Alternate aggregation pathways of the Alzheimer β-amyloid peptide -: An in vitro model of preamyloid

Deposition of amyloid-beta (A beta) 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 beta (also called preamyloid) in diffuse plaques: is ndt associated with neurodegeneration. Depending on the conditions, A beta 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 A beta, CD data indicated that A beta 40 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 A beta 40 levels. The critical concentration separating these two pathways was 10 muM. 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 beta of AD and that conditions can be established to form amorphous A beta in vitro. This would allow for investigations to better understand the relationship between fibrillar and amorphous A beta and could have significant impact upon efforts to find therapies for AD.