title: Influence of residue 22 on the folding, aggregation profile, and toxicity of the Alzheimer's amyloid beta peptide.
abstract: Several biophysical techniques have been used to determine differences in the aggregation profile (i.e., the secondary structure, aggregation propensity, dynamics, and morphology of amyloid structures) and the effects on cell viability of three variants of the amyloid beta peptide involved in Alzheimer's disease. We focused our study on the Glu22 residue, comparing the effects of freshly prepared samples and samples aged for at least 20 days. In the aged samples, a high propensity for aggregation and beta-sheet secondary structure appears when residue 22 is capable of establishing polar (Glu22 in wild-type) or hydrophobic (Val22 in E22V) interactions. The Arctic variant (E22G) presents a mixture of mostly disordered and alpha-helix structures (with low beta-sheet contribution). Analysis of transmission electron micrographs and atomic force microscopy images of the peptide variants after aging showed significant quantitative and qualitative differences in the morphology of the formed aggregates. The effect on human neuroblastoma cells of these Abeta(12-28) variants does not correlate with the amount of beta-sheet of the aggregates. In samples allowed to age, the native sequence was found to have an insignificant effect on cell viability, whereas the Arctic variant (E22G), the E22V variant, and the slightly-aggregating control (F19G-F20G) had more prominent effects.
authors: Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden. apm@dbb.su.se
authors: Alex
authors: A
authors: Perálvarez-Marín
authors: Laura
authors: L
authors: Mateos
authors: Ce
authors: C
authors: Zhang
authors: Shalini
authors: S
authors: Singh
authors: Angel
authors: A
authors: Cedazo-Mínguez
authors: Neus
authors: N
authors: Visa
authors: Ludmilla
authors: L
authors: Morozova-Roche
authors: Astrid
authors: A
authors: Gräslund
authors: Andreas
authors: A
authors: Barth
mesh_terms: D000375:Aging; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D002942:Circular Dichroism; D003224:Congo Red; D006801:Humans; D018625:Microscopy, Atomic Force; D046529:Microscopy, Electron, Transmission; D009447:Neuroblastoma / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D017510:Protein Folding; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017550:Spectroscopy, Fourier Transform Infrared; D013696:Temperature
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C092395:amyloid beta-protein (12-28); D003224:Congo Red