Journal Article

Glycation exacerbates the neuronal toxicity of β-amyloid

Li, X-H, Wang, J-Z, Jiang, X, Lv, B-L, Zhou, X-W, Cheng, X-S, Liu, R, Du, L-L, Zhang, Y

2013

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 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