Alternate Aggregation Pathways of Alzheimer β-Amyloid Peptides
Alzheimer’s Disease (AD) is a neuropathological disorder characterized by the progressive deposition in the brain of insoluble amyloid plaques and vascular deposits consisting primarily of the 4.5 kDa β-amyloid peptide (Aβ). There is increasing evidence that formation of these fibrillar deposits leads to the neurodegeneration observed in AD. Elucidating the mechanism of this polymerization process is therefore of great importance in the development of potential inhibitors. The detailed mechanism of Aβ production is still unclear, however there is increasing evidence that Aβ is initially produced through an endocytic-recycling pathway . We have therefore investigated the association of Aβ at endosomal pH in an attempt to identify the initial stages of Aβ fibrillogenesis. Because individual techniques have inherent shortcomings, we employed several techniques for monitoring Aβ association, which include fluorescence resonance energy transfer (FRET), dynamic light scattering (DLS), atomic force microscopy (AFM), and electron microscopy (EM).