The insulin/Akt signaling pathway is targeted by intracellular beta-amyloid.
Intraneuronal beta-amyloid (Abeta(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 Abeta. 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 Abeta42 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, Abeta(i) expression inhibited both insulin-induced Akt phosphorylation and activity. In vitro experiments identified that beta-amyloid (Abeta), especially oligomer preparations, specifically interrupted the PDK-dependent activation of Akt. Abeta(i) also blocked the association between PDK and Akt in cell-based and in vitro experiments. Importantly, Abeta 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 Abeta-induced energy failure and neuronal death.
Lee
Han-Kyu
HK
Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA.
Kumar
Pravir
P
Fu
Qinghao
Q
Rosen
Kenneth M
KM
Querfurth
Henry W
HW
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D017874:Immediate-Early Proteins / Q000502:physiology; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000502:physiology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction; D000099184:Serum-Glucocorticoid Regulated Kinases
D016229:Amyloid beta-Peptides; D017874:Immediate-Early Proteins; D007328:Insulin; D010446:Peptide Fragments; D018129:Phosphatidylinositol Phosphates; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D000099184:Serum-Glucocorticoid Regulated Kinases; C075222:amyloid beta-protein (1-42); C060974:phosphatidylinositol 3,4,5-triphosphate