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MBC in Press, published online ahead of print January 14, 2009
Mol. Biol. Cell 10.1091/mbc.E08-07-0777

A more recent version of this article appeared on March 1, 2009
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Submitted on July 29, 2008
Revised on November 20, 2008
Accepted on January 5, 2009

The Insulin/Akt Signaling Pathway Is Targeted by Intracellular {beta}-Amyloid

Han-Kyu Lee, Pravir Kumar, Qinghao Fu, Kenneth M. Rosen, and Henry W. Querfurth

Department of Neurology, Caritas St. Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, MA 02135

Monitoring Editor: M. Bishr Omary

Intraneuronal {beta}-amyloid (A{beta}i) accumulates early in Alzheimer’s disease (AD) and Inclusion Body Myositis. Several organelles, receptor molecules, homeostatic processes and signal transduction components have been identified as sensitive to A{beta}. While prior studies implicate the insulin-PI3K-Akt signaling cascade, a specific step within this or any essential metabolic or survival pathway has not emerged as a molecular target. We tested the effect of A{beta}42 on each component of this cascade. In AD brain, the association between PDK and Akt, phospho-Akt levels and its activity were all decreased relative to control. In cell culture, A{beta}i expression inhibited both insulin-induced Akt phosphorylation and activity. In vitro experiments identified that A{beta}, especially oligomer preparations, specifically interrupted the PDK-dependent activation of Akt. A{beta}i also blocked the association between PDK and Akt in cell-based and in vitro experiments. Importantly, A{beta} did not interrupt Akt or PI3K activities (once stimulated) nor did it affect more proximal signal events. These results offer a novel therapeutic strategy to neutralize {beta}-amyloid-induced energy failure and neuronal death.

Address correspondence to: Henry W. Querfurth (henry.querfurth{at}tufts.edu)




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F.-F. Liao and H. Xu
Insulin Signaling in Sporadic Alzheimer's Disease
Sci. Signal., June 9, 2009; 2(74): pe36 - pe36.
[Abstract] [Full Text] [PDF]


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