Alzheimer’s Disease Tau Consortium: Post-Translational Modifications and Tau Ultrastructure; Impact of Amyloid Beta on Tau In Vivo

Dr. Duff has long studied how changes in the tau protein contribute to Alzheimer’s disease and related disorders. In earlier work, she developed novel mouse models showing that different tau mutations can trigger disease through distinct biological routes. Some mutations lead to excessive chemical modification of tau, while others promote the formation of tau “seeds” that spread pathology through the brain. Building on this foundation, Dr. Duff and Dr. Frank are now using these models to understand how these pathways emerge very early in disease and how amyloid influences tau behavior, particularly in seed-driven forms of pathology.

They are pursuing this work through three complementary aims. First, they are cataloging all chemical modifications of tau in mouse models with and without amyloid pathology to determine how amyloid alters tau processing. Second, they are expanding this analysis to examine broader protein changes in the brain, allowing them to identify signaling pathways that distinguish hyperphosphorylation-driven tau pathology from seed-driven mechanisms. Third, they are using advanced imaging methods to visualize the three-dimensional structure of tau and amyloid at near-atomic resolution and comparing these structures to those found in human brain tissue.

During the previous funding period, the team made substantial progress. They showed that two tau mutations produce strikingly different disease profiles. One mutation led to extensive tau modification and early damage to synapses and neuronal structure, along with memory-related impairments, but did not generate tau seeds. The other mutation produced tau seeds that emerged with age, despite relatively less early modification of tau. Protein-level analyses reinforced these differences, revealing distinct cellular pathways affected in each model. The team also successfully isolated tau filaments from aged mice and confirmed their amyloid-like structure, establishing a strong foundation for detailed structural studies.

Together, these findings provide compelling evidence that tau pathology can arise through fundamentally different biological routes and position this project to define how amyloid selectively influences seed-driven tau pathology. This work has important implications for understanding disease progression and for designing therapies that are tailored to the specific mechanisms driving tau pathology in different patients.