title: Aβ-AGE aggravates cognitive deficit in rats via RAGE pathway.
abstract: β-Amyloid (Aβ) accumulation has been proved to be responsible for the pathogenesis of Alzheimer's disease (AD). However, it is not yet clear what makes Aβ accumulate and become toxic in the AD brains. Our previous studies demonstrated that glycated Aβ (Aβ-AGE) could be formed, and it exacerbated the authentic Aβ-mediated neurotoxicity in vitro, but we did not show the role of Aβ-AGE in vivo and the underlying mechanism. In the current study, we synthesized Aβ-AGE by incubating Aβ with methylglyoxal in vitro, and then stereotactically injected Aβ-AGE into lateral ventricle of Sprague-Dawley (SD) rats. We found that Aβ-AGE aggravated Aβ-induced cognitive impairment, which was characterized by higher speed of deterioration of long-term potentiation (LTP), more decrease of dendritic spines density and more down-regulation of synaptic proteins. We also observed the overexpression of receptor for advanced glycation endproducts receptor for AGEs (RAGE) and the activation of downstream molecular (GSK3, NF-κB, p38) in RAGE-mediated pathways. On the other hand, simultaneous application of RAGE antibody or GSK3 inhibitor LiCl reversed the cognitive decline amplified by Aβ-AGE. Our data revealed that in vivo the Aβ-AGE is more toxic than Aβ, and Aβ-AGE could lead to the aggravation of AD-like pathology though the RAGE pathway, suggesting that Aβ-AGE and RAGE may be new therapeutic targets for AD.
authors.affiliation: Institute of Traumatic Brain Injury and Neurology, Pingjin Hospital, Logistics University of Chinese People's Armed Police Forces, Tianjin 300162, China.
authors.forename: C
authors.initials: C
authors.lastname: Chen
authors.affiliation: Institute of Traumatic Brain Injury and Neurology, Pingjin Hospital, Logistics University of Chinese People's Armed Police Forces, Tianjin 300162, China.
authors.forename: X-H
authors.initials: XH
authors.lastname: Li
authors.affiliation: Institute of Traumatic Brain Injury and Neurology, Pingjin Hospital, Logistics University of Chinese People's Armed Police Forces, Tianjin 300162, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Tu
authors.affiliation: Institute of Traumatic Brain Injury and Neurology, Pingjin Hospital, Logistics University of Chinese People's Armed Police Forces, Tianjin 300162, China.
authors.forename: H-T
authors.initials: HT
authors.lastname: Sun
authors.affiliation: Institute of Traumatic Brain Injury and Neurology, Pingjin Hospital, Logistics University of Chinese People's Armed Police Forces, Tianjin 300162, China.
authors.forename: H-Q
authors.initials: HQ
authors.lastname: Liang
authors.affiliation: Institute of Traumatic Brain Injury and Neurology, Pingjin Hospital, Logistics University of Chinese People's Armed Police Forces, Tianjin 300162, China.
authors.forename: S-X
authors.initials: SX
authors.lastname: Cheng
authors.affiliation: Institute of Traumatic Brain Injury and Neurology, Pingjin Hospital, Logistics University of Chinese People's Armed Police Forces, Tianjin 300162, China. Electronic address: Zhangsai718@yahoo.com.
authors.forename: S
authors.initials: S
authors.lastname: Zhang
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D003072:Cognition Disorders / Q000139:chemically induced*; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006031:Glycosylation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000473:pathology / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D016328:NF-kappa B; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D016194:Receptors, N-Methyl-D-Aspartate; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3
keywords: AD; AGEs; AP; APP; Alzheimer’s disease; Aβ; Aβ-AGE; DV; EDTA; EPSP; GSK3; HFS; LTP; MAPK; ML; NF-κB; PB; PCR; PS; PSD; RAGE; advanced glycation end-products; amyloid precursor protein; anterior to posterior; dorsal to ventral; ethylenediaminetetraacetic acid; excitatory postsynaptic potential; glycated Aβ; glycation; glycogen synthase kinase 3; high-frequency stimulation; long-term potentiation; mid to lateral; mitogen-activated protein kinases; nuclear factor κB; pAb; phosphate buffer; polyclonal antibody; polymerase chain reaction; population spike; postsynaptic density; receptor for AGEs; receptor of advanced glycation endproducts; synthase kinase-3; β-amyloid