The Insulin/Akt Signaling Pathway Is Targeted by Intracellular β-Amyloid

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. Although 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 beta-amyloid (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 A beta-induced energy failure and neuronal death.