Specific domains of Aβ facilitate aggregation on and association with lipid bilayers

Abstract

A hallmark of Alzheimer's disease, a late-onset neurodegenerative disease, is the deposition of neuritic amyloid plaques composed of aggregated forms of the β-amyloid peptide (Aβ). Aβ forms a variety of nanoscale, toxic aggregate species ranging from small oligomers to fibrils. Aβ 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 Aβ play in regulating its aggregation and interaction with lipid membranes may provide insights into the fundamental interaction between Aβ and cellular surfaces. We investigated the interaction and aggregation of several Aβ fragments (Aβ1-11, Aβ1-28, Aβ10-26, Aβ12-24, Aβ16-22, Aβ22-35, and Aβ1-40) in the presence of supported model total brain lipid extract (TBLE) bilayers. These fragments represent a variety of chemically unique domains within Aβ, that is, the extracellular domain, the central hydrophobic core, and the transmembrane domain. Using scanning probe techniques, we elucidated aggregate morphologies for these different Aβ 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 Aβ sequence. Aβ10-26, Aβ16-22, Aβ22-35, and Aβ1-40 aggregated into a variety of distinct fibrillar aggregates and disrupted the bilayer structure, resulting in altered mechanical properties of the bilayer. Aβ1-11, Aβ1-28, and Aβ12-24 had minimal interaction with lipid membranes, forming only sparse oligomers.