Amyloid βA4 of Alzheimer’s Disease: Structural Requirements for Folding and Aggregation

Abstract

Alzheimer’s disease is known to be the most common cause for a dementia in elderly people. Its specific pathological markers are extracellular protein depositions (i.e., amyloid) in the brain. The main component of this amyloid is “βA4,” a peptide comprising 43 amino acids. It is highly insoluble under physiological conditions and aggregates into dense clusters of filaments. We have used βA4 isolated from amyloid plaque cores as well as synthetic peptides corresponding to the natural βA4 sequence and analogue peptides to determine requirements for aggregation and the secondary structure of βA4. Infrared and circular dichroism spectroscopy of βA4 peptides showed that their secondary structure consists of a β-turn flanked by two strands of β-sheet. Purified βA4 peptides are soluble in water and are precipitated by the addition of salts, suggesting that aggregation depends upon a hydrophobic effect. Accordingly, the substitution of hydrophobic residues led to βA4 variants with reduced amyloidogenicity. Analogues showed lower β-sheet contents after solubilization in water and in the solid state. Although still forming filaments, some variants did not aggregate into the highly condensed depositions that are typical for amyloid; they could also be solubilized in 200 mM NaCl and KCl. When mixed with βA4 peptides bearing the natural sequence, two analogues could inhibit the formation of filaments in vitro. They may open the opportunity for a rational therapy of Alzheimer’s disease.