• C Chen, X-H Li, Y Tu, H-T Sun, H-Q Liang, S-X Cheng, and S Zhang.
• Institute of Traumatic Brain Injury and Neurology, Pingjin Hospital, Logistics University of Chinese People's Armed Police Forces, Tianjin 300162, China.
• Neuroscience. 2014 Jan 17;257:1-10.

Abstractβ-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.Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

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