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

Deposition of amyloid-beta (A beta) aggregates in the brain is a defining c haracteristic 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 a ssociated 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 d etermine 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 -structur ed aggregate or an unfolded aggregate with the structured aggregate forming at high peptide concentrations and the unstructured aggregate forming at l ow A beta 40 levels. The critical concentration separating these two pathwa ys 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, mobil e, and accessible to water. When examined by electron microscopy, the struc tured aggregate appeared as protofibrillar structures and formed classic am yloid fibrils over a period of several weeks. The unstructured aggregate wa s not visible by electron microscopy and did not generate fibrils, These fi ndings suggest that the unstructured aggregate shares many properties with the amorphous A beta of AD and that conditions can be established to form a morphous A beta in vitro. This would allow for investigations to better und erstand the relationship between fibrillar and amorphous A beta and could h ave significant impact upon efforts to find therapies for AD.