Controlling {beta}-amyloid oligomerization by the use of naphthalene sulfonates: trapping low molecular weight oligomeric species.
Aggregation of proteins and peptides has been shown to be responsible for several diseases known as amyloidoses, which include Alzheimer disease (AD), prion diseases, among several others. AD is a neurodegenerative disorder caused primarily by the aggregation of beta-amyloid peptide (Abeta). Here we describe the stabilization of small oligomers of Abeta by the use of sulfonated hydrophobic molecules such as AMNS (1-amino-5-naphthalene sulfonate); 1,8-ANS (1-anilinonaphthalene-8-sulfonate) and bis-ANS (4,4'-dianilino-1,1'-binaphthyl-5,5'-disulfonate). The experiments were performed with either Abeta-1-42 or with Abeta-13-23, a shorter version of Abeta that is still able to form amyloid fibrils in vitro and contains amino acid residues 16-20, previously shown to be essential to peptide-peptide interaction and fibril formation. All sulfonated molecules tested were able to prevent Abeta aggregation in a concentration dependent fashion in the following order of efficacy: 1,8-ANS < AMNS < bis-ANS. Size exclusion chromatography revealed that in the presence of bis-ANS, Abeta forms a heterogeneous population of low molecular weight species that proved to be toxic to cell cultures. Since the ANS compounds all have apolar rings and negative charges (sulfonate groups), both hydrophobic and electrostatic interactions may contribute to interpeptide contacts that lead to aggregation. We also performed NMR experiments to investigate the structure of Abeta-13-23 in SDS micelles and found features of an alpha-helix from Lys(16) to Phe(20). 1H TOCSY spectra of Abeta-13-23 in the presence of AMNS displayed a chemical-shift dispersion quite similar to that observed in SDS, which suggests that in the presence of AMNS this peptide might adopt a conformation similar to that reported in the presence of SDS. Taken together, our studies provide evidence for the crucial role of small oligomers and their stabilization by sulfonate hydrophobic compounds.
Ferrão-Gonzales
Astria D
AD
Instituto de Bioquímica Médica, Programa de Biologia Estrutural, Centro Nacional de Ressonāncia Magnética Nuclear, Universidade Federal do Rio de Janeiro, Av. Bauhínia, 400-21941-590-Rio de Janeiro, RJ, Brazil.
Robbs
Bruno K
BK
Moreau
Vitor Hugo
VH
Ferreira
Aricéle
A
Juliano
Luiz
L
Valente
Ana Paula
AP
Almeida
Fabio C L
FC
Silva
Jerson L
JL
Foguel
Debora
D
D000682:Amyloid / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000817:Anilino Naphthalenesulfonates / Q000737:chemistry*; D000818:Animals; D000838:Anions / Q000737:chemistry; D052160:Benzothiazoles; D001671:Biochemistry / Q000379:methods; D002460:Cell Line; D002845:Chromatography; D003224:Congo Red / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005456:Fluorescent Dyes / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008027:Light; D008239:Lysine / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008823:Micelles; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D008970:Molecular Weight; D009282:Naphthalenesulfonates / Q000737:chemistry*; D010446:Peptide Fragments / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D010649:Phenylalanine / Q000737:chemistry; D011328:Prions / Q000737:chemistry; D017433:Protein Structure, Secondary; D012542:Scattering, Radiation; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry; D013053:Spectrophotometry; D055672:Static Electricity; D013451:Sulfonic Acids / Q000737:chemistry; D013696:Temperature; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology; D013997:Time Factors
D000682:Amyloid; D016229:Amyloid beta-Peptides; D000817:Anilino Naphthalenesulfonates; D000838:Anions; D052160:Benzothiazoles; D005456:Fluorescent Dyes; D008823:Micelles; D009282:Naphthalenesulfonates; D010446:Peptide Fragments; D010455:Peptides; D011328:Prions; D013451:Sulfonic Acids; D013778:Tetrazolium Salts; D013844:Thiazoles; C000600713:amyloid beta-protein (13-23); C009462:thioflavin T; D012967:Sodium Dodecyl Sulfate; D003224:Congo Red; D010649:Phenylalanine; C027132:1-anilino-8-naphthalenesulfonate; C035763:5,5'-bis(8-(phenylamino)-1-naphthalenesulfonate); C022616:thiazolyl blue; D008239:Lysine; C022042:1-naphthylamine-5-sulfonic acid