Background: Self-assembly of the amyloid-beta peptide (Abeta) has been implicated in the pathogenesis of Alzheimer's disease (AD). As a result, synthetic molecules capable of inhibiting Abeta self-assembly could serve as therapeutic agents and endogenous molecules that modulate Abeta self-assembly may influence disease progression. However, increasing evidence implicating a principal pathogenic role for small soluble Abeta aggregates warns that inhibition at intermediate stages of Abeta self-assembly may prove detrimental. Here, we explore the inhibition of Abeta1-40 self-assembly by serum albumin, the most abundant plasma protein, and the influence of this inhibition on Abeta1-40 activation of endothelial cells for monocyte adhesion.
Results: It is demonstrated that serum albumin is capable of inhibiting in a dose-dependent manner both the formation of Abeta1-40 aggregates from monomeric peptide and the ongoing growth of Abeta1-40 fibrils. Inhibition of fibrillar Abeta1-40 aggregate growth is observed at substoichiometric concentrations, suggesting that serum albumin recognizes aggregated forms of the peptide to prevent monomer addition. Inhibition of Abeta1-40 monomer aggregation is observed down to stoichiometric ratios with partial inhibition leading to an increase in the population of small soluble aggregates. Such partial inhibition of Abeta1-40 aggregation leads to an increase in the ability of resulting aggregates to activate endothelial cells for adhesion of monocytes. In contrast, Abeta1-40 activation of endothelial cells for monocyte adhesion is reduced when more complete inhibition is observed.
Conclusion: These results demonstrate that inhibitors of Abeta self-assembly have the potential to trap small soluble aggregates resulting in an elevation rather than a reduction of cellular responses. These findings provide further support that small soluble aggregates possess high levels of physiological activity and underscore the importance of resolving the effect of Abeta aggregation inhibitors on aggregate size.