Deposition of monomeric, not oligomeric, A beta mediates growth of Alzheimer's disease amyloid plaques in human brain preparations

Senile plaques composed of the peptide A beta contribute to the pathogenesi s of Alzheimer's disease (AD), and mechanisms underlying their formation an d growth may be exploitable as therapeutic targets. To examine the process of amyloid plaque growth in human brain, we have utilized size exclusion ch romatography (SEC), translational diffusion measured by NMR, and in vitro m odels of A beta amyloid growth to identify the oligomerization state of A b eta that is competent to add onto an existing amyloid deposit. SEC of radio labeled and unlabeled A beta over a concentration range of 10(-10)-10(-4) M demonstrated that the freshly dissolved peptide eluted as a single low mol ecular weight species, consistent with monomer or dimer. This low molecular weight A beta species isolated by SEC was competent to deposit onto preexi sting amyloid in preparations of AD cortex, with first-order kinetic depend ence on soluble A beta concentration, establishing that solution-phase olig omerization is not rate limiting. Translational diffusion measurements of t he low molecular weight A beta fraction demonstrate that the form of the pe ptide active in plaque deposition is a monomer. In deliberately aged (>6 we eks) A beta solutions, a high molecular weight (>100 000 M-r) species was d etectable in the SEC column void. In contrast to the active monomer, assemb led A beta isolated from the column showed Little or no focal association w ith AD tissue. These studies establish that, at least in vitro, A beta exis ts as a monomer at physiological concentrations and that deposition of mono mers, rather than of oligomeric A beta assemblies, mediates the growth of e xisting amyloid in human brain preparations.