Biophysical Studies of the Amyloid Beta Peptide Involved in Alzheimer's Disease

Abstract

The amyloid β (Aβ) peptide consists of 39-43 residues and is the major component of the neuritic plaques in the brains of Alzheimer's disease (AD) patients. It is possible to study the peptide self-aggregation process (“amyloid formation”, structures as well as kinetics) using biophysical methods such as NMR, fluorescence or CD spectroscopy. The interactions of Aβ with small molecules or metal ions that modulate the aggregation process can be studied in semi-stationary states. Kinetic effects on the aggregation process can be followed by fluorescence, after labeling the amyloid material rich in β-structure by the amyloid-specific dye Thioflavin T (ThT). The β-hairpin structure of the peptide with a mainly unstructured N-terminus appears to be a basic unit for formation of the higher order amyloid structures associated with insoluble fibrils. Fluorescence Correlation Spectroscopy (FCS) shows the heterogeneity of the aggregation process of ThT-labeled Aβ, in terms of time dependent amyloid aggregate sizes on a single particle level. Modulation of the amyloid formation by Zn(II) or Cu(II) ions binding to specific residues in the N-terminus of the Aβ peptide can be followed by FCS, showing changes in structures as well as kinetics for the aggregation process. Understanding the basic properties and reactions of the major participants in the chemical processes leading to AD gives a firm basis for the future development of agents that may be used in therapies against AD.