Specific domains of Aß 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 ß-amyloid peptide (Aß). Aß forms a variety of nanoscale, toxic aggregate species ranging from small oligomers to fibrils. Aß 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 Aß play in regulating its aggregation and interaction with lipid membranes may provide insights into the fundamental interaction between Aß and cellular surfaces. We investigated the interaction and aggregation of several Aß fragments (Aß1-11, Aß1-28, Aß10-26, Aß12-24, Aß16-22, Aß22-35, and Aß1-40) in the presence of supported model total brain lipid extract (TBLE) bilayers. These fragments represent a variety of chemically unique domains within Aß, that is, the extracellular domain, the central hydrophobic core, and the transmembrane domain. Using scanning probe techniques, we elucidated aggregate morphologies for these different Aß 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 Aß sequence. Aß10-26, Aß16-22, Aß22-35, and Aß1-40 aggregated into a variety of distinct fibrillar aggregates and disrupted the bilayer structure, resulting in altered mechanical properties of the bilayer. Aß1-11, Aß1-28, and Aß12-24 had minimal interaction with lipid membranes, forming only sparse oligomers.

Point mutations in Aß induce polymorphic aggregates at liquid/solid interfaces.

A pathological hallmark of Alzheimer's disease (AD), a late onset neurodegenerative disease, is the development of neuritic amyloid plaques, composed predominantly of aggregates of the ß-amyloid (Aß) peptide. It has been demonstrated that Aß can aggregate into a variety of polymorphic aggregate structures under different chemical environments, and a potentially important environmental factor in dictating aggregate structure is the presence of surfaces. There are also several mutations clustered around the central hydrophobic core of Aß (E22G Arctic mutation, E22K Italian mutation, D23N Iowa mutation, and A21G Flemish mutation). These mutations are associated with hereditary diseases ranging from almost pure cerebral amyloid angiopathy (CAA) to typical Alzheimer's disease pathology. The goal of this study was to determine how these mutations influence the morphology of Aß aggregates under free solution conditions and at an anionic surface/liquid interface. While the rate of formation of specific aggregates was altered by mutations in Aß under free solution conditions, the respective aggregate morphologies were similar. However, aggregation occurring directly on a negatively charged mica surface resulted in distinct aggregate morphologies formed by different mutant forms of Aß. These studies provide insight into the potential role anionic surfaces play in dictating the formation of Aß polymorphic aggregate structures.