1. Restoration of aberrant mTOR signaling by intranasal rapamycin reduces oxidative damage: Focus on HNE-modified proteins in a mouse model of down syndrome
- Author
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Chiara Lanzillotta, Fabio Di Domenico, Marzia Perluigi, Massimo Castagnola, Federica Iavarone, D. Allan Butterfield, Eugenio Barone, Olivia Defever, Ilaria Zuliani, Antonella Tramutola, Cesira Foppoli, Federica Vincenzoni, and Andrea Arena
- Subjects
Male ,Proteomics ,0301 basic medicine ,Down syndrome ,Clinical Biochemistry ,Protein aggregation ,medicine.disease_cause ,Biochemistry ,Mice ,0302 clinical medicine ,mTOR Rapamycin ,lcsh:QH301-705.5 ,education.field_of_study ,lcsh:R5-920 ,Chemistry ,TOR Serine-Threonine Kinases ,Cell biology ,Intranasal ,Administration ,mTOR ,Female ,Alzheimer's disease ,lcsh:Medicine (General) ,Signal Transduction ,Proteasome Endopeptidase Complex ,Population ,03 medical and health sciences ,Autophagy ,medicine ,Animals ,Rapamycin ,education ,Settore BIO/10 - BIOCHIMICA ,Administration, Intranasal ,PI3K/AKT/mTOR pathway ,Sirolimus ,Protein-bound HNE ,Animal ,Organic Chemistry ,Protein phosphatase 2 ,Novel targets of lipoxidation and potential therapeutic strategy ,medicine.disease ,Disease Models, Animal ,030104 developmental biology ,Proteasome ,lcsh:Biology (General) ,Oxidative stress ,Disease Models ,down syndrome ,oxidative stress ,protein-bound hne ,rapamycin ,mtor ,Biomarkers ,030217 neurology & neurosurgery - Abstract
Increasing 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., Graphical abstract Image 1
- Published
- 2019
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