Irccs Centro Sgiovanni Of Dio Fatebenefratelli

Brescia, Italy

Irccs Centro Sgiovanni Of Dio Fatebenefratelli

Brescia, Italy
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Squitti R.,AFaR Osp. Fatebenefratelli | Squitti R.,Biomedical University of Rome | Ghidoni R.,Proteomics Unit | Ghidoni R.,Irccs Centro Sgiovanni Of Dio Fatebenefratelli | And 10 more authors.
Journal of Alzheimer's Disease | Year: 2011

In patients affected by Alzheimer's disease (AD), serum copper not bound to ceruloplasmin ('free' copper) appears elevated, slightly but significantly enough to distinguish AD patients from healthy elderly subjects. In this paper we tested the hypothesis that this is also the case for individuals affected by mild cognitive impairment (MCI). A sample of 83 MCI subjects were compared with 100 elderly control subjects in terms of levels of serum copper, free copper, ceruloplasmin, apolipoprotein E4 genotype (APOE4), iron, transferrin, and total antioxidant capacity (TRAP). The groups were also compared in terms of demographic and cardiovascular risk factors. The comparison with an additional group of 105 mild to moderate AD patients was also evaluated. The possible effects of copper dysfunction on cognitive decline were evaluated by multinomial logistic regression analysis. A linear regression model was applied to define the role of metals and antioxidant dysfunction in explaining Mini-Mental Status Examination (MMSE) variations. APOE4 and free copper differentiated the MCI group from the healthy control group. The probability of aquiring MCI increased by about 24% for each free copper unit (μmol/L) increment. APOE4 and free copper differentiated the MCI group also from the AD group. APOE4 and free copper appeared associated to MMSE worsening, as did age and gender. These results suggest that free copper can help in discriminating MCI subjects from healthy controls, but not on an individual basis. © 2011 IOS Press and the authors. All rights reserved.

Lescai F.,University College London | Lescai F.,University of Bologna | Pirazzini C.,University of Bologna | D'Agostino G.,University of Bologna | And 20 more authors.
Journal of Alzheimer's Disease | Year: 2010

A recent genome-wide study on late-onset Alzheimer's disease identified a SNP (rs5984894) on Xq21.3 in the PCDH11X gene strongly associated with LOAD individuals of European descent from the United States. We genotyped the same polymorphism in 1222 cases and 938 controls from central-northern Italy and could not confirm the association on the Italian population: multivariate logistic regression adjusted for gender and APOE ε4 allele resulted in a global p value of 0.56. © 2010 - IOS Press and the authors.

Ghidoni R.,Proteomics Unit | Ghidoni R.,Irccs Centro Sgiovanni Of Dio Fatebenefratelli | Paterlini A.,Proteomics Unit | Albertini V.,Proteomics Unit | And 7 more authors.
Neurobiology of Aging | Year: 2011

It has recently become clear that proteins associated with neurodegenerative disorders can be selectively incorporated into intraluminal vesicles of multivesicular bodies and subsequently released within exosomes. Multiple lines of research support a neuroprotective role for cystatin C in Alzheimer's disease (AD). Herein we demonstrate that cystatin C, a protein targeted to the classical secretory pathway by its signal peptide sequence, is also secreted by mouse primary neurons in association with exosomes. Immunoproteomic analysis using SELDI-TOF MS revealed the presence in exosomes of at least 9 different cystatin C glycoforms. Moreover, the over-expression of familial AD-associated presenilin 2 mutations (PS2 M239I and PS2 T122R) resulted in reduced levels of all cystatin C forms (native and glycosylated) and of amyloid-β precursor protein (APP) metabolites within exosomes. A better understanding of the mechanisms involved in exosomal processing and release may have important implications for the fight against AD and other neurodegenerative diseases. © 2009 Elsevier Inc.

Polito L.,Mario Negri Institute for Pharmacological Research | Polito L.,Golgi Cenci Foundation | Kehoe P.G.,University of Bristol | Davin A.,Mario Negri Institute for Pharmacological Research | And 17 more authors.
Alzheimer's and Dementia | Year: 2013

Background: Human sirtuins are a current hotspot for research in neurodegenerative disorders, including Alzheimer's disease (AD). This study investigated whether genetic variants in two members of the sirtuin family, SIRT2 and SIRT3, affected AD susceptibility. Methods: A genetic case-control study was performed, comprising 534 probable AD cases and 638 nondemented control subjects from the north of Italy and Canton Ticino, Switzerland (discovery population). The study was focused on SIRT2 rs10410544, SIRT3 rs4980329, and SIRT3 rs536715 single nucleotide polymorphisms (SNPs). These SNPs were genotyped by real-time polymerase chain reaction allelic discrimination assay or restriction fragment length polymorphism. The SNPs rs7412 and rs429358, mapping within the apolipoprotein E (APOE) gene, were genotyped by realtime polymerase chain reaction allelic discrimination assay too. In a replication population comprising 756 AD cases and 847 nondemented control subjects, SIRT2 rs10410544, APOE rs7412, and APOE rs429358 were genotyped as mentioned previously. Results: In the discovery population, we observed an association between SIRT2 rs10410544 T allele and AD (adjusted odds ratio [OR] 5 1.23, 95% confidence interval [CI]: 1.02-1.50, P 5.02, after correction for sex, age, and APOE 34 genotype). The association between AD and SIRT2 rs10410544 T allele was only present in APOE 34 noncarriers (adjusted OR 5 1.29, 95% CI: 1.03- 1.61, P 5.03). The replication study did not confirm this evidence. However, the combined analysis on the two cohorts detected the association (adjusted OR 5 1.17, 95% CI: 1.02-1.35, P 5.02), and only APOE 34 noncarriers were at risk (adjusted OR 5 1.2, 95% CI: 1.02-1.43, P 5.03). Conclusions: The SIRT2 rs10410544 Tallele deserves further investigation as a novel minor genetic risk factor for AD in the APOE 34-negative Caucasian population. © 2013 The Alzheimer's Association. All rights reserved.

Meli G.,European Brain Research Institute EBRI | Lecci A.,European Brain Research Institute EBRI | Manca A.,European Brain Research Institute EBRI | Krako N.,European Brain Research Institute EBRI | And 6 more authors.
Nature Communications | Year: 2014

A' 2 oligomers (A' 2Os) are crucially involved in Alzheimer's Disease (AD). However, the lack of selective approaches for targeting these polymorphic A' 2 assemblies represents a major hurdle in understanding their biosynthesis, traffic and actions in living cells. Here, we established a subcellularly localized conformational-selective interference (CSI) approach, based on the expression of a recombinant antibody fragment against A' 2Os in the endoplasmic reticulum (ER). By CSI, we can control extra- and intracellular pools of A' 2Os produced in an AD-relevant cell model, without interfering with the maturation and processing of the A' 2 precursor protein. The anti-A' 2Os intrabody selectively intercepts critical A' 2O conformers in the ER, modulating their assembly and controlling their actions in pathways of cellular homeostasis and synaptic signalling. Our results demonstrate that intracellular A' 2 undergoes pathological oligomerization through critical conformations formed inside the ER. This establishes intracellular A' 2Os as key targets for AD treatment and presents CSI as a potential targeting strategy. © 2014 Macmillan Publishers Limited. All rights reserved.

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