Alternate aggregation pathways of the Alzheimer beta-amyloid peptide. An in vitro model of preamyloid.
Deposition of amyloid-beta (Abeta) aggregates in the brain is a defining characteristic of Alzheimer's disease (AD). Fibrillar amyloid, found in the cores of senile plaques, is surrounded by dystrophic neurites. In contrast, the amorphous Abeta (also called preamyloid) in diffuse plaques is not associated with neurodegeneration. Depending on the conditions, Abeta will also form fibrillar or amorphous aggregates in vitro. In this present study, we sought to characterize the properties of the amorphous aggregate and determine whether we could establish an in vitro model for amorphous Abeta. CD data indicated that Abeta40 assembled to form either a beta-structured aggregate or an unfolded aggregate with the structured aggregate forming at high peptide concentrations and the unstructured aggregate forming at low Abeta40 levels. The critical concentration separating these two pathways was 10 microm. Fluorescence emission and polarization showed the structured aggregate was tightly packed containing peptides that were not accessible to water. Peptides in the unstructured aggregate were loosely packed, mobile, and accessible to water. When examined by electron microscopy, the structured aggregate appeared as protofibrillar structures and formed classic amyloid fibrils over a period of several weeks. The unstructured aggregate was not visible by electron microscopy and did not generate fibrils. These findings suggest that the unstructured aggregate shares many properties with the amorphous Abeta of AD and that conditions can be established to form amorphous Abeta in vitro. This would allow for investigations to better understand the relationship between fibrillar and amorphous Abeta and could have significant impact upon efforts to find therapies for AD.
Huang
T H
TH
Division of Molecular and Structural Biology, Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada.
Yang
D S
DS
Fraser
P E
PE
Chakrabartty
A
A
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D002942:Circular Dichroism; D005454:Fluorescence Polarization; D005456:Fluorescent Dyes; D006801:Humans; D008854:Microscopy, Electron; D008954:Models, Biological; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D058225:Plaque, Amyloid / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D012995:Solubility; D013050:Spectrometry, Fluorescence
D016229:Amyloid beta-Peptides; D005456:Fluorescent Dyes; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)