ABS 073: Investigating the effects of tau acetylation mimics on tau microtubule dynamics

Aristotle Apostolakis ¹ and Ryan Kornblit ⁶ , Sarah Barker ³ ⁴ ⁵ ⁶ , Min-Kyoo Shin ³ ⁴ ⁵ ,Edwin Vázquez-Rosa ³ ⁴ ⁵, Andrew A. Pieper ³ ⁴ ⁵ ⁸

¹ Brown University (Health and Human Biology), Providence, RI
² Department of Neuroscience, School of Medicine, Case Western Reserve University, Cleveland, OH
³ Harrington Discovery Institute, University Hospitals, Cleveland, OH
⁴ Department of Psychiatry, University Hospitals, Cleveland, OH
⁵ Geriatric Research Education and Clinical Center (GRECC), Louis Stokes Cleveland VA Medical Center, Cleveland, OH
⁶ Department of Pathology, Case Western Reserve University, Cleveland, OH
⁷ Seoul National University, South Korea
⁸ Translational Therapeutics Core, Cleveland Alzheimer’s Disease Research Center, Cleveland, OH

Van Wickle (2025) Volume 1, ABS 073

Introduction: Nearly 7 million people in the U.S. suffer from dementia caused by Alzheimer’s Disease (AD). (Brookmeyer, 2018) Further, traumatic brain injury (TBI) is the greatest environmental risk factor for AD and is third overall behind genetics and aging. (Armstrong, 2019) Tau is a microtubule-binding protein that stabilizes neuronal microtubules, but in AD and TBI, tau undergoes post-translational modifications that lead to its loss of function and pathologic aggregation. Particularly, acetylated tau (ac-tau) is induced by TBI, is elevated early in AD pathology, and is highest in subjects with AD and a history of TBI. When acetylated at lysine residues, there is a change in local charge and polarity, interfering with tau’s normal microtubule binding. This loss of tau binding leads to microtubule collapse, protein aggregation, and neuronal dysfunction. (Bravo, 2024) The Pieper lab previously established the significance of tau acetylation using in vivo models. (Shin, 2021). To build on this foundation, we use an in vitro approach to explore tau acetylation’s impact on microtubule binding dynamics, using acetylation mimics. By simulating acetylation at lysine residues, we are able to explore the site-specific impact of these modifications on microtubule binding. Understanding such interactions could reveal mechanisms of tau pathology in neurodegeneration and point to therapeutic candidates to treat neurodegeneration.

Methods: Not published

Results: Not published

Discussion: Not published