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Restoration of aberrant mTOR signaling by intranasal rapamycin reduces oxidative damage: Focus on HNE-modified proteins in a mouse model of down syndrome

dc.contributor.authorDi Domenico F.
dc.contributor.authorTramutola A.
dc.contributor.authorBarone E.
dc.contributor.authorLanzillotta C.
dc.contributor.authorDefever O.
dc.contributor.authorArena A.
dc.contributor.authorZuliani I.
dc.contributor.authorFoppoli C.
dc.contributor.authorIavarone F.
dc.contributor.authorVincenzoni F.
dc.contributor.authorCastagnola M.
dc.contributor.authorButterfield D.A.
dc.contributor.authorPerluigi M.
dc.date.accessioned2020-09-02T22:16:18Z
dc.date.available2020-09-02T22:16:18Z
dc.date.issued2019
dc.identifier10.1016/j.redox.2019.101162
dc.identifier.citation23, , -
dc.identifier.issn22132317
dc.identifier.urihttps://hdl.handle.net/20.500.12728/4267
dc.descriptionIncreasing evidences support the notion that the impairment of intracellular degradative machinery is responsible for the accumulation of oxidized/misfolded proteins that ultimately results in the deposition of protein aggregates. These events are key pathological aspects of “protein misfolding diseases”, including Alzheimer disease (AD). Interestingly, Down syndrome (DS) neuropathology shares many features with AD, such as the deposition of both amyloid plaques and neurofibrillary tangles. Studies from our group and others demonstrated, in DS brain, the dysfunction of both proteasome and autophagy degradative systems, coupled with increased oxidative damage. Further, we observed the aberrant increase of mTOR signaling and of its down-stream pathways in both DS brain and in Ts65Dn mice. Based on these findings, we support the ability of intranasal rapamycin treatment (InRapa) to restore mTOR pathway but also to restrain oxidative stress resulting in the decreased accumulation of lipoxidized proteins. By proteomics approach, we were able to identify specific proteins that showed decreased levels of HNE-modification after InRapa treatment compared with vehicle group. Among MS-identified proteins, we found that reduced oxidation of arginase-1 (ARG-1) and protein phosphatase 2A (PP2A) might play a key role in reducing brain damage associated with synaptic transmission failure and tau hyperphosphorylation. InRapa treatment, by reducing ARG-1 protein-bound HNE levels, rescues its enzyme activity and conceivably contribute to the recovery of arginase-regulated functions. Further, it was shown that PP2A inhibition induces tau hyperphosphorylation and spatial memory deficits. Our data suggest that InRapa was able to rescue PP2A activity as suggested by reduced p-tau levels. In summary, considering that mTOR pathway is a central hub of multiple intracellular signaling, we propose that InRapa treatment is able to lower the lipoxidation-mediated damage to proteins, thus representing a valuable therapeutic strategy to reduce the early development of AD pathology in DS population. © 2019 The Authors
dc.language.isoen
dc.publisherElsevier B.V.
dc.subjectDown syndrome
dc.subjectmTOR
dc.subjectOxidative stress
dc.subjectProtein-bound HNE
dc.subjectRapamycin
dc.subject4 hydroxynonenal
dc.subjectarginase
dc.subjectarginase 1
dc.subjectmammalian target of rapamycin
dc.subjectphosphoprotein phosphatase 2A
dc.subjectrapamycin
dc.subjecttau protein
dc.subjectbiological marker
dc.subjectproteasome
dc.subjectrapamycin
dc.subjecttarget of rapamycin kinase
dc.subjectAlzheimer disease
dc.subjectamnesia
dc.subjectanimal experiment
dc.subjectanimal model
dc.subjectanimal tissue
dc.subjectantioxidant activity
dc.subjectArticle
dc.subjectbrain protection
dc.subjectcontrolled study
dc.subjectdose response
dc.subjectDown syndrome
dc.subjectenzyme activity
dc.subjectenzyme inhibition
dc.subjectfemale
dc.subjectlipid peroxidation
dc.subjectmale
dc.subjectmouse
dc.subjectmouse model
dc.subjectmTOR signaling
dc.subjectnonhuman
dc.subjectoxidation
dc.subjectoxidative stress
dc.subjectpriority journal
dc.subjectprotein analysis
dc.subjectprotein phosphorylation
dc.subjectproteomics
dc.subjectspatial memory
dc.subjectsynaptic transmission
dc.subjecttreatment duration
dc.subjectanimal
dc.subjectautophagy
dc.subjectdisease model
dc.subjectdrug effect
dc.subjectintranasal drug administration
dc.subjectmetabolism
dc.subjectprocedures
dc.subjectsignal transduction
dc.subjectAdministration, Intranasal
dc.subjectAnimals
dc.subjectAutophagy
dc.subjectBiomarkers
dc.subjectDisease Models, Animal
dc.subjectDown Syndrome
dc.subjectFemale
dc.subjectMale
dc.subjectMice
dc.subjectOxidative Stress
dc.subjectProteasome Endopeptidase Complex
dc.subjectProteomics
dc.subjectSignal Transduction
dc.subjectSirolimus
dc.subjectTOR Serine-Threonine Kinases
dc.titleRestoration of aberrant mTOR signaling by intranasal rapamycin reduces oxidative damage: Focus on HNE-modified proteins in a mouse model of down syndrome
dc.typeArticle


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