Specific Domains of Aβ Facilitate Aggregation on and Association with Lipid Bilayers

A hallmark of Alzheimer's disease, a late-onset neurodegenerative disease, is the deposition of neuritic amyloid plaques composed of aggregated forms of the beta-amyloid peptide (A beta). A beta forms a variety of nanoscale, toxic aggregate species ranging from small oligomers to fibrils. A beta and many of its aggregate forms strongly interact with lipid membranes, which may represent an important step in several toxic mechanisms. Understanding the role that specific regions of A beta play in regulating its aggregation and interaction with lipid membranes may provide insights into the fundamental interaction between A beta and cellular surfaces. We investigated the interaction and aggregation of several A beta fragments (A beta(1-11), A beta(1-28), A beta(10-26), A beta(12-24), A beta(16-22), A beta(22-35), and A beta(1-40)) in the presence of supported model total brain lipid extract (TBLE) bilayers. These fragments represent a variety of chemically unique domains within A beta, that is, the extracellular domain, the central hydrophobic core, and the transmembrane domain. Using scanning probe techniques, we elucidated aggregate morphologies for these different A beta fragments in free solution and in the presence of TBLE bilayers. These fragments formed a variety of oligomeric and fibrillar aggregates under free solution conditions. Exposure to TBLE bilayers resulted in distinct aggregate morphologies compared to free solution and changes in bilayer stability dependent on the A beta sequence. A beta(10-26), A beta(16-22), A beta(22-36), and A beta(1-40) aggregated into a variety of distinct fibrillar aggregates and disrupted the bilayer structure, resulting in altered mechanical properties of the bilayer. A beta(1-11), A beta(1-28), and A beta(12-24) had minimal interaction with lipid membranes, forming only sparse oligomers. (C) 2013 Elsevier Ltd. All rights reserved.