Tau Disaggregation by a CNS-Permeable Small Molecule Reduces Fibril and Oligomer Burden and Preserves Proteostasis and Behavior
Mostowfi, N.; Foreman, R.; Wang, J.; Khoury, R.; Albanese, A.; Ma, Q. L.; Cohn, W.; Petzinger, G.; Jakowec, M. W.; Ahmed, S.; Seidler, P. M.
Show abstract
Pathological tau aggregates drive neuronal dysfunction in Alzheimers disease (AD) and related tauopathies, yet no approved therapy eliminates existing tau neurofibrillary tangles. Here, we report the development of a coumarin-based small-molecule series that disaggregates tau fibrils and oligomers through a stacking-driven co-assembly mechanism. Structure-activity relationships identified PT-13 as a lead compound that inhibits tau seeding by AD brain-derived matter and reduces aggregate burden measured across both fibrillar and oligomeric tau species. Mechanistic studies demonstrate that disaggregation does not generate soluble oligomeric intermediates, addressing a central question in the field. PT-13 is brain-penetrant and well tolerated in vivo. In a tauopathy mouse model, PT-13 treatment reduces tau pathology while preserving behavioral function, proteasome capacity, and synaptic integrity. These findings establish small-molecule tau disaggregation as a viable therapeutic strategy and provide a molecular framework for the design of aggregate-directed therapeutics in neurodegeneration.
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