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| 1 | Intranasal rapamycin ameliorates Alzheimerlike cognitive decline in a mouse model of Down syndrome显示文摘Background:Down syndrome(DS)individuals,by the age of 40s,are at increased risk to develop Alzheimer-like dementia,with deposition in brain of senile plaques and neurofibrillary tangles.Our laboratory recently demonstrated the disturbance of PI3K/AKT/mTOR axis in DS brain,prior and after the development of Alzheimer Disease(AD).The aberrant modulation of the mTOR signalling in DS and AD age-related cognitive decline affects crucial neuronal pathways,including insulin signaling and autophagy,involved in pathology onset and progression.Within this context,the therapeutic use of mTOR-inhibitors may prevent/attenuate the neurodegenerative phenomena.By our work we aimed to rescue mTOR signalling in DS mice by a novel rapamycin intranasal administration protocol(InRapa)that maximizes brain delivery and reduce systemic side effects.Methods:Ts65Dn mice were administered with InRapa for 12 weeks,starting at 6 months of age demonstrating,at the end of the treatment by radial arms maze and novel object recognition testing,rescued cognition.Results:The analysis of mTOR signalling,after InRapa,demonstrated in Ts65Dn mice hippocampus the inhibition of mTOR(reduced to physiological levels),which led,through the rescue of autophagy and insulin signalling,to reduced APP levels,APP processing and APP metabolites production,as well as,to reduced tau hyperphosphorylation.In addition,a reduction of oxidative stress markers was also observed.Discussion:These findings demonstrate that chronic InRapa administration is able to exert a neuroprotective effect on Ts65Dn hippocampus by reducing AD pathological hallmarks and by restoring protein homeostasis,thus ultimately resulting in improved cognition.Results are discussed in term of a potential novel targeted therapeutic approach to reduce cognitive decline and AD-like neuropathology in DS individuals. | Antonella Tramutola Chiara Lanzillotta Eugenio Barone Andrea Arena Ilaria Zuliani Luciana Mosca Carla Blarzino D.Allan Butterfield Marzia Perluigi Fabio Di Domenico | 2018 | Translational Neurodegeneration2018，7，1： | 3 |
| 2 | Biliverdin Reductase-A correlates with inducible nitric oxide synthasein in atorvastatin treated aged canine brain显示文摘Alzheimer's disease is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Recent preclinical and epidemiological studies proposed statins as a possible therapeutic drug for Alzheimer's disease, but the exact mechanisms of action are still unknown. Biliverdin reductase-A is a pleiotropic enzyme involved in cellular stress responses. It not only transforms biliverdin-IX alpha into the antioxidant bilirubin-IX alpha but its serine/threonine/ tyrosine kinase activity is able to modulate cell signaling networks. We previously reported the beneficial effects of atorvastatin treatment on biliverdin reductase-A and heme oxygenase-1 in the brains of a well characterized pre-clinical model of Alzheimer's disease, aged beagles, together with observed improvement in cognition. Here we extend our knowledge of the effects of atorvastatin on inducible nitric oxide synthase in parietal cortex, cerebellum and liver of the same animals. We demonstrated that atorvastatin treatment (80 mg/day for 14.5 months) to aged beagles selectively increased inducible nitric oxide synthase in the parietal cortex but not in the cerebellum. In contrast, inducible nitric oxide synthase protein levels were significantly decreased in the liver. Significant positive correlations were found between biliverdin reductase-A and inducible nitric oxide synthase as well as heme oxygenase-1 protein levels in the parietal cortex. The opposite was observed in the liver. Inducible nitric oxide synthase up-regulation in the parietal cortex was positively associated with improved biliverdin reductase-A functions, whereas the oxidative-induced impairment of biliverdin reductase-A in the liver negatively affected inducible nitric oxide synthase expression, thus suggesting a role for biliverdin reductase-A in atorvastatin-dependent inducible nitric oxide synthase changes. Interestingly, increased inducible nitric oxide synthase levels in the parietal cortex were not associated with higher oxidative/nitrosative stress levels. We hypothesize that biliverdin reductase-A-dependent inducible nitric oxide synthase regulation strongly contributes to the cognitive improvement observed following atorvastatin treatment. | Fabio Di Domenico Marzia Perluigi Eugenio Barone | 2013 | Neural Regeneration Research2013，8，21： | 2 |
| 3 | Oxidatively modified pro-teins in Alzheimer ’ s disease ( AD ),mild cognitive impairmentand animal models of AD: roJe of Abeta in pathogenesis显示文摘 | Sultana R Perluigi M Butterfield DA | 2009 | ActaNeuropathol2009，118，： | 1 |
| 4 | Oxidatively modified proteins in Alzheimer's disease (AD), mild cognitive impair- ment and animal models of AD: role of Abeta in pathogenesis 显示文摘 | Sultana R Perluigi M Butterfield DA | 2009 | Acta Neuropathol2009，118，： | 1 |
| 5 | Proteomic analysis of 4-hydroxy-2-nonenal-modified proteins in G93A-SOD1 transgenic mice-A model of familial amyotrophic lateral sclerosis显示文摘 | Perluigi M Poon HF Hensley K | 2005 | Free Radical Bio Med2005，38，： | 1 |
| 6 | In vivo protection by the xanthate tricyclodecan-9-yl-xanthogenate against amyloid beta-peptide(1-42)- induced oxidative stress显示文摘 | Perluigi M Joshi G Sultana R | 2006 | Neuroscience2006，138，4： | 1 |
| 7 | Redox proteomics in aging rat brain:involvement of mitochondrial reduced glutathi-one status and mitochondrial protein oxidation in the aging process显示文摘 | Perluigi M Di Domenico F Giorgi A | 2010 | J Neurosci Res2010，88，16： | 1 |
| 8 | Oxidative stress?in? Alzheimer's disease brain: ne-w insights fi'om redox proteomies 显示文摘 | Butterfield DA Perluigi M Sultana R | 2006 | Eur J Pharmacol2006，545，1： | 1 |
| 9 | Oxidatively modified proteins in Alzheimer's disease ( AD),mild cognitive impairment and animal models of AD: role of Abeta in pathogenesis显示文摘 | Sultana R Perluigi M Butterfield DA | 2009 | Acta Neuropathol2009，118，1： | 1 |
| 10 | Redox proteomic identification of 4-hydroxy-2-nonenal-modified brain proteins in amnestic mild cognitive impairment: insight into the role of lipid peroxidation in the progression and pathogenesis of Alzheimer's disease显示文摘 | Reed T Perluigi M Sultana R | 2008 | Neurobiol Dis2008，30，1： | 1 |
| 11 | Oxidatively modified proteins in Alzheimer′s disease (AD),mild cognitive impairment and animal models of AD:role of Abeta in pathogenesis显示文摘 | Sultana R Perluigi M Butterfield DA | 2009 | Acta Neuropathol2009，118，1： | 1 |
| 12 | Oxidative stress in Mzheimer's disease brain: New insights from redox proteomics 显示文摘 | Butterfield D A Perluigi M Sultana R | 2006 | Eur J Pharos2006，545，1： | 1 |
| 13 | Redox proteomic analysis of carbonylated brain proteins in mild cognitive impairment and early alzheimer's disease 显示文摘 | Sultana R Perluigi M Newman SF | 2010 | Antioxid Redox Signal2010，12，3： | 1 |
| 14 | Oxidatively modified proteins in Alzheimer' s disease (AD) , mild cognitive impairment and ani- mal models of AD : role of Abeta in pathogenesis 显示文摘 | Sultana R Perluigi M Butterfield DA | 2009 | Acta Neuro- pathol2009，118，1： | 1 |
| 15 | Lipid peroxidation triggers neurodegeneration:A redox proteomics view into the Alzheimer disease brain显示文摘 | Sultana R Perluigi M Allan Butterfield D | 2013 | Free Radic Biol Med2013，62，： | 1 |
| 16 | Oxidatively modified pro- teins in Alzheimer's disease (AD), mild cognitive impairment andanimal models of AD: role of Abeta in pathogenesis显示文摘 | Sultana R Perluigi M Butterfield DA | 2009 | Acta Neuropathol2009，118，： | 1 |
| 17 | Oxidative stress in Alzheimer's disease brain:new insights from redox proteomics显示文摘 | Butterfiled D A Perluigi M Sultana R | 2006 | Eur J Pharmacol2006，545，1： | 1 |
| 18 | Oxidative stress in Alzheimer's disease brain:new insights from redox proteomics显示文摘 | Butterfield DA Perluigi M Sultana R | 2006 | Eur J Pharmacol2006，545，： | 1 |
| 19 | Oxidatively modified pro-teins in Alzheimer's disease (AD), mild cognitive impainnent andanimal models of AD: role of Abeta in pathogenesis 显示文摘 | Sultana R Perluigi M Butterfield DA | 2009 | Acta Neuro-pathol2009，118，1： | 1 |
| 20 | Proteomics strategies to analyze HPV-transformed cells: relevance to cervical cancer显示文摘 | Di Domenico F De Marco F Perluigi M | 2013 | Expert Rev Proteomics2013，10，： | 1 |
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