Modulation of aggregate size- and shape-distributions of the amyloid-beta peptide by a designed beta-sheet breaker.
A peptide with 42 amino acid residues (Abeta42) plays a key role in the pathogenesis of the Alzheimer's disease. It is highly prone to self aggregation leading to the formation of fibrils which are deposited in amyloid plaques in the brain of diseased individuals. In our study we established a method to analyze the aggregation behavior of the Abeta peptide with a combination of sedimentation velocity centrifugation and enhanced data evaluation software as implemented in the software package UltraScan. Important information which becomes accessible by this methodology is the s-value distribution and concomitantly also the shape-distribution of the Abeta peptide aggregates generated by self-association. With this method we characterized the aggregation modifying effect of a designed beta-sheet breaker molecule. This compound is built from three head-to-tail connected aminopyrazole moieties and represents a derivative of the already described Tripyrazole. By addition of this compound to a solution of the Abeta42 peptide the maximum of the s-value distribution was clearly shifted to smaller s-values as compared to solutions where only the vehicle DMSO was added. This shift to smaller s-values was stable for at least 7 days. The information about size- and shape-distributions present in aggregated Abeta42 solutions was confirmed by transmission electron microscopy and by measurement of amyloid formation by thioflavin T fluorescence.
Nagel-Steger
Luitgard
L
Institute for Physical Biology, Geb.26.12.U1, Heinrich-Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany. nagelst@biophys.uni-duesseldorf.de
Demeler
Borries
B
Meyer-Zaika
Wolfgang
W
Hochdörffer
Katrin
K
Schrader
Thomas
T
Willbold
Dieter
D
D016229:Amyloid beta-Peptides / Q000737:chemistry*; D052160:Benzothiazoles; D002119:Calcium Carbonate; D002499:Centrifugation, Density Gradient; D002951:Citrates; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D004338:Drug Combinations; D005453:Fluorescence; D008277:Magnesium Oxide; D046529:Microscopy, Electron, Transmission; D008970:Molecular Weight; D010446:Peptide Fragments / Q000737:chemistry*; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D012815:Signal Processing, Computer-Assisted; D012984:Software; D013844:Thiazoles; D013997:Time Factors
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D002951:Citrates; D004338:Drug Combinations; D010446:Peptide Fragments; C050615:Suby's G solution; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C009462:thioflavin T; D008277:Magnesium Oxide; D002119:Calcium Carbonate; D004121:Dimethyl Sulfoxide