Hansmann, U. H. E. — Page 2

bioRxiv2018

The Effect of Retro-inverse D-Amino Acid Aβ-peptides on Aβ- Fibril Formation

Peptides build from D-amino acids resist enzymatic degradation. The resulting extended time of biological activity makes them prime candidates for the development of pharmaceuticals. Of special interest are D-retro inverso (DRI)peptides where a reversed sequence of D-amino acids leads to molecules with almost the same structure, stability and bioactivity as the parent L-peptides but increased resistance to proteolytic degradation. Here, we study the effect of DRI-A{beta}40 and DRI-A{beta}42 peptides on fibril formation. Using molecular dynamics simulations, we compare the stability of typical amyloid fibril models with such where the L-peptides are replaced by DRI-A{beta}40 and DRI-A{beta}42 peptides. We then explore the likelihood for cross fibrilization of A{beta} L-and DRI-peptides by investigating how presence of DRI peptides alters elongation and stability of L-A{beta}-fibrils. Our data suggest that full-length DRI-peptides may enhance the fibril formation and decrease the ratio of soluble toxic A{beta} oligomers, pointing out a potential for D-amino-acid-based drug design targeting Alzheimers disease.

biochemistry↗

bioRxiv2018

Large Fatty Acid-derived Aβ42 oligomers Form Ring-like Assemblies

As the primary toxic species in the etiology of Alzheimer disease (AD) are low molecular weight oligomers of A{beta}, it is crucial to understand the structure of A{beta} oligomers for gaining molecular insights into AD pathology. We have earlier demonstrated that in the presence of fatty acids A{beta}42 peptides assemble as 12-24mer oligomers. These Large Fatty Acid-derived Oligomers (LFAOs) exist predominantly as 12mers at low, and as 24mers at high concentrations. The 12mers are more neurotoxic than the 24mers and undergo self-replication, while the latter propagate to morphologically distinct fibrils with succinct pathological consequences. In order to glean into their functional differences and similarities, we have determined their structures in greater detail by combining molecular dynamic simulations with biophysical measurements. We conjecture that the LFAO are made of A{beta} units in an S-shaped conformation, with the 12mers forming a double-layered hexamer ring (6 x 2) while the structure of 24mers is a double-layered dodecamer ring (12 x 2). A closer inspection of the (6 x 2) and (12 x 2) structures reveals a concentration and pH dependent molecular reorganization in the assembly of 12 to 24mers, that seems to be the underlying mechanism for the observed biophysical and cellular properties of LFAOs.

biophysics↗