Amyloid‐β interrupts the PI3K‐Akt‐mTOR signaling pathway that could be involved in brain‐derived neurotrophic factor‐induced Arc expression in rat cortical neurons

Abstract

The deposition of amyloid-beta (Abeta) contributes to the pathogenesis of Alzheimer's disease. Even at low levels, Abeta may interfere with various signaling cascades critical for the synaptic plasticity that underlies learning and memory. Brain-derived neurotrophic factor (BDNF) is well known to be capable of inducing the synthesis of activity-regulated cytoskeleton-associated protein (Arc), which plays a fundamental role in modulating synaptic plasticity. Our recent study has demonstrated that treatment of fibrillar Abeta at a nonlethal level was sufficient to impair BDNF-induced Arc expression in cultured rat cortical neurons. In this study, BDNF treatment alone induced the activation of the phosphatidylinositol 3-kinase-Akt-mammlian target of rapamycin (PI3K-Akt-mTOR) signaling pathway, the phosphorylation of eukaryotic initiation factor 4E binding protein (4EBP1) and p70 ribosomal S6 kinase (p70S6K), the dephosphorylation of eukaryotic elongation factor 2 (eEF2), and the expression of Arc. Interrupting the PI3K-Akt-mTOR signaling pathway by inhibitors prevented the effects of BDNF, indicating the involvement of this pathway in BDNF-induced 4EBP1 phosphorylation, p70S6K phosphorylation, eEF2 dephosphorylation, and Arc expression. Nonlethal Abeta pretreatment partially blocked these effects of BDNF. Double- immunofluorescent staining in rat cortical neurons further confirmed the coexistence of eEF2 dephosphorylation and Arc expression following BDNF treatment regardless of the presence of Abeta. These results reveal that, in cultured rat cortical neurons, Abeta interrupts the PI3K-Akt-mTOR signaling pathway that could be involved in BDNF-induced Arc expression. Moreover, this study also provides the first evidence that there is a close correlation between BDNF-induced eEF2 dephosphorylation and BDNF-induced Arc expression. (c) 2009 Wiley-Liss, Inc.

Chronic Psychosocial Stress Exacerbates Impairment of Synaptic Plasticity in β-Amyloid Rat Model of Alzheimers Disease: Prevention by Nicotine

“…Signaling pathways other than the CaMKIV-CREB pathway could be involved in the interactive effects of stress, A and nicotine. For example, multiple studies have demonstrated the involvement of the phosphatidylinositol 3-kinaseAkt (PI3K/AKT) [102,103] and Janus kinase 2 (JAK2)/ signal transducer and activator of transcription 3 (STAT3) [104] signal transduction pathways in A -induced cell death and memory loss. These pathways are also involved in cell response to oxidative stress [e.g.…”

Tribbles Pseudokinase 3 Induces Both Apoptosis and Autophagy in Amyloid-β-induced Neuronal Death

“…mTOR is the master regulator of autophagy (52,70). The signaling cascade PI3K/Akt/mTOR is inhibited by A␤ (71). Trib3 inhibits the Akt/mTOR axis and leads to autophagy in human glioma cells (7).…”

Brain-Derived Neurotrophic Factor and Alzheimer’s Disease: Physiopathology and Beyond

“…Sublethal doses of b-amyloid 42 down-regulate BDNF expression in cultured cortical neurons and impair BDNF intra-cellular trafficking (Poon et al 2011). Another important effect of b-amyloid 42 in cultured neurons is the impairment of BDNF-induced Arc expression (Chen et al 2009;Echeverria et al 2007;Wang et al 2006). This is an immediate early response gene that is rapidly activated by BDNF and whose product, Arc protein, is thought to be an important mediator of BDNF effects in synaptic plasticity and long-term potentiation formation (Bramham et al 2008).…”