This project is focused on understanding how amyloid plaques drive the formation and spread of tau tangles, a key step in Alzheimer’s disease progression. The team is studying dystrophic neurites — swollen, damaged parts of neurons that form around amyloid plaques and are rich in abnormal tau. They propose that these damaged neurites act as early “hotspots” where tau pathology begins and spreads, triggered by contact between amyloid and neuronal membranes that harms neurons by altering calcium balance and activating enzymes that modify tau.
To test this idea, the team is pursuing three complementary aims. They are examining whether small amyloid fragments can directly trigger the formation of dystrophic neurites, identifying proteins that accumulate within these damaged structures, particularly those involved in tau modification, and determining whether dystrophic neurites serve as a source of tau seeds that can spread pathology through the brain.
During the first year of funding, the team made strong progress. They showed that their engineered antibodies bind tightly to amyloid plaques in a mouse model of Alzheimer’s, slow plaque growth, and significantly reduce the number of dystrophic neurites, especially around rapidly growing plaques. Higher levels of these antibodies also block additional amyloid from attaching to plaques, suggesting that blocking growth can limit further damage. In contrast, a similar engineered antibody did not reduce neuritic injury, likely because it does not bind plaques as effectively. In parallel, the group has begun purifying tau seeds from human Alzheimer’s brain tissue and is generating mice that carry both amyloid plaques and human tau, setting the stage for the next phase of experiments.
In the coming year, the team will directly test whether reducing dystrophic neurites can slow the spread of pathological tau. By comparing how human tau seeds propagate in mice treated with different engineered antibodies, they aim to determine whether reducing dystrophic neurites by blocking amyloid growth at plaque edges can protect neurons and interrupt the earliest steps of tau transmission. If successful, this work could reveal a new understanding of the link between amyloid plaques and tau-driven neurodegeneration, and a new strategy for breaking it.
