Abstract
Amyloid-beta (Ab) proteins play an important role in a number of neurodegenerative diseases. Ab is found in senile plaques in brains of Alzeimer’s disease patients. The 42 residues of the monomer form dimers which stack to fibrils gaining several micrometers in length. Using Ab fibrils with 13C and 15N marker substitution, we developed an innovative approach to obtain insights to structural and chemical information of the protein. We deposited the modified protein fibrils to pre-sharped aluminium needles with >100-nm apex diameters and, using the position-sensitive mass-to-charge spectrometry technique of atom probe tomography, we acquired the chemically-resolved three dimensional information for every detected ion evaporated in small fragments from the protein. We also discuss the influence of experimental parameters such as pulse energy and pulse frequency of the used Laser beam which lead to differences in the size of the gained fragments, developing the capability of localising metal atom within Ab plaques.
Highlights
Amyloid-beta (Aβ) proteins are involved in a number of neurodegenerative diseases[1,2,3,4,5]
A large number of different structure models has been published over the last years[20], which have been discovered using different methods such as nuclear magnetic resonance (NMR)[21,22,23,24,25,26,27], atomic force microscopy (AFM)[28], cryo-EM29–33, scanning transmission electron microscopy (STEM)[34], x-ray crystallography[35,36,37] or a combination of those methods
The first aspect we address is the preparation of specimens appropriate for reproducible atom probe tomography (APT) analysis of amyloid-beta fibrils
Summary
Amyloid-beta (Aβ) proteins are involved in a number of neurodegenerative diseases[1,2,3,4,5]. Depending on the protocol used for in vitro studies, a wide range of different morphologies of the fibrils can be found For this reason, a large number of different structure models has been published over the last years[20], which have been discovered using different methods such as nuclear magnetic resonance (NMR)[21,22,23,24,25,26,27], atomic force microscopy (AFM)[28], cryo-EM29–33, scanning transmission electron microscopy (STEM)[34], x-ray crystallography[35,36,37] or a combination of those methods. APT which is well established in the materials sciences is the chemically most sensitive and highest resolving probing technique used to characterize microstructures and local compositions of complex metallic alloys and semiconductors down to near atomic scale[38,39]. In early designs of the atom probe microscope, single amino acids, nucleic acids and other polymers were successfully analyzed[57,58,59,60]
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