Residues 17-20 and 30-35 of beta-amyloid play critical roles in aggregation.
We examined the effects of co-incubating nine different Abeta peptide fragments with full-length Abeta1-40 (Abeta40) on protein aggregation. Six fragments enhanced aggregation of Abeta40 (Abeta1-28, 12-28, 17-28, 10-20, 25-35 and 17-40), while three others did not (Abeta1-11, 1-16, and 20-29). All of the peptides that enhanced aggregation contained either residues 17-20 or 30-35, indicating the importance of these regions for promoting aggregation of full-length Abeta. Abeta25-35 in particular increased both the rate and extent of aggregation of Abeta40 considerably as indicated by fluorescence staining. Atomic force microscope imaging (AFM) indicates the increase in fluorescence staining with Abeta25-35 is primarily due to increased formation of oligomers and protofibrils rather than formation of large amyloid fibrils. AFM images of Abeta25-35 when incubated alone also indicate formation of aggregates and long thin filaments. The increase in formation of the small toxic oligomeric morphology of Abeta40, along with formation of Abeta25-35 oligomers and thin filaments, represent two different potential pathways for Abeta25-35 toxicity. The critical roles of residues 17-20 and 30-35 of Abeta provide further insight into mechanism that underlie the formation of toxic aggregates in Alzheimer Disease (AD) and suggest targets for the design of beta-sheet breakers to modulate the aggregation and inhibit toxicity of full-length Abeta.
Liu
Ruitian
R
Department of Chemical and Materials Engineering, Arizona State University, Tempe, Arizona.
McAllister
Chad
C
Department of Microbiology, Arizona State University, Tempe, Arizona.
Lyubchenko
Yuri
Y
Department of Microbiology, Arizona State University, Tempe, Arizona.
Sierks
Michael R
MR
Department of Chemical and Materials Engineering, Arizona State University, Tempe, Arizona.
D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D000595:Amino Acid Sequence / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D046911:Macromolecular Substances; D018625:Microscopy, Atomic Force; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D058225:Plaque, Amyloid / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary / Q000502:physiology
D016229:Amyloid beta-Peptides; D003603:Cytotoxins; D046911:Macromolecular Substances; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C074636:amyloid beta-protein (25-35)