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Rigacci S.,University of Florence | Stefani M.,University of Florence | Stefani M.,Research Center on the Molecular Basis of Neurodegeneration
Expert Review of Neurotherapeutics | Year: 2014

A common molecular feature of amyloid neurodegenerative diseases is the unfolding/misfolding of specific proteins/peptides which consequently become prone to aggregate into toxic assemblies and deposits that are the key histopathological trait of these pathologies. Apart from the rare early-onset familiar forms, these neurodegenerative diseases are age-associated disorders whose symptoms appear in aged people after long incubation periods. This makes the therapeutic approach particularly compelling and boosts the search for both early diagnostic tools and preventive approaches. In this last respect, natural compounds commonly present in foods and beverages are considered promising molecules, at least on the bench side. The so-called 'nutraceutical approach' suggests life-long healthy diets, particularly focusing on food molecules that are candidates to enter clinical trials as such or following a targeted molecular engineering. Natural phenols abundant in 'healthy' foods such as extra virgin olive oil, red wine, green tea, red berries and spices, appear particularly promising. © Informa UK, Ltd. Source


Relini A.,University of Genoa | Relini A.,Research Center on the Molecular Basis of Neurodegeneration | Marano N.,University of Genoa | Marano N.,Lawrence University | Gliozzi A.,University of Genoa
Advances in Colloid and Interface Science | Year: 2014

Many degenerative diseases such as Alzheimer's and Parkinson's involve proteins that have a tendency to misfold and aggregate eventually forming amyloid fibers. This review describes the use of monolayers, bilayers, supported membranes, and vesicles as model systems that have helped elucidate the mechanisms and consequences of the interactions between amyloidogenic proteins and membranes. These are twofold: membranes favor the formation of amyloid structures and these induce damage in those membranes. We describe studies that show how interfaces, especially charged ones, favor amyloidogenic protein aggregation by several means. First, surfaces increase the effective protein concentration reducing a three-dimensional system to a two-dimensional one. Second, charged surfaces allow electrostatic interactions with the protein. Anionic lipids as well as rafts, rich in cholesterol and gangliosides, prove to play an especially important role. Finally, these amphipathic systems also offer a hydrophobic environment favoring conformational changes, oligomerization, and eventual formation of mature fibers. In addition, we examine several models for membrane permeabilization: protein pores, leakage induced by extraction of lipids, chaotic pores, and membrane tension, presenting illustrative examples of experimental evidence in support of these models. The picture that emerges from recent work is one where more than one mechanism is in play. Which mechanism prevails depends on the protein, its aggregation state, and the lipid environment in which the interactions occur. © 2013 Elsevier B.V. Source


Diomede L.,Istituto di Ricerche Farmacologiche Mario Negri | Rigacci S.,University of Florence | Rigacci S.,Research Center on the Molecular Basis of Neurodegeneration | Romeo M.,Istituto di Ricerche Farmacologiche Mario Negri | And 4 more authors.
PLoS ONE | Year: 2013

The presence of amyloid aggregates of the 42 amino acid peptide of amyloid beta (Aβ42) in the brain is the characteristic feature of Alzheimer's disease (AD). Amyloid beta (Aβ deposition is also found in muscle fibers of individuals affected by inclusion body myositis (sIBM), a rare muscular degenerative disease affecting people over 50. Both conditions are presently lacking an effective therapeutic treatment. There is increasing evidence to suggest that natural polyphenols may prevent the formation of toxic amyloid aggregates; this applies also to oleuropein aglycone (OLE), the most abundant polyphenol in extra virgin olive oil, previously shown to hinder amylin and Aβ aggregation. Here we evaluated the ability of OLE to interfere with Aβ proteotoxicity in vivo by using the transgenic CL2006 and CL4176 strains of Caenorhabditis elegans, simplified models of AD and of sIBM, which express human Aβ in the cytoplasm of body wall muscle cells. OLE-fed CL2006 worms displayed reduced Aβ plaque deposition, less abundant toxic Aβ oligomers, remarkably decreased paralysis and increased lifespan with respect to untreated animals. A protective effect was also observed in CL4176 worms but only when OLE was administered before the induction of the Aβ transgene expression. These effects were specific, dose-related, and not mediated by the known polyphenolic anti-oxidant activity, suggesting that, in this model organism, OLE interferes with the Aβ aggregation skipping the appearance of toxic species, as already shown in vitro for Aβ42. © 2013 Diomede et al. Source


Borchi E.,University of Florence | Bargelli V.,University of Florence | Guidotti V.,University of Florence | Berti A.,University of Florence | And 6 more authors.
Redox Biology | Year: 2014

The presence of amyloid aggregates of human islet amyloid polypeptide (hIAPP), a hallmark of type 2 diabetes, contributes to pancreatic β-cell impairment, where oxidative stress plays a key role. A contribution of NADPH oxidase to reactive oxygen species (ROS) generation after cell exposure to micromolar concentrations of hIAPP aggregates has been suggested. However, little is known about β-cells exposure to lower amounts of hIAPP aggregates, similar to those found in human pancreas. Thus, we aimed to investigate the events resulting from RIN-5F cells exposure to nanomolar concentrations of toxic hIAPP aggregates. We found an early and transient rise of NADPH oxidase activity resulting from increased Nox1 expression following the engagement of receptor for advanced glycation end-products (RAGE) by hIAPP aggregates. Unexpectedly, NADPH oxidase activation was not accompanied by a significant ROS increase and the lipoperoxidation level was significantly reduced. Indeed, cell exposure to hIAPP aggregates affected the antioxidant defences, inducing a significant increase of the expression and activity of catalase and glutathione peroxidase. We conclude that exposure of pancreatic β-cells to nanomolar concentrations of hIAPP aggregates for a short time induces an hormetic response via the RAGE-Nox1 axis; the latter stimulates the enzymatic antioxidant defences that preserve the cells against oxidative stress damage. © 2013 The Authors. Source


Pellistri F.,University of Genoa | Bucciantini M.,University of Florence | Bucciantini M.,Research Center on the Molecular Basis of Neurodegeneration | Invernizzi G.,University of Milan Bicocca | And 14 more authors.
Biochimica et Biophysica Acta - Molecular Cell Research | Year: 2013

This work aims at elucidating the relation between morphological and physicochemical properties of different ataxin-3 (ATX3) aggregates and their cytotoxicity. We investigated a non-pathological ATX3 form (ATX3Q24), a pathological expanded form (ATX3Q55), and an ATX3 variant truncated at residue 291 lacking the polyQ expansion (ATX3/291δ). Solubility, morphology and hydrophobic exposure of oligomeric aggregates were characterized. Then we monitored the changes in the intracellular Ca2+ levels and the abnormal Ca2+ signaling resulting from aggregate interaction with cultured rat cerebellar granule cells. ATX3Q55, ATX3/291δ and, to a lesser extent, ATX3Q24 oligomers displayed similar morphological and physicochemical features and induced qualitatively comparable time-dependent intracellular Ca2+ responses. However, only the pre-fibrillar aggregates of expanded ATX3 (the only variant which forms bundles of mature fibrils) triggered a characteristic Ca2+ response at a later stage that correlated with a larger hydrophobic exposure relative to the two other variants. Cell interaction with early oligomers involved glutamatergic receptors, voltage-gated channels and monosialotetrahexosylganglioside (GM1)-rich membrane domains, whereas cell interaction with more aged ATX3Q55 pre-fibrillar aggregates resulted in membrane disassembly by a mechanism involving only GM1-rich areas. Exposure to ATX3Q55 and ATX3/291δ aggregates resulted in cell apoptosis, while ATX3Q24 was substantially innocuous. Our findings provide insight into the mechanisms of ATX3 aggregation, aggregate cytotoxicity and calcium level modifications in exposed cerebellar cells.© 2013 Elsevier B.V. Source

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