Surface Effects on Mutant Aβ Aggregation

Abstract

Alzheimer's Disease (AD) is a late onset neurodegenerative disease, that is part of a group of diseases commonly classified as ‘protein misfolding’ diseases. Such diseases are defined by the rearrangement of specific proteins to non-native conformations, promoting the formation and deposition of toxic, nanoscale aggregates within tissues or cellular compartments. A pathological hallmark of AD is the development of neuritic amyloid plaques comprised predominantly of aggregated β-amyloid (Aβ). Aggregated Aβ has several forms, including spherical oligomers, annular aggregates, protofibrils, and amyloid fibrils. The precise mechanisms by which protein aggregates are toxic remains unclear. In kinetic and thermodynamic studies, conformational changes can be induced in proteins encountering surfaces and may play a role in nucleating and inducing aggregate formation. A series of point mutations, clustered around the 22 amino acid of Aβ, alter the aggregation kinetics of Aβ and are associated with familial forms of AD. These mutations alter the charge properties of Aβ, providing an excellent system to determine the role electrostatic surface interactions play in Aβ aggregation. We hypothesize that the altered charge of mutant Aβ peptides will influence their interactions with model surfaces, resulting in altered aggregation both kinetically and morphologically. To test this hypothesis, we used in situ atomic force microscopy to directly observe the aggregation of wild type (WT) and mutant Aβ peptides on mica under near physiological conditions. These results were compared with aggregates formed under free solution conditions. While the mutations altered Aβ aggregation kinetics under free solution conditions, the respective aggregate morphologies were indistinguishable. However, aggregation of Aβ WT and mutants on the mica surface differed not only kinetically but also morphologically. These studies provide insight into the valuable role surface chemistries may play in Aβ aggregation and the onset of familial AD.