Glycation exacerbates the neuronal toxicity of β-amyloid

Accumulation evidence shows that beta-amyloid (A beta) is a neurotoxic and accumulation of A beta is responsible for the pathology of Alzheimer's disease (AD). However, it is currently not fully understood what makes A beta toxic and accumulated. Previous studies demonstrate that A beta is a suitable substrate for glycation, producing one form of the advanced glycation endproducts (AGEs). We speculated that A beta-AGE formation may exacerbate the neurotoxicity. To explore whether the A beta-AGE is more toxic than the authentic A beta and to understand the molecular mechanisms, we synthesized glycated A beta by incubating A beta with methylglyoxal (MG) in vitro and identified the formation of glycated A beta by fluorescence spectrophotometer. Then, we treated the primary hippocampal neurons cultured 8 days in vitro with A beta-AGE or A beta for 24 h. We observed that glycation exacerbated neurotoxicity of A beta 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 beta. Thereafter, we found that A beta is also glycated with an age-dependent elevation of AGEs in Tg2576 mice, whereas inhibition of A beta-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 beta is more toxic. We propose that the glycated A beta with the altered secondary structure may be a more suitable ligand than A beta for RAGE and subsequent activation of GSK-3 that can lead to cascade pathologies of AD, therefore glycated A beta may be a new therapeutic target for AD.