The role of big tau in preventing tau pathology

In Alzheimer’s disease (AD), selective brain regions such as the cortex and hippocampus are heavily affected by tau pathology and associated degeneration, but the cerebellum and brainstem mostly remain intact. Recently, I confirmed that the level of big tau, previously known as a major tau isoform in the peripheral nervous system (PNS), is significantly higher in the cerebellum and brainstem than in the forebrain. Big tau has a highly distinct protein structure with an extremely longer N-terminal region due to the inclusion of exons 4a and 6 of the MAPT gene, which suggests that big tau may behave differently compared to regular tau isoforms. Indeed, I discovered that big tau has several properties that can remarkably resist pathological changes that regular tau isoforms are subject to, such as aggregation and hyperphosphorylation. I also found that, compared to regular tau isoforms, big tau has an increased microtubule-binding capacity and degrades more rapidly due to enhanced ubiquitination, all pointing to big tau’s reduced susceptibility to AD-related pathological changes. My additional analysis of postmortem human brain tissues further suggested an intriguing link between an elevated level of pathology-resisting big tau and the absence of overt tau pathology in the cerebellum of AD patients. Based on these findings, I hypothesize that the structurally unique big tau plays an important role in protecting the brain from developing tau pathology. I will test this hypothesis by examining which features of big tau’s unique protein structure contribute to its resistance against pathological changes. Also, as a proof of concept, I will determine if big tau can truly suppress tau pathology in the brain using a novel mouse model that expresses big tau instead of endogenous mouse tau as well as neuronal culture. To ultimately inspire ideas of therapeutic strategies to up- regulate big tau, I will investigate splicing factors that can critically regulate big tau splicing. The proposed studies will not only extend our knowledge of the big tau isoform that has remained largely unexplored for several decades, but also suggest a novel idea that the biology of “PNS” big tau can be utilized to target tau pathology in the brain. Thus, findings from this work will provide critical insights into the complexity of tau pathophysiology through both conceptual and methodological innovation. The K22 award will provide me with the protected research time to conduct the proposed studies as a junior independent investigator and build the scientific foundation for future R01 applications from my lab. The completion of the proposed research will also help my lab become the leading research team that pioneers the investigation into the big tau pathophysiology. Ultimately, the K22 award will help me achieve my long-term research goal of finding effective ways to prevent and/or reverse pathological changes associated with disease proteins in AD and related dementia, which closely aligns with NIA’s mission. Project Number: 1K22AG095317-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Dah-eun Chung | Institution: RUTGERS, THE STATE UNIV OF N.J., PISCATAWAY, NJ | Award Amount: $225,256 | Activity Code: K22 | Study Section: Career Development for Established Investigators and Conference Grants Study Section[AGCD-4] View on NIH RePORTER: https://reporter.nih.gov/project-details/11213299