Abstract
Disrupted clearance of amyloid beta (Aβ) from the brain enhances its aggregation and formation of amyloid plaques in Alzheimer's disease. The most abundant protein constituent of circulating high-density lipoprotein (HDL) particles, apoA-I, readily crosses the blood-brain barrier from periphery circulation, exhibits low-micromolar binding affinity for soluble, neurotoxic forms of Aβ, and modulates Aβ aggregation and toxicity in vitro. Its highly conserved N-terminal sequence, (42)LNLKLLD(48) ('LN'), has been proposed as a binding region for Aβ. However, high-resolution structural characterisation of the mechanism of HDL-Aβ interaction is very difficult to attain. Molecular dynamics simulations were conducted to investigate for the first time the interaction of Aβ and the 'LN' segment of apoA-I. Favourable binding of Aβ by HDLs was found to be driven by hydrophobic and hydrogen-bonding interactions predominantly between the 'LN' segment of apoA-I and Aβ. Preferential binding of Aβ may proceed in small, protein-rich HDLs whereby solvent-exposed hydrophobic 'LN' segments of apoA-I interact specifically with Aβ, stabilising it on the HDL surface in a possibly non-amyloidogenic conformation, facilitating effective Aβ clearance. These findings rationalise the potentially therapeutic role of HDLs in reducing Aβ aggregation and toxicity, and of peptide mimics of the apoA-I interacting region in blocking Aβ aggregation.