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

Abstract

Intraneuronal ␤-amyloid (A␤ 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␤. 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␤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␤ i expression inhibited both insulin-induced Akt phosphorylation and activity. In vitro experiments identified that ␤-amyloid (A␤), especially oligomer preparations, specifically interrupted the PDK-dependent activation of Akt. A␤ i also blocked the association between PDK and Akt in cell-based and in vitro experiments. Importantly, A␤ 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␤-induced energy failure and neuronal death. INTRODUCTIONThere is widening recognition that Alzheimer's disease (AD) is closely linked to a state of relative insulin resistance in the brain, so-called "type III diabetes" (de la Monte et al., 2006). Levels of insulin-like growth factor I (IGF-I), insulin, and/or cognate receptors are dysregulated in AD brain (Messier and Teutenberg, 2005;Moloney et al., 2008). In normal brain, IGF-I and insulin promote glucose utilization, energy metabolism, and neuronal survival (Hoyer, 2004), largely through PI3K/Akt/GSK-3␤ signaling (Bondy and Cheng, 2004). Insulin receptors (IRs) populate neuronal synapses and astrocytes in memory-processing brain regions (Lee et al., 2005). Acute insulin treatment increased memory function in rats on a passive-avoidance task (Park et al., 2000) and in small studies involving normal adults and AD patients (Craft and Watson, 2004), consistent with positive effects on synaptic plasticity (Horwood et al., 2006). How ␤-amyloid, a major culprit neurotoxin in AD, could cause central insulin resistance is unknown.Intraneuronal ␤-amyloid (A␤i) in particular, is a significant factor in the early pathogenesis of AD LaFerla et al., 2007). Inclusion body myositis (IBM), another disorder associated with intracellular ␤-amyloid (A␤) deposits, is a major cause of skeletal muscle inflammation and degeneration in the elderly. Cytoplasmic A␤ induces programmed cell death (apoptosis) in a number of experimental and transgenic models (Magrane et al., 2005;Oakley et al., 2006).Interference with or alteration of the Akt signaling pathway has emerged as an important feature in several neurodegenerative diseases characterized by neuronal attrition including AD and schizophrenia (Emamian et al., 2004;Griffin et al., 2005). In previous studies of the effects of intracellular A␤ on this pathway using primary cortical neurons as well as Tg257...

Aβ-Induced Insulin Resistance and the Effects of Insulin on the Cholesterol Synthesis Pathway and Aβ Secretion in Neural Cells

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A novel defense mechanism that is activated on amyloid-β insult to mediate cell survival: role of SGK1-STAT1/STAT2 signaling

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Amyloid Precursor Protein (APP) Affects Global Protein Synthesis in Dividing Human Cells

“…2E). Previous studies have suggested that APP can influence ERK and/or Akt activation (Nizzari et al, 2007; Lee et al, 2009). We observed decreased ERK‐1 and ‐2 phosphorylation at 24, 48, and 72 h after siRNA‐mediated knockdown of APP in NSCLC cell lines A549 and H1299 (Fig.…”

“…More specifically, APP seems to promote cell growth through activation of extracellular signal‐regulated protein kinase (ERK), an event also observed in neuronal cells (Nizzari et al, 2007). Additionally, APP, or its fragments, appears to interact with Akt signaling (Lee et al, 2009). …”