Specific Sequences within Beta-Amyloid Mediate Aggregation Associated with Lipid Membranes

A hallmark of Alzheimer's disease (AD), a late onset neurodegenerative disease, is the presence of neuritic amyloid plaques deposited within the brain comprised of beta-amyloid (As) peptide aggregates. As forms a variety of nanoscale, toxic aggregates which have been shown to strongly interact with supported lipid bilayers, which may represent a key step in potential toxic mechanisms. Understanding how specific regions of As regulate its aggregation in the absence and presence of surfaces can provide insight into the fundamental interaction of As with cellular surfaces. We investigated the interaction of specific fragments of As (As1-11, As1-28, Abeta10-26, As12-24, As16-22, As22-35, and As1-40) with lipid membranes. These sequences represent a variety of chemically unique regions along As, i.e., the extracellular domain, the central hydrophobic core, and transmembrane domain. We determined how these As sequences alter aggregate morphology and induce mechanical changes of lipid bilayers using various scanning probe microscopic techniques, and compared these aggregates with those formed under free solution conditions. In free solution, oligomer and fibrillar aggregate species were formed with varied rate of formation and morphology, i.e. smaller fragments (As1-11, As12-24, As16-22, and As22-35) formed smaller oligomers, and shorter, less rigid fibrils. Interaction with model lipid bilayers resulted in distinct aggregates and changes in bilayer stability dependent on the As fragment. As10-26, As16-22, As22-35, and As1-40 caused disruption of the lipid bilayer structure upon exposure and resulted in a variety of distinct fibrillar aggregates. These interactions were associated with altered mechanical properties of the lipid bilayer. Conversely, As1-11, As1-28, and As12-24 had minimal interaction with a lipid membrane, forming only oligomers. These studies illustrate the potential role of specific amino acid sequences within As on aggregation and interactions with lipid membranes.