Structure and dynamics of excited rare states of the Alzheimer's disease beta-amyloid peptide studied by high-pressure NMR

• Grant number: 13/23758-6
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: February 01, 2014
• End date: January 31, 2015
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Claudia Elisabeth Munte
• Grantee: Italo Augusto Cavini
• Supervisor: Hans Robert Kalbitzer
• Host Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• Institution abroad: University of Regensburg, Germany
• Associated to the scholarship: 13/04433-9 - Structure and dynamics of excited rare states of the Alzheimer's disease beta-amyloid peptide studied by high-pressure NMR, BP.DD

Abstract

The main histological feature in Alzheimer's disease is the presence of amyloid plaques in patient's brain. The most abundant element of these plaques is the beta-amyloid peptide (Abeta). The peptide is produced through a proteolytic cleavage of the amyloid precursor protein (APP), resulting predominantly in the Abeta(1-40) and Abeta(1-42) forms, the latter being the more toxic species. Initially soluble, the peptide assembles into oligomers, that are the primary toxic species, and finally forms the fibrils of the amyloid plaques. While the peptide is assumed to have an alpha-helical conformation in a membrane environment and as part of APP, the peptide usually is assumed to have a predominantly unstructured conformation in solution that only transiently forms helical secondary structure elements. In contrast, the peptide has a beta-strand conformation within the amyloid fibrils of the senile plaques. The refolding of Abeta from a partially alpha-helical to a beta-strand conformation is assumed to be a critical step in pathogenesis of AD. The mechanism of this conversion is still unknown, its understanding is however crucial for the understanding of AD in general and the development of effective molecular therapies. Recent experiments performed on human Abeta(1-40) peptide samples suggest the existence of two different conformers of monomeric Abeta in solution - a compactly folded state and a partly unfolded state - coexisting with oligomers and fibrillar structures in a complex, dynamic equilibrium. Possibly only one of these states presents a high-affinity to existing fibrils, thereby promoting amyloid fibrillar formation. Despite the aggregation kinetics in different Abeta peptides may be distinct, similar monomeric states are expected in the Abeta(1-42) peptide. By characterizing thermodynamically this equilibrium and solving the structure of these two states using high pressure NMR techniques, their role for polymerization should be explored and may be helpful in drug-design for preventing the amyloid formation. (AU)