Abeta-globulomers are formed independently of the fibril pathway.
Soluble A beta-oligomers are currently discussed as the major causative species for the development of Alzheimer's disease (AD). Consequently, the beta-amyloid cascade hypothesis was extended by A beta-oligomers and their central neuropathogenic role in AD. However, the molecular structure of A beta-oligomers and their relation to amyloid fibril formation remains elusive. Previously we demonstrated that incubation of A beta(1-42) with SDS or fatty acids induces the formation of a homogeneous globular A beta-oligomer termed A beta-globulomer. In this study we investigated the role of A beta-globulomers in the aggregation pathway of A beta-peptide. We used in vitro assays such as thioflavin-T binding and aggregation inhibitors like Congo red to reveal that A beta-peptide in its A beta-globulomer conformation is a structural entity which is independent from amyloid fibril formation. In addition, cellular Alzheimer's-like plaque forming assays show the resistance of A beta-globulomers to deposition as amyloid plaques. We hypothesize that a conformational switch of A beta is decisive for either fibril formation or alternatively and independently A beta-globulomer formation.
Gellermann
Gerald P
GP
Neuroscience Discovery Research, Abbott GmbH & Co. KG, Knollstrasse, D-67061 Ludwigshafen, Germany.
Byrnes
Helga
H
Striebinger
Andreas
A
Ullrich
Kathrin
K
Mueller
Reinhold
R
Hillen
Heinz
H
Barghorn
Stefan
S
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D001253:Astrocytes / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D051379:Mice; D008810:Mice, Inbred C57BL; D016874:Neurofibrillary Tangles / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D058225:Plaque, Amyloid / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D015398:Signal Transduction / Q000502:physiology*
D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)