Surfaces modulate β-amyloid peptide aggregation associated with Alzheimer's disease.

• Main Author: Yates, Elizabeth Anne
• Format: Text
• Language: unknown
• Published: The Research Repository @ WVU 2013
• Subjects: Arctic
• Online Access: https://researchrepository.wvu.edu/etd/10076; https://researchrepository.wvu.edu/cgi/viewcontent.cgi?article=11073&context=etd

A hallmark of Alzheimer's disease, a late onset neurodegenerative disease, is the presence of neuritic amyloid plaques deposited within the brain composed of β-amyloid (Aβ) peptide aggregates. Aβ can aggregate into a variety of polymorphic aggregate structures under different chemical environments, specifically affected by the presence of differing surfaces. There are several point mutations clustered around the central hydrophobic core of Aβ (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 to typical Alzheimer's disease pathology with both plaques and tangles. To determine how these different point mutations, which modify both peptide charge and hydrophobic character, altered Aβ aggregation and morphology under free solution conditions, at an anionic surface/liquid interface and in the presence of supported lipid bilayers, atomic force microscopy was used. Additionally, the non-native conformation of Aβ leads to the formation 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 Aβ regulate its aggregation in the absence and presence of surfaces can provide insight into the fundamental interaction of Aβ with cellular surfaces. Specific fragments of Aβ (Aβ1-11, Aβ 1-28, Aβ10-26, Aβ12-24, Aβ 16-22, Aβ22-35, and Aβ1-40), represent a variety of chemically unique regions along Aβ, i.e., the extracellular domain, the central hydrophobic core, and transmembrane domain. Using various scanning probe microscopic techniques, the interaction of these Aβ sequences with lipid membranes was shown to alter aggregate morphology and induce mechanical changes of lipid bilayers compared to aggregates formed under free solution conditions. Lastly, in order to determine how chemical environment can lead to distinct polymorph fibril formation influencing disease pathology, various peptide preparation and fibril growth conditions of Aβ were studied in free solution and with a model lipid membrane.