Title:Inhibition of Tau Protein Aggregation by Rhodanine-based Compounds Solubilized Via Specific Formulation Additives to Improve Bioavailability and Cell Viability
Volume: 14
Issue: 7
Author(s): Eckhard Mandelkow*, Marcus Pickhardt, Carmen Lawatscheck and Hans G. Borner*
Affiliation:
- CAESAR Research Institute, Ludwig- Erhard-Allee, 2, 53175; Max-Planck-Institute for Metabolism Research, Gleuerlerstr. 50, 50931 Koln,Germany
- Department of Chemistry, Laboratory for Organic Synthesis of Functional Systems, Humboldt-Universität zu Berlin, Brook-Taylor-Str. 2, 12489 Berlin,Germany
Keywords:
Alzheimer's disease, bioconjugates, combinatorial screening, Tau protein, cell model, aggregation modulator, rhodanine.
Abstract: Background: Anti-aggregation drugs play an important role in therapeutic approaches for
Alzheimer’s disease. We have previously developed a number of compounds that are able to inhibit the
pathological aggregation of Tau protein. One common obstacle to application is the limited penetration
across the plasma membranes into cells, where Tau aggregation occurs in the cytosol. We used an inducible
N2a cell line which expresses the repeat domain of tau and develops tau aggregates.
Objective: Several peptide-polymer conjugates were synthesized to enhance the uptake of compounds
into cells and thus to improve their biomedical application. The aim of this study was to test whether the
peptide-inhibitor complexes still retain their inhibitory activity on Tau aggregation.
Method: We screened peptide sequences with high binding capacity to a subset of aggregation inhibitors
and identified them by fluorescence microscopy and MALDI MS/MS with regard to drug solubility and
effective complexion. To explore whether the synthesized complexes can influence the aggregation propensity
of Tau we performed in vitro and cellular assays. The effect on toxicity was investigated by
measuring apoptosis markers.
Results/Conclusion: The tested peptide-compound complexes show no decrease in the total Tau levels
but decreased ratios of soluble to pelletable Tau species. This indicates a conversion of insoluble Tau
oligomers into soluble forms which appear to be less toxic than the insoluble ones, as seen by a decrease
of apoptotic cells. Thus the peptide-compound complexes have a higher potency than the compounds
alone due to improved bioavailability of the drug.
