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Biliverdin reductase-A impairment links brain insulin resistance with increased Aβ production in an animal model of aging: Implications for Alzheimer disease

dc.contributor.authorTriani F.
dc.contributor.authorTramutola A.
dc.contributor.authorDi Domenico F.
dc.contributor.authorSharma N.
dc.contributor.authorButterfield D.A.
dc.contributor.authorHead E.
dc.contributor.authorPerluigi M.
dc.contributor.authorBarone E.
dc.date.accessioned2020-09-02T22:29:25Z
dc.date.available2020-09-02T22:29:25Z
dc.date.issued2018
dc.identifier10.1016/j.bbadis.2018.07.005
dc.identifier.citation1864, 10, 3181-3194
dc.identifier.issn09254439
dc.identifier.urihttps://hdl.handle.net/20.500.12728/6445
dc.descriptionBrain insulin resistance is associated with an increased Aβ production in AD although the molecular mechanisms underlying this link are still largely unknown. Biliverdin reductase-A (BVR-A) is a unique Ser/Thr/Tyr kinase regulating insulin signalling. Studies from our group, demonstrated that BVR-A impairment is among the earliest events favoring brain insulin resistance development. Furthermore, reported a negative association between BVR-A protein levels/activation and BACE1 protein levels in the parietal cortex of aged beagles (an animal model of AD), thus suggesting a possible interaction. Therefore, we aimed to demonstrate that BVR-A impairment is a molecular bridge linking brain insulin resistance with increased Aβ production. Age-associated changes of BVR-A, BACE1, insulin signalling cascade and APP processing were evaluated in the parietal cortex of beagles and experiments to confirm the hypothesized mechanism(s) have been performed in vitro in HEK293APPswe cells. Our results show that BVR-A impairment occurs early with age and is associated with brain insulin resistance. Furthermore, we demonstrate that BVR-A impairment favors CK1-mediated Ser phosphorylation of BACE1 (known to mediate BACE1 recycling to plasma membrane) along with increased Aβ production in the parietal cortex, with age. Overall, our results suggest that the impairment of BVR-A is an early molecular event contributing to both (I) the onset of brain insulin resistance and (II) the increased Aβ production observed in AD. We, therefore, suggest that by targeting BVR-A activity it could be possible to delay the onset of brain insulin resistance along with an improved regulation of the APP processing. © 2018 Elsevier B.V.
dc.language.isoen
dc.publisherElsevier B.V.
dc.subjectAlzheimer disease
dc.subjectBACE1
dc.subjectBilivedin reductase-A
dc.subjectCanine
dc.subjectDog
dc.subjectInsulin resistance
dc.subject3 nitrotyrosine
dc.subjectamyloid beta protein
dc.subjectamyloid precursor protein
dc.subjectbeta secretase 1
dc.subjectbiliverdin
dc.subjectbiliverdin reductase A
dc.subjectinsulin
dc.subjectoxidoreductase
dc.subjectunclassified drug
dc.subjectamyloid precursor protein
dc.subjectAPP protein, human
dc.subjectaspartic proteinase
dc.subjectBACE1 protein, human
dc.subjectbiliverdin reductase
dc.subjectcyclin dependent kinase inhibitor
dc.subjectoxidoreductase
dc.subjectsecretase
dc.subjectaged
dc.subjectaging
dc.subjectAlzheimer disease
dc.subjectanimal experiment
dc.subjectanimal model
dc.subjectanimal tissue
dc.subjectArticle
dc.subjectbeagle
dc.subjectcell membrane
dc.subjectcontrolled study
dc.subjectembryo
dc.subjectHEK293 cell line
dc.subjecthuman
dc.subjecthuman cell
dc.subjecthuman tissue
dc.subjectin vitro study
dc.subjectin vivo study
dc.subjectinsulin resistance
dc.subjectinsulin signaling
dc.subjectmale
dc.subjectnonhuman
dc.subjectparietal cortex
dc.subjectpriority journal
dc.subjectprotein function
dc.subjectprotein phosphorylation
dc.subjectprotein processing
dc.subjectaging
dc.subjectAlzheimer disease
dc.subjectanimal
dc.subjectbrain
dc.subjectdisease model
dc.subjectdog
dc.subjectinsulin resistance
dc.subjectmetabolism
dc.subjectphosphorylation
dc.subjectAged
dc.subjectAging
dc.subjectAlzheimer Disease
dc.subjectAmyloid beta-Protein Precursor
dc.subjectAmyloid Precursor Protein Secretases
dc.subjectAnimals
dc.subjectAspartic Acid Endopeptidases
dc.subjectBrain
dc.subjectCyclin-Dependent Kinase Inhibitor Proteins
dc.subjectDisease Models, Animal
dc.subjectDogs
dc.subjectHEK293 Cells
dc.subjectHumans
dc.subjectInsulin Resistance
dc.subjectMale
dc.subjectOxidoreductases Acting on CH-CH Group Donors
dc.subjectPhosphorylation
dc.titleBiliverdin reductase-A impairment links brain insulin resistance with increased Aβ production in an animal model of aging: Implications for Alzheimer disease
dc.typeArticle


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