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The Triangle of Death in Alzheimer's Disease Brain: The Aberrant Cross-Talk among Energy Metabolism, Mammalian Target of Rapamycin Signaling, and Protein Homeostasis Revealed by Redox Proteomics

dc.contributor.authorDi Domenico F.
dc.contributor.authorBarone E.
dc.contributor.authorPerluigi M.
dc.contributor.authorButterfield D.A.
dc.date.accessioned2020-09-02T22:16:17Z
dc.date.available2020-09-02T22:16:17Z
dc.date.issued2017
dc.identifier10.1089/ars.2016.6759
dc.identifier.citation26, 8, 364-387
dc.identifier.issn15230864
dc.identifier.urihttps://hdl.handle.net/20.500.12728/4266
dc.descriptionSignificance: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder and represents one of the most disabling conditions. AD shares many features in common with systemic insulin resistance diseases, suggesting that it can be considered as a metabolic disease, characterized by reduced insulin-stimulated growth and survival signaling, increased oxidative stress (OS), proinflammatory cytokine activation, mitochondrial dysfunction, impaired energy metabolism, and altered protein homeostasis. Recent Advances: Reduced glucose utilization and energy metabolism in AD have been associated with the buildup of amyloid-β peptide and hyperphosphorylated tau, increased OS, and the accumulation of unfolded/misfolded proteins. Mammalian target of rapamycin (mTOR), which is aberrantly activated in AD since early stages, plays a key role during AD neurodegeneration by, on one side, inhibiting insulin signaling as a negative feedback mechanism and, on the other side, regulating protein homeostasis (synthesis/clearance). Critical Issues: It is likely that the concomitant and mutual alterations of energy metabolism-mTOR signaling-protein homeostasis might represent a self-sustaining triangle of harmful events that trigger the degeneration and death of neurons and the development and progression of AD. Intriguingly, the altered cross-talk between the components of such a triangle of death, beyond altering the redox homeostasis of the neuron, is further exacerbated by increased levels of OS that target and impair key components of the pathways involved. Redox proteomic studies in human samples and animal models of AD-like dementia led to identification of oxidatively modified components of the pathways composing the triangle of death, therefore revealing the crucial role of OS in fueling this aberrant vicious cycle. Future Directions: The identification of compounds able to restore the function of the pathways targeted by oxidative damage might represent a valuable therapeutic approach to slow or delay AD. © Copyright 2017, Mary Ann Liebert, Inc.
dc.language.isoen
dc.publisherMary Ann Liebert Inc.
dc.subjectAlzheimer disease
dc.subjectenergy metabolism
dc.subjectmTOR
dc.subjectprotein degradation
dc.subjectamyloid beta protein
dc.subjectinsulin
dc.subjectmammalian target of rapamycin
dc.subjectproteasome
dc.subjectubiquitin
dc.subjectinsulin
dc.subjectproteasome
dc.subjecttarget of rapamycin kinase
dc.subjectubiquitin
dc.subjectAlzheimer disease
dc.subjectautophagy
dc.subjectdegenerative disease
dc.subjectenergy metabolism
dc.subjectglucose utilization
dc.subjecthuman
dc.subjectnegative feedback
dc.subjectnonhuman
dc.subjectpriority journal
dc.subjectprotein homeostasis
dc.subjectprotein phosphorylation
dc.subjectprotein synthesis
dc.subjectproteomics
dc.subjectReview
dc.subjectsignal transduction
dc.subjectunfolded protein response
dc.subjectAlzheimer disease
dc.subjectanimal
dc.subjectbrain
dc.subjectcase control study
dc.subjecthomeostasis
dc.subjectmetabolism
dc.subjectnerve cell
dc.subjectoxidation reduction reaction
dc.subjectoxidative stress
dc.subjectpathology
dc.subjectprocedures
dc.subjectproteomics
dc.subjectAlzheimer Disease
dc.subjectAnimals
dc.subjectAutophagy
dc.subjectBrain
dc.subjectCase-Control Studies
dc.subjectEnergy Metabolism
dc.subjectHomeostasis
dc.subjectHumans
dc.subjectInsulin
dc.subjectNeurons
dc.subjectOxidation-Reduction
dc.subjectOxidative Stress
dc.subjectProteasome Endopeptidase Complex
dc.subjectProteomics
dc.subjectSignal Transduction
dc.subjectTOR Serine-Threonine Kinases
dc.subjectUbiquitin
dc.subjectUnfolded Protein Response
dc.titleThe Triangle of Death in Alzheimer's Disease Brain: The Aberrant Cross-Talk among Energy Metabolism, Mammalian Target of Rapamycin Signaling, and Protein Homeostasis Revealed by Redox Proteomics
dc.typeReview


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