Boris Schmidt on Dyeing Worms for an Extra-Long, Healthy Lifespan?

COMMENT The remarkable life-extending activity of the high curcumin concentrations requires additional experimental data for evaluation. Aqueous solutions of curcumin are not stable over three days (see decreased toxicity in zebrafish embryo); there are even ...

Boris Schmidt on Resveratrol selectively remodels soluble oligomers and fibrils of amyloid Abeta into off-pathway conformers.

COMMENT Resveratrol was reported in 8,000 publications and 7,332 biological studies so far. Most cases reported an activity in the range of 1-50 mMol for the inhibition of enzymes and protein-protein interaction. What is the underlying principle for this ...

Boris Schmidt on Nonspecificity of binding of gamma-secretase modulators to the amyloid precursor protein.

COMMENT This is one of the most interesting papers on γ-secretase modulation I have seen in a while. Applying sophisticated NMR experiments and subtle detergent/C99 preparations, it describes effects on NSAID aggregation at high concentrations. The paper ...

Boris Schmidt on Modulation of gamma-secretase specificity using small molecule allosteric inhibitors.

COMMENT This is an interesting paper. The lead structure, hydroxycoumarin, is rapidly accessible and thus quite well known; SciFinder lists 560 close analogues covering 193 publications. The compound class is a frequent hitter in high throughput screening assays. ...

Boris Schmidt on Selective modulation of amyloid-beta peptide degradation by flurbiprofen, fenofibrate, and related compounds regulates Abeta levels.

COMMENT The results are noteworthy. However, how do these findings relate to the activity of γ-secretase modulators in reconstituted assays? Moreover, the statement that "flurbiprofen remains one of the most potent SALAs reported" is simply wrong. At an ...

Boris Schmidt on Design, synthesis and structure-activity relationships of 1,3,4-oxadiazole derivatives as novel inhibitors of glycogen synthase kinase-3beta.

COMMENT Although these inhibitors bind to the ATP site, the novel structural moiety displays impressing selectivity over other kinases. Schmidt_Boris 0 ...

Boris Schmidt on Chicago: Out of the Blue—A Tau-based Treatment for AD?

COMMENT Is methylene blue, a rather old drug, finally on the way to becoming a cure? Speculation and criticism come by the dozen. The blue urine may enhance placebo effects. Therefore it would be worthwhile to investigate human brain penetration before we start ...

Boris Schmidt on Enhanced clearance of Abeta in brain by sustaining the plasmin proteolysis cascade.

COMMENT The Aβ lowering in vivo activity may be due to the very high structural analogy of PAZ-417 to indomethacin and thus γ-secretase modulation. The additional phenyl group is tolerated by γ-secretase (see flurbiprofen). Therefore, the observed effect (at the ...

Boris Schmidt on EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers.

COMMENT This is interesting news for EGCG indeed. The authors already mention the caveats: poor oral availability, poor brain penetration. Moreover, EGCG displays promiscuous activity (BACE, 20 S proteasome) on many targets. The small therapeutic window imposes ...

Boris Schmidt on Platinum-based inhibitors of amyloid-beta as therapeutic agents for Alzheimer's disease.

COMMENT This is novel and interesting work; however, it raises questions concerning approved AD targets and recent progress in the understanding of DNA repair. Clioquinol, which was advanced for AD therapy by some of the authors, failed for metal chelation ...

Boris Schmidt on Valsartan lowers brain beta-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease.

COMMENT The analysis of the pleitropic effects of Valsartan is striking. The potential of a class effect amongst the sartan drug family should be investigated further. Several of the inactive compounds in the first assay round are not the real Valsartan competing ...

Boris Schmidt on Expression profiling in APP23 mouse brain: inhibition of Abeta amyloidosis and inflammation in response to LXR agonist treatment.

COMMENT Riddell et al. reported that TO-901317, a liver X receptor (LXR) agonist, at brain concentrations of 5 μMol/l reduced Aβ42 levels in the Tg2576 mouse model and reversed the contextual memory deficit in these mice. They came to the conclusion that TO ...

Boris Schmidt on Presenilin Loss of Function—Plan B for AD?

COMMENT Shen and Kelleher's PNAS paper raises interesting questions, and it compiles data in favor of provocative answers. But what incontrovertible data did the authors ignore? I agree with the comments made by Christian Czech. The pharmacology of γ ...

Boris Schmidt on Intra- or intercomplex binding to the gamma-secretase enzyme. A model to differentiate inhibitor classes.

COMMENT Finally, a very sound analysis provides a model to explain the strange pharmacology of gamma-secretase modulators and inhibitors. It can even incorporate the previous report on partial active site knock-outs. Schmidt_Boris 0 ...

Boris Schmidt on Concentration-dependent modulation of amyloid-beta in vivo and in vitro using the gamma-secretase inhibitor, LY-450139.

COMMENT LY-450139 did not have an easy start. There was always the issue of Notch selectivity. One serious case of gastrointestinal bleeding occured in the phase Ib/IIa trials, but that was assigned to Barrett oesephagus and not to impaired Notch signaling. The ...