutaneously infusion of aminoguanidine for 3 months significantly rescued the early cognitive deficit in mice. Our data reveal for the first time that the glycated A β is more toxic. We propose that the glycated A β with the altered secondary structure may be a more suitable ligand than A β for RAGE and subsequent activation of GSK-3 that can lead to cascade pathologies of AD, therefore glycated A β may be a new therapeutic target for AD.