Qi C, Lövestam S, Murzin AG, Peak-Chew S, Franco C, Bogdani M, Latimer C, Murrell JR, Cullinane PW, Jaunmuktane Z, Bird TD, Ghetti B, Scheres SH, Goedert M. Tau filaments with the Alzheimer fold in human MAPT mutants V337M and R406W. Nat Struct Mol Biol. 2025 Mar 5; Epub 2025 Mar 5 PubMed.
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UCB Pharma Belgium
It is important to have structural insights on tau in the different tauopathies and to recognize the differences. Looking at this from a drug discovery perspective, the difference in folds will matter most where molecules need to directly bind to the final folded tau form—a molecule that binds to one form may not bind equally well to a different one. For example, this can explain in part why some tau PET tracers that are good enough for AD are not good enough for PSP. In contrast, for molecules that never interact with different tau folds, such as therapeutics aiming at lowering expression of tau or degrading all tau monomers, the final tau pathology fold should not be critical. For antibody therapeutics, it should depend on whether the antibody in question is designed to specifically take out one of the fold forms and whether these fold forms are actually present in the material that spreads through the brain, which is currently unknown.…More
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