The Binding of Apolipoprotein E to Oligomers and Fibrils of Amyloid-β Alters the Kinetics of Amyloid Aggregation

Deposition of amyloid-beta (A beta) in Alzheimer's disease (AD) is strongly correlated with the APOE genotype. However, the role of apolipoprotein E (apoE) in A beta aggregation has remained unclear. Here we have used different apoE preparations, such as recombinant protein or protein isolated from cultured astrocytes, to examine the effect of apoE on the aggregation of both A beta(1-40) and A beta(1-42). The kinetics of aggregation, measured by the loss of fluorescence of tetramethylrhodamine-labeled A beta, is shown to be dramatically slowed by the presence of substoichiometric concentrations of apoE. Using these concentrations, we conclude that apoE binds primarily to and affects the growth of oligomers that lead to the nuclei required for fibril growth. At higher apoE concentrations, the protein also binds to A beta fibrils, resulting in fibril stabilization and a slower rate of fibril growth. The aggregation of A beta(1-40) is dependent on the apoE isoform, being the most dramatic for apoE4 and less so for apoE3 and apoE2. Our results indicate that the detrimental role of apoE4 in AD could be related to apoE-induced stabilization of the soluble but cytotoxic oligomeric forms and intermediates of A beta, as well as fibril stabilization.