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

Senile plaques composed of the peptide A beta contribute to the pathogenesis of Alzheimer's disease (AD), and mechanisms underlying their formation and growth may be exploitable as therapeutic targets. To examine the process of amyloid plaque growth in human brain, we have utilized size exclusion chromatography (SEC), translational diffusion measured by NMR, and in vitro models of A beta amyloid growth to identify the oligomerization state of A beta that is competent to add onto an existing amyloid deposit. SEC of radiolabeled 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 molecular weight species, consistent with monomer or dimer. This low molecular weight A beta species isolated by SEC was competent to deposit onto preexisting amyloid in preparations of AD cortex, with first-order kinetic dependence on soluble A beta concentration, establishing that solution-phase oligomerization is not rate limiting. Translational diffusion measurements of the low molecular weight A beta fraction demonstrate that the form of the peptide active in plaque deposition is a monomer. In deliberately aged (>6 weeks) A beta solutions, a high molecular weight (>100 000 M-r) species was detectable in the SEC column void. In contrast to the active monomer, assembled A beta isolated from the column showed Little or no focal association with AD tissue. These studies establish that, at least in vitro, A beta exists as a monomer at physiological concentrations and that deposition of monomers, rather than of oligomeric A beta assemblies, mediates the growth of existing amyloid in human brain preparations.