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Commun Biol. 2019 Mar 22;2:112. doi: 10.1038/s42003-019-0359-9. eCollection 2019.

Activated cofilin exacerbates tau pathology by impairing tau-mediated microtubule dynamics.

Author information

1
1USF Health Byrd Alzheimer's Institute, University of South Florida, Morsani College of Medicine, Tampa, FL 33613 USA.
2
2Department of Molecular Pharmacology and Physiology, University of South Florida, Morsani College of Medicine, Tampa, FL 33613 USA.
3
3Department of Molecular Medicine, University of South Florida, Morsani College of Medicine, Tampa, FL 33613 USA.
4
James A. Haley Veteran's Administration Hospital, Tampa, FL 33612 USA.

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. While the accumulation of Aβ is pivotal to the etiology of AD, both the microtubule-associated protein tau (MAPT) and the F-actin severing protein cofilin are necessary for the deleterious effects of Aβ. However, the molecular link between tau and cofilin remains unclear. In this study, we found that cofilin competes with tau for direct microtubule binding in vitro, in cells, and in vivo, which inhibits tau-induced microtubule assembly. Genetic reduction of cofilin mitigates tauopathy and synaptic defects in Tau-P301S mice and movement deficits in tau transgenic C. elegans. The pathogenic effects of cofilin are selectively mediated by activated cofilin, as active but not inactive cofilin selectively interacts with tubulin, destabilizes microtubules, and promotes tauopathy. These results therefore indicate that activated cofilin plays an essential intermediary role in neurotoxic signaling that promotes tauopathy.

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