Pathological autophagic vacuoles (AVs) accumulate in the brains of Alzheimer's disease (AD) patients, but the mechanisms by which they are induced are unknown. In this study, we found that the formation of AVs was mediated by activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) in the brains of APP/PS1 double transgenic mice, amyloid-beta peptide (Aβ) pathology-bearing model mouse. Injection of sunitinib malate, AMPK inhibitor, to the mice lowered AV formation in their brains. Consistent with our in vivo observations, treatment of SH-SY5Y cells with Aβ enhanced the induction of autophagosomes, which was mediated by Ca(2+)/calmodulin-dependent protein kinase kinase-beta (CaMKKβ)-AMPK signaling, as shown using various inhibitors and small interfering RNA (siRNA). CaMKKβ is a calcium-activated kinase, and the depletion of intracellular calcium by BAPTA-AM, a Ca(2+) chelator, also curtailed Aβ-induced autophagy. Finally, the inhibition of receptor for advanced glycation end products (RAGE) attenuated autophagsome formation and AMPK signaling. Conversely, RAGE overexpression amplified the induction of autophagy. These results implicate the regulation of the Aβ-induced formation of AVs by the RAGE-calcium-CaMKKβ-AMPK pathway and suggest that modulation of autophagosome formation and the interaction between Aβ and RAGE are beneficial in the treatment and prevention of Alzheimer's disease.
Copyright © 2012 Elsevier Inc. All rights reserved.