Alternate Aggregation Pathways of the Alzheimer β-Amyloid Peptide

T. H. Jackson Huang, Dun-Sheng Yang, Paul E. Fraser, Avijit Chakrabartty
2000 Journal of Biological Chemistry  
Deposition of amyloid-␤ (A␤) 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 A␤ (also called preamyloid) in diffuse plaques is not associated with neurodegeneration. Depending on the conditions, A␤ will also form fibrillar or amorphous aggregates in vitro. In this present study, we sought to characterize the properties of the amorphous
more » ... ate and determine whether we could establish an in vitro model for amorphous A␤. CD data indicated that A␤40 assembled to form either a ␤-structured aggregate or an unfolded aggregate with the structured aggregate forming at high peptide concentrations and the unstructured aggregate forming at low A␤40 levels. The critical concentration separating these two pathways was 10 M. 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 A␤ of AD and that conditions can be established to form amorphous A␤ in vitro. This would allow for investigations to better understand the relationship between fibrillar and amorphous A␤ and could have significant impact upon efforts to find therapies for AD. ease; HPLC, high performance liquid chromatography; NBD, 6-(N-(7nitrobenz-2-oxa-1,3-diazol-4-yl)amino)hexanoic acid.
doi:10.1074/jbc.m005698200 pmid:10961999 fatcat:2w2wueru2felpclcvvuilvs6oa