Rhodanine can Visualize Neurofibrillary Tangles

There is a high demand for the development of an imaging agent for neurofibrillary tangles (NFTs) detection in Alzheimer’s diagnosis.

A series of rhodanine-3-acetic acids was synthesized and evaluated for fluorescence imaging of NFTs in brain tissues of AD patients. Five out of seven probes have shown excellent binding affinity to NFTs over amyloid plaques in the Thiazine red R displacement assay.


However, the selectivity in this in vitro assay is not confirmed by the histopathological evaluation, which indicates significant differences in the binding sites in the assays.


Probe 6 showed binding affinity (IC₅₀ = 19 nM) to tau aggregates which is the highest among this series. Probes 2, 3, 4 and 5 display IC₅₀ values of lower than 100 nM to tau aggregates to displace Thiazine red R.


Evaluation of the cytotoxicity of these five probes with human liver carcinoma cells revealed that these compounds excert negligible cytotoxicity.

The in vivo studies with zebrafish embryos confirmed negligible cytotoxicity at 24 and 72 h post fertilization.

 

 

 

 

 

 

Cyanine Dyes Can Modulate tau Aggregation.

A structure−activity relationship for symmetrical cyanine inhibitors of human tau aggregation was elaborated using a filter trap assay.

 

Antagonist activity depended on cyanine heterocycle, polymethine bridge length, and the nature of meso- and N-substituents. One potent member of the series, 3,3′-diethyl-9-methylthiacarbocyanine iodide (compound 11), retained submicromolar potency and had calculated physical properties consistent with blood−brain barrier and cell membrane penetration.

 

 

Exposure of organotypic slices prepared from JNPL3 transgenic mice (which express human tau harboring the aggregation prone P301L tauopathy mutation) to compound 11 for one week revealed a biphasic dose response relationship. Low nanomolar concentrations decreased insoluble tau aggregates to half those observed in slices treated with vehicle alone.

 

 

In contrast, high concentrations (≥300 nM) augmented tau aggregation and produced abnormalities in tissue tubulin levels. These data suggest that certain symmetrical carbocyanine dyes can modulate tau aggregation in the slice biological model at concentrations well below those associated with toxicity.

 

 

http://pubs.acs.org/doi/abs/10.1021/jm900116d?prevSearch=N744&searchHistoryKey=

 

 

Tranilast Binds to Aβ Monomers and Promotes Aβ Fibrillation

AD may be a potential complication for tranilast usage in elderly patients.

The antiallergy and potential anticancer drug tranilast has been patented for treating Alzheimer’s disease (AD), in which amyloid β-protein (Aβ) plays a key pathogenic role.

 

 

We used solution NMR to determine that tranilast binds to Aβ40 monomers with 300 μM affinity.

 

Remarkably, tranilast increases Aβ40 fibrillation more than 20-fold in the thioflavin T assay at a 1:1 molar ratio, as well as significantly reducing the lag time.

 

 

Tranilast likely promotes fibrillation by shifting Aβ monomer conformations to those capable of seed formation and fibril elongation. Molecular docking results qualitatively agree with NMR chemical shift perturbation, which together indicate that hydrophobic interactions are the major driving force of the Aβ–tranilast interaction.

 

 

These data suggest that AD may be a potential complication for tranilast usage in elderly patients.

http://pubs.acs.org/doi/abs/10.1021/bi400426t?prevSearch=tranilast&searchHistoryKey=