Aggregation state and neurotoxic properties of Alzheimer beta-amyloid peptide.
The behaviour of synthetic batches of beta-amyloid (beta A) 1-40 peptide in solution has been studied. The effects of beta A1-40 on a PC12 cell toxicity assay was dependent upon the time of preincubation of an aqueous solution of the peptide before application to the cells. Fibrillization of the beta A1-40, quantitatively assessed by the binding of Congo red to amyloid fibrils, also increased in a time dependent manner over the 168 h incubation period studied. The degree of Congo red binding, in the absence of any preincubation, differed between two synthetically distinct batches of the peptide. The rate of development of fibril formation during subsequent incubation also differed between the two batches and appeared to parallel the effects on cell viability. Infra-red spectroscopic analysis revealed beta-sheet formation for both batches and other more subtle conformational differences between the peptides. Electron microscope examination of the batches of beta A1-40 confirmed the difference in occurrence and development of fibrils. At high magnification, fibrils of both batches exhibited a helical structure. The results suggest that the development of neurotoxicity of beta A1-40 is related to the fibrillar state of the peptide.
Howlett
D R
DR
SmithKline Beecham Pharmaceuticals, Harlow, Essex, UK.
Jennings
K H
KH
Lee
D C
DC
Clark
M S
MS
Brown
F
F
Wetzel
R
R
Wood
S J
SJ
Camilleri
P
P
Roberts
G W
GW
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D009474:Neurons / Q000187:drug effects*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000737:chemistry / Q000633:toxicity*; D051381:Rats; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)