title: Tribbles Pseudokinase 3 Induces Both Apoptosis and Autophagy in Amyloid-β-induced Neuronal Death.
abstract: Amyloid-β (Aβ)-induced neuron death is considered central to the pathogenesis of Alzheimer's disease (AD). Among several death modalities, autophagy and apoptosis play important roles in Aβ-induced neuron death suggesting that there may be regulatory mechanisms that initiate both cell death pathways. However, molecules that govern both pathways have not been identified. Here, we report that, upon Aβ treatment, tribbles pseudokinase 3 (Trib3, an ortholog ofDrosophila Tribbles) is up-regulated in neurons bothin vivoandin vitroIncreased Trib3 levels inhibited the activity of the kinase Akt by interacting with it. As a result, forkhead box O1 (FoxO1), a transcription factor that is negatively regulated by Akt, was activated, translocated to the nucleus, and induced the pro-apoptotic geneBCL2-like 11(Bim). Conversely, FoxO1 responded to Aβ insult by binding to theTrib3gene promoter, enhancing its expression. Our investigations further revealed that Trib3 also induces autophagy. We found that Trib3 indirectly activates unc-51-like autophagy-activating kinase1 (Ulk1) by impeding phosphorylation of, and thus inactivating, a negative regulator of Ulk1, mechanistic target of rapamycin. Ulk1 activation augmented autophagosome formation and reduced autophagy flux. Thus, Trib3 was required for formation of autophagosomes, which accumulated in neurons as autophagic flux was thwarted. Most importantly, silencing endogenous Trib3 strongly protected neurons from Aβ insult. Our results suggest that a self-amplifying feed-forward loop among Trib3, Akt, and FoxO1 in Aβ-treated neurons induces both apoptosis and autophagy, culminating in neuron death. Thus, Trib3 may serve as a potential therapeutic target for AD.
authors.affiliation: From the Cell Biology and Physiology Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, India.
authors.forename: Suraiya
authors.initials: S
authors.lastname: Saleem
authors.affiliation: From the Cell Biology and Physiology Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, India biswassc@gmail.com subhasbiswas@iicb.res.in.
authors.forename: Subhas Chandra
authors.initials: SC
authors.lastname: Biswas
mesh_terms: D016229:Amyloid beta-Peptides / Q000008:administration & dosage*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001343:Autophagy / Q000502:physiology*; D016923:Cell Death / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology*; D016716:PC12 Cells; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D000071161:Forkhead Box Protein O1
chemical_list: D016229:Amyloid beta-Peptides; D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; C502443:Trib3 protein, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1
keywords: Alzheimer disease; Bim; FOXO; TRB3; amyloid-β (Aβ); apoptosis; autophagy; cell culture; cell death; neurodegenerative disease