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