Research

Every neurodegenerative disease exhibits regional brain vulnerability—pathology and the downstream toxicity affecting only selective brain regions but leaving others mostly intact. While the exact mechanisms are unclear, this phenomenon makes one speculate whether resistant brain regions possess certain factors that can protect against disease-related changes.

In Alzheimer’s disease (AD), the most common cause of dementia, the microtubule-associated protein tau aggregates and accumulates in selective brain regions like the cortex and hippocampus, while sparing other regions like the cerebellum and brainstem. We previously discovered that an understudied “big tau” splice isoform, more highly expressed in the resistant brain regions than in the vulnerable forebrain, can uniquely resist several pathological changes that affect regular tau isoforms. Can we benefit from big tau’s pathology-resisting properties to design new therapies for AD and other tauopathies? Utilizing cellular and genetic mouse models as well as postmortem human brain tissues, we will leverage our investigation into big tau pathophysiology as a novel framework to test our big question: whether we can capitalize on protective factors in the resistant brain regions to prevent neurodegenerative diseases.

Directions

Unlike regular tau isoforms, big tau is strikingly less prone to pathological changes. Is it feasible to develop treatment options for AD by utilizing big tau’s pathology-resisting properties? If so, will it have therapeutic applications beyond AD, given that there are more than 20 tauopathies? We will further explore this possibility by evaluating big tau’s protective capacity using cellular models and genetic mouse models.

Tau is encoded by the MAPT gene that undergoes extensive alternative splicing. Despite numerous past studies on tau splicing, the splicing regulations of big tau remain entirely unknown. Elucidating what splicing factors control big tau splicing will not only expand our knowledge of tau’s alternative splicing mechanisms and but also inform us how to design big tau-targeting therapeutic strategies.

Alternative splicing can expand the biological functions of a protein through its different isoforms with varying structures. Similarly, big tau’s highly distinct protein structure prompts us to think that it may play unique or additional physiological roles compared to regular tau. By further defining the biological functions of big tau, we will better understand the complete picture of tau pathophysiology, especially in a brain region-specific manner.