Tau Disaggregation by a CNS-Permeable Small Molecule Reduces Fibril and Oligomer Burden and Preserves Proteostasis and Behavior
- 1University of Southern California
Abstract
Pathological tau aggregates drive neuronal dysfunction in Alzheimer's 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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BibTeX
@misc{mostowfi2026disaggregation,
title = {{Tau Disaggregation by a CNS-Permeable Small Molecule Reduces Fibril and Oligomer Burden and Preserves Proteostasis and Behavior}},
author = {N. Mostowfi and R. Foreman and J. Wang and R. Khoury and A. Albanese and Q. L. Ma and W. Cohn and G. Petzinger and M. W. Jakowec and S. Ahmed and P. M. Seidler},
howpublished = {bioRxiv},
year = {2026},
month = jun,
doi = {10.64898/2026.06.09.731185},
url = {https://www.biorxiv.org/content/10.64898/2026.06.09.731185v2},
note = {CC BY},
}
RIS
TY - UNPB
TI - Tau Disaggregation by a CNS-Permeable Small Molecule Reduces Fibril and Oligomer Burden and Preserves Proteostasis and Behavior
AU - N. Mostowfi
AU - R. Foreman
AU - J. Wang
AU - R. Khoury
AU - A. Albanese
AU - Q. L. Ma
AU - W. Cohn
AU - G. Petzinger
AU - M. W. Jakowec
AU - S. Ahmed
AU - P. M. Seidler
PY - 2026
DA - 2026/06/09
PB - bioRxiv
DO - 10.64898/2026.06.09.731185
UR - https://www.biorxiv.org/content/10.64898/2026.06.09.731185v2
AB - Pathological tau aggregates drive neuronal dysfunction in Alzheimer's 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.
ER -