The Interaction between apolipoprotein E and Alzheimer's amyloid β-peptide is dependent on β-peptide conformation

Abstract

An important feature of Alzheimer's disease (AD) is the cerebral deposition of amyloid. The main component of the amyloid is a 39-44-amino acid residue protein called amyloid β (Aβ), which also exists as a normal protein in biological fluids, known as soluble Aβ. A major risk factor for late-onset AD is the inheritance of the apolipoprotein (apo) E4 isotype of apoE. How apoE is involved in the pathogenesis of AD is unclear; however, evidence exists for a direct apoE/Aβ interaction. We and others have shown that apoE copurifies with Aβ from AD amyloid plaques and that under certain in vitro conditions apoE promotes a β-sheet structure in Aβ peptides. Currently we document the high affinity binding of Aβ peptides to both human recombinant apoE3 and -E4 with a KD of 20 nM. This interaction is greatly influenced by the conformational state of the Aβ peptide used. Furthermore, we show that the fibril modulating effect of apoE is also influenced by the initial secondary structure of the Aβ peptide. The preferential binding of apoE to Aβ peptides with a β-sheet conformation can in part explain the copurification of Aβ and apoE from AD amyloid plaques.