Aβ-AGE AGGRAVATES COGNITIVE DEFICIT IN RATS VIA RAGE PATHWAY

beta-Amyloid (A beta) accumulation has been proved to be responsible for the pathogenesis of Alzheimer's disease (AD). However, it is not yet clear what makes A beta accumulate and become toxic in the AD brains. Our previous studies demonstrated that glycated A beta (A beta-AGE) could be formed, and it exacerbated the authentic A beta-mediated neurotoxicity in vitro, but we did not show the role of A beta-AGE in vivo and the underlying mechanism. In the current study, we synthesized A beta-AGE by incubating A beta with methylglyoxal in vitro, and then stereotactically injected A beta-AGE into lateral ventricle of Sprague-Dawley (SD) rats. We found that A beta-AGE aggravated A beta-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-jB, p38) in RAGE-mediated pathways. On the other hand, simultaneous application of RAGE antibody or GSK3 inhibitor LiCl reversed the cognitive decline amplified by A beta-AGE. Our data revealed that in vivo the A beta-AGE is more toxic than A beta, and A beta-AGE could lead to the aggravation of AD-like pathology though the RAGE pathway, suggesting that A beta-AGE and RAGE may be new therapeutic targets for AD. (C) 2013 IBRO. Published by Elsevier Ltd. All rights reserved.