title: Glycation exacerbates the neuronal toxicity of β-amyloid.
abstract: Accumulation evidence shows that β-amyloid (Aβ) is a neurotoxic and accumulation of Aβ is responsible for the pathology of Alzheimer's disease (AD). However, it is currently not fully understood what makes Aβ toxic and accumulated. Previous studies demonstrate that Aβ is a suitable substrate for glycation, producing one form of the advanced glycation endproducts (AGEs). We speculated that Aβ-AGE formation may exacerbate the neurotoxicity. To explore whether the Aβ-AGE is more toxic than the authentic Aβ and to understand the molecular mechanisms, we synthesized glycated Aβ by incubating Aβ with methylglyoxal (MG) in vitro and identified the formation of glycated Aβ by fluorescence spectrophotometer. Then, we treated the primary hippocampal neurons cultured 8 days in vitro with Aβ-AGE or Aβ for 24 h. We observed that glycation exacerbated neurotoxicity of Aβ 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 Aβ. Thereafter, we found that Aβ is also glycated with an age-dependent elevation of AGEs in Tg2576 mice, whereas inhibition of Aβ-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 Aβ is more toxic. We propose that the glycated Aβ with the altered secondary structure may be a more suitable ligand than Aβ for RAGE and subsequent activation of GSK-3 that can lead to cascade pathologies of AD, therefore glycated Aβ may be a new therapeutic target for AD.
authors.affiliation: Department of Pathophysiology, Key Laboratory of Neurological Diseases of Ministry of Education, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: X-H
authors.initials: XH
authors.lastname: Li
authors.forename: L-L
authors.initials: LL
authors.lastname: Du
authors.forename: X-S
authors.initials: XS
authors.lastname: Cheng
authors.forename: X
authors.initials: X
authors.lastname: Jiang
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: B-L
authors.initials: BL
authors.lastname: Lv
authors.forename: R
authors.initials: R
authors.lastname: Liu
authors.forename: J-Z
authors.initials: JZ
authors.lastname: Wang
authors.forename: X-W
authors.initials: XW
authors.lastname: Zhou
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D017127:Glycation End Products, Advanced / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006031:Glycosylation; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018782:Maze Learning; D008568:Memory; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D016229:Amyloid beta-Peptides; D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3