Screening for inhibitors of tau polymerization.
The histopathological diagnosis of Alzheimer's disease relies on two kinds of proteinaceous aggregates: the extracellular plaques built from filaments of the Abeta-peptide and the intracellular tangles consisting of tau polymerized into Paired Helical Filaments (PHFs). The order of aggregation events is still under debate, but it is well accepted that tau-related changes have an important impact on the viability of neurons. In neurons, early morphological changes are seen in axons which begin to loose and retract synapses. This process is accompanied by an increase of aggregated tau protein. Thus the prevention of tau aggregation seems to be a valuable target for therapy of Alzheimer's disease. Here we present a screening procedure by which we identified inhibitors of tau polymerization. In the primary screen we used a thioflavin-S based assay which detects PHF formation in solution. These initial hits were further analyzed for their capacity to depolymerize preformed PHFs. These results were confirmed by several secondary assays (tryptophan fluorescence, pelleting, filter trapping and electron microscopy). By this approach it is possible to identify small molecule compounds which prevent or reverse the aggregation of tau and thereby might improve the viability of neurons in a therapeutic approach.
Pickhardt
Marcus
M
Max-Planck-Unit for Structural Molecular Biology, Notkestrasse 85, 22607 Hamburg, Germany.
von Bergen
Martin
M
Gazova
Zuzana
Z
Hascher
Antje
A
Biernat
Jacek
J
Mandelkow
Eva-Maria
EM
Mandelkow
Eckhard
E
D000544:Alzheimer Disease / Q000188:drug therapy / Q000473:pathology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D016875:tau Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D018696:Neuroprotective Agents; D016875:tau Proteins