Inhibition of Abeta Amyloid Growth and Toxicity by Silybins: The Crucial Role of Stereochemistry(95 visite)(PDF pubblico99 visite) Sciacca MFM, Romanucci V, Zarrelli A, Monaco I, Lolicato F, Spinella N, Galati C, Grasso G, D'Urso L, Romeo M, Diomede L, Salmona M, Bongiorno C, Di Fabio G, La Rosa C, Milardi D
Impact factor: 4.211, Impact factor a 5 anni: 4.621
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Parole chiave: Alzheimer, S Disease, Chiral Drugs, Natural Compounds, Neurodegeneration, Neuroprotection,
Affiliazioni:
*** IBB - CNR *** Institute of Biostructures and Bioimages-Catania, National Research Council, Via Paolo Gaifami 8, 95126 Catania, Italy., Department of Chemical Sciences, University of Napoli "Federico II" , Via Cintia 4, I-80126 Napoli, Italy., Department of Physics, University of Helsinki , P.O. Box 64, FI-00014 Helsinki, Finland., Department of Physics, Tampere University of Technology , P.O. Box 692, FI-33101 Tampere, Finland., STMicroelectronics , Stradale Primosole 50, 95121 Catania, Italy., Dipartimento di Scienze Chimiche, Universita degli Studi di Catania , Viale Andrea Doria 6, 95125 Catania, Italy., IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri" , Via Giuseppe La Masa 19, 20156, Milano, Italy., Institute for Microelectronics and Microsystems, National Research Council, Stradale Primosole 50, 95121 Catania, Italy.,
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The self-assembling of the amyloid beta (Abeta) peptide into neurotoxic aggregates is considered a central event in the pathogenesis of Alzheimer's disease (AD). Based on the "amyloid hypothesis", many efforts have been devoted to designing molecules able to halt disease progression by inhibiting Abeta self-assembly. Here, we combine biophysical (ThT assays, TEM and AFM imaging), biochemical (WB and ESI-MS), and computational (all-atom molecular dynamics) techniques to investigate the capacity of four optically pure components of the natural product silymarin (silybin A, silybin B, 2,3-dehydrosilybin A, 2,3-dehydrosilybin B) to inhibit Abeta aggregation. Despite TEM analysis demonstrated that all the four investigated flavonoids prevent the formation of mature fibrils, ThT assays, WB and AFM investigations showed that only silybin B was able to halt the growth of small-sized protofibrils thus promoting the formation of large, amorphous aggregates. Molecular dynamics (MD) simulations indicated that silybin B interacts mainly with the C-terminal hydrophobic segment 35MVGGVV40 of Abeta40. Consequently to silybin B binding, the peptide conformation remains predominantly unstructured along all the simulations. By contrast, silybin A interacts preferentially with the segments 17LVFF20 and 27NKGAII32 of Abeta40 which shows a high tendency to form bend, turn, and beta-sheet conformation in and around these two domains. Both 2,3-dehydrosilybin enantiomers bind preferentially the segment 17LVFF20 but lead to the formation of different small-sized, ThT-positive Abeta aggregates. Finally, in vivo studies in a transgenic Caenorhabditis elegans strain expressing human Abeta indicated that silybin B is the most effective of the four compounds in counteracting Abeta proteotoxicity. This study underscores the pivotal role of stereochemistry in determining the neuroprotective potential of silybins and points to silybin B as a promising lead compound for further development in anti-AD therapeutics.
Antonini A, Vitale C, Barone P, Cilia R, Righini A, Bonuccelli U, Abbruzzese G, Ramat S, Petrone A, Quatrale R, Marconi R, Ceravolo R, Stefani A, Lopiano L, Zappia M, Capus L, Morgante L, Tamma F, Tinazzi M, Colosimo C, Guerra UP, Valzania F, Fagioli G, Distefano A, Bagnato A, Feggi L, Anna S, Maria Teresa Rosaria De Cr, Nobili F, Mazzuca N, Baldari S, Eleopra R, Bestetti A, Benti R, Varrone A, Volterrani D, Massa R, Stocchi F, Schillaci O, Dore F, Zibetti M, Castellano G, Battista SG, Giorgetti G * The relationship between cerebral vascular disease and parkinsonism: The VADO study(171 visite) Parkinsonism Relat D (ISSN: 1353-8020, 1873-5126, 1873-5126electronic), 2012; 18(6): 775-780. Impact Factor:3.274 DettagliEsporta in BibTeXEsporta in EndNote
Bruni AC, Bernardi L, Colao R, Rubino E, Smirne N, Frangipane F, Terni B, Curcio SA, Mirabelli M, Clodomiro A, Di Lorenzo R, Maletta R, Anfossi M, Gallo M, Geracitano S, Tomaino C, Muraca MG, Leotta A, Lio SG, Pinessi L, Rainero I, Sorbi S, Nee L, Milan G, Pappata S, Postiglione A, Abbamondi N, Forloni G, St George Hyslop P, Rogaeva E, Bugiani O, Giaccone G, Foncin JF, Spillantini MG, Puccio G * Worldwide distribution of PSEN1 Met146Leu mutation: A large variability for a founder mutation(115 visite) Neurology (ISSN: 0028-3878, 1526-632x, 1526-632xelectronic), 2010 Mar 9; 74(10): 798-806. Impact Factor:8.017 DettagliEsporta in BibTeXEsporta in EndNote
184 Records (159 escludendo Abstract e Conferenze). Impact factor totale: 733.321 (648.295 escludendo Abstract e Conferenze). Impact factor a 5 anni totale: 763.059 (662.195 escludendo Abstract e Conferenze).
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