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Impairment of biliverdin reductase-A promotes brain insulin resistance in Alzheimer disease: A new paradigm

dc.contributor.authorBarone E.
dc.contributor.authorDi Domenico F.
dc.contributor.authorCassano T.
dc.contributor.authorArena A.
dc.contributor.authorTramutola A.
dc.contributor.authorLavecchia M.A.
dc.contributor.authorCoccia R.
dc.contributor.authorButterfield D.A.
dc.contributor.authorPerluigi M.
dc.date.accessioned2020-09-02T22:12:58Z
dc.date.available2020-09-02T22:12:58Z
dc.date.issued2016
dc.identifier10.1016/j.freeradbiomed.2015.12.012
dc.identifier.citation91, , 127-142
dc.identifier.issn08915849
dc.identifier.urihttps://hdl.handle.net/20.500.12728/3681
dc.descriptionClinical studies suggest a link between peripheral insulin resistance and cognitive dysfunction. Interestingly, post-mortem analyses of Alzheimer disease (AD) subjects demonstrated insulin resistance in the brain proposing a role for cognitive deficits observed in AD. However, the mechanisms responsible for the onset of brain insulin resistance (BIR) need further elucidations. Biliverdin reductase-A (BVR-A) emerged as a unique Ser/Thr/Tyr kinase directly involved in the insulin signaling and represents an up-stream regulator of the insulin signaling cascade. Because we previously demonstrated the oxidative stress (OS)-induced impairment of BVR-A in human AD brain, we hypothesize that BVR-A dysregulation could be associated with the onset of BIR in AD. In the present work, we longitudinally analyze the age-dependent changes of (i) BVR-A protein levels and activation, (ii) total oxidative stress markers levels (PC, HNE, 3-NT) as well as (iii) IR/IRS1 levels and activation in the hippocampus of the triple transgenic model of AD (3xTg-AD) mice. Furthermore, ad hoc experiments have been performed in SH-SY5Y neuroblastoma cells to clarify the molecular mechanism(s) underlying changes observed in mice. Our results show that OS-induced impairment of BVR-A kinase activity is an early event, which starts prior the accumulation of Aβ and tau pathology or the elevation of TNF-α, and that greatly contribute to the onset of BIR along the progression of AD pathology in 3xTg-Ad mice. Based on these evidence we, therefore, propose a new paradigm for which: OS-induced impairment of BVR-A is firstly responsible for a sustained activation of IRS1, which then causes the stimulation of negative feedback mechanisms (i.e. mTOR) aimed to turn-off IRS1 hyper-activity and thus BIR. Similar alterations characterize also the normal aging process in mice, positing BVR-A impairment as a possible bridge in the transition from normal aging to AD. © 2015 Elsevier Inc. All rights reserved.
dc.language.isoen
dc.publisherElsevier Inc.
dc.subject3xTg-AD mice
dc.subjectAlzheimer disease
dc.subjectBiliverdin reductase-A
dc.subjectInsulin resistance
dc.subjectOxidative stress
dc.subject3 nitrotyrosine
dc.subject4 hydroxynonenal
dc.subjectamyloid beta protein
dc.subjectbiliverdin reductase a
dc.subjectcarbonyl derivative
dc.subjectinsulin
dc.subjectinsulin receptor
dc.subjectinsulin receptor substrate 1
dc.subjectmammalian target of rapamycin
dc.subjectmessenger RNA
dc.subjectoxidoreductase
dc.subjectprotein carbonyl
dc.subjecttau protein
dc.subjecttumor necrosis factor alpha
dc.subjectunclassified drug
dc.subjectbiliverdin reductase
dc.subjectoxidoreductase
dc.subjecttarget of rapamycin kinase
dc.subjecttumor necrosis factor
dc.subjectaging
dc.subjectAlzheimer disease
dc.subjectanimal experiment
dc.subjectanimal model
dc.subjectanimal tissue
dc.subjectArticle
dc.subjectcomparative study
dc.subjectcontrolled study
dc.subjectenzyme activity
dc.subjecthippocampus
dc.subjectimmunohistochemistry
dc.subjectimmunoreactivity
dc.subjectin vitro study
dc.subjectinsulin resistance
dc.subjectinsulin treatment
dc.subjectlongitudinal study
dc.subjectmale
dc.subjectmouse
dc.subjectneuroblastoma cell
dc.subjectnitration
dc.subjectnitrosative stress
dc.subjectnonhuman
dc.subjectoxidative stress
dc.subjectpriority journal
dc.subjectprotein blood level
dc.subjectprotein phosphorylation
dc.subject129 mouse
dc.subjectAlzheimer disease
dc.subjectanimal
dc.subjectC57BL mouse
dc.subjectenzymology
dc.subjectgenetics
dc.subjecthuman
dc.subjectmetabolism
dc.subjectprotein processing
dc.subjecttransgenic mouse
dc.subjecttumor cell line
dc.subjectAging
dc.subjectAlzheimer Disease
dc.subjectAnimals
dc.subjectCell Line, Tumor
dc.subjectHippocampus
dc.subjectHumans
dc.subjectInsulin Resistance
dc.subjectMale
dc.subjectMice, 129 Strain
dc.subjectMice, Inbred C57BL
dc.subjectMice, Transgenic
dc.subjectOxidative Stress
dc.subjectOxidoreductases Acting on CH-CH Group Donors
dc.subjectProtein Processing, Post-Translational
dc.subjectTOR Serine-Threonine Kinases
dc.subjectTumor Necrosis Factor-alpha
dc.titleImpairment of biliverdin reductase-A promotes brain insulin resistance in Alzheimer disease: A new paradigm
dc.typeArticle


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