Biophysical Comparison of Soluble Amyloid-β(1-42) Protofibrils, Oligomers, and Protofilaments

Some of the pathological hallmarks of the Alzheimer's disease brain, are senile plaques composed of insoluble amylbid-beta protein (A beta) fibrils. However, much of the recent emphasis in research has been on soluble A beta aggregates in response to,a growing body of evidence that shows that these species may be more neurotoxic than fibrils. Within this subset of 105 soluble aggregated A beta are protofibrils and oligomers. Although each species has been Widely investigated separately, few studies have directly compared 104 and contrasted their physical properties, In this work, we examined well-recognized preparations of A beta(1-42) oligorners and protofibrils with or multiangle (MALS) and dynamic (DLS) light, scattering in line With, or following, size-exclusion chromatography (SEC). Multiple SEC MALS analyses of protofibrils revealed molecular weight (M-w) gradients ranging from 200 to 2600 kDa. Oligomeric A beta species are generally considered to be a smaller and more nascent than protofibrils. However, oligother M-w values ranged from 225 to 3000 kDa, larger than that for protofibrils. Root-mean-square radius, (R-g) values correlated with the M-w trends, with protofibril Rg values ranging from 16 to 35 nm, while oligomers produced one population at 40-43 nth with a more disperse population from 22 to 39 run. Hydrodynamic radius (R-H) measurements by DLS and thiofiavin T fluorescence measurements indicated that protofibrils and oligomers had commonalities, yet electron microscopy revealed morphological differences between the two. SEC-purified A beta(1-42) monomer at lower concentrations was slower to nucleate but formed protofibrils (150 kDa) or soluble protofilaments (3000 kDa) depending on the buffer type. The findings from these studies shed new light on the similarities and differences between distinct soluble aggregated A beta species.