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Structure and dynamics of rare states of the Alzheimer's disease beta-amyloid peptide

Grant number: 13/05203-7
Support type:Scholarships abroad - Research
Effective date (Start): August 01, 2013
Effective date (End): July 31, 2014
Field of knowledge:Biological Sciences - Biophysics - Molecular Biophysics
Principal Investigator:Claudia Elisabeth Munte
Grantee:Claudia Elisabeth Munte
Host: Hans Robert Kalbitzer
Home Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
Local de pesquisa : University of Regensburg, Germany  

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. Initially soluble and with a helical tendency, the peptide assembles into oligomers, that are the primary toxic species, and finally forms the fibrils of the amyloid plaques with a beta-sheet conformation. 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 Abeta 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. In order to characterize structurally and thermodynamically these monomeric states, as well as understand its mode of interaction with the fibrils, we will perform, in this project, high pressure Nuclear Magnetic Resonance studies on Abeta peptide samples. For this purpose a recently microprocessor-controlled pressure jump unit will be used, that is able to introduce fast, strong pressure changes at any point in the pulse sequence. Additionally, rare states may be stabilised, allowing the characterisation of these intermediate states in the process of fibril formation. (AU)