118
Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery Poster Session II
64-POS
Board 17
Assembly of the Alzheimer's Disease Associated Amyloid beta Peptide during the Lag
Phase of Fibril Formation
Luitgard Nagel-Steger
1,2
, Oleksandr Brener
1,2
, Martin Wolff
1,2
, Dmitry Unuchek
4
, Bo Zhang
1,3
,
Dieter Willbold
1,2
.
1
RC-Juelich, Juelich, Germany,
2
Heinrich-Heine-University, Duesseldorf, Germany,
3
RC-
Juelich, Juelich, Germany,
4
Moscow Institute of Physics and Technology, Dolgoprudniy,
Russian Federation.
One of the most important targets in Alzheimer’s therapy is still the proteolytic fragment of the
amyloid precursor protein, called amyloid beta peptide. This fragment is between 39 and 43
amino acids long and is marked by its high tendency to self-associate. The self-assembly, which
finally leads to the formation of amyloid fibrils, has to proceed via an unknown number of
intermediate structures, among which a more potent therapeutic target than the fibril is
suspected. Additionally other pathways might exist, leading also to the formation of small
oligomeric species, which might as well as the on-pathway species be responsible for the toxic
effects the Abeta peptide exerts on neuronal cells.
OBJECTIVE: Identification and characterization of early, distinct assemblies of the amyloid beta
peptide in solution regarding size, shape and fraction.
METHODS: Sedimentation velocity centrifugation, complemented by density gradient
centrifugation, atomic force microscopy, fluorescence assays and CD-spectroscopy were utilized.
RESULTS: Aside from the monomeric peptide a set of globular assemblies have been identified
in solutions which were still in the lag phase of amyloid formation. These species had increased
beta sheet content, were negative for thioflavin T staining and exhibited a stronger cytotoxicity
than amyloid fibrils at the same mg/ml concentrations.
CONCLUSIONS: By sedimentation velocity centrifugation size-, shape information and fraction
of distinct oligomeric species of the amyloid beta peptide could be retrieved simultaneously from
the same sample solution.
