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2023 Alzheimer's Association Research Grant (AARG)

Determining the Impact of Tau Aggregates on Neuron Loss with 2P Imaging

Can a new method of visualizing tau protein in the brain help reveal how tau clumps promote disease-related nerve cell death?

Rachel Bennett, Ph.D.
Massachusetts General Hospital
Boston, MA - United States


The brain cell’s nutrient and energy transport system is organized in parallel strands like railroad tracks. These tracks allow nutrients to travel across the cell, delivering key materials throughout the cell, providing them with energy and keeping them healthy. Tau protein normally helps keep the tracks straight. However, in Alzheimer’s and other brain diseases, the shape of tau becomes modified or “misfolded,” a change that may lead to tau accumulation. In the early stages of tau accumulation, the proteins form small protein clumps called oligomers. These oligomers then continue to accumulate into tau tangles (a hallmark of many brain diseases). Scientists, however, are uncertain whether oligomers or tangles promote the most nerve cell damage in such diseases. 

In initial research with mice engineered to develop tau, Dr. Rachel Bennett and colleagues studied the role of tau tangles in the health and survival of nerve cells. They found that only about 5% of neurons that died over a 4-week period contained tau tangles. Other evidence showed that an anti-tau therapy (a therapy that can use the body’s own immune system to lower the accumulation of abnormal tau) halted both nerve cell loss and the production of newly-misfolded tau molecules, but it did not clear previously-formed tau tangles. Collectively, these results indicate that tau oligomers may play a more important role than tangles in disease-related brain damage.

Research Plan

Dr. Bennett and colleagues will now conduct a larger study of tau and brain cell health in mice engineered to develop misfolded tau. They will visualize and monitor tau activity with a novel technique called “2P” imaging. This method involves a fluorescent dye that can “highlight” individual tau molecules, oligomers and tangles in the mouse brains. First, the researchers will examine how tau is processed – and how tau oligomers may form – in young mice that have yet to develop tau tangles. Next, Dr. Bennett and team will assess how tau oligomers and other early-stage tau aggregates may impact nerve cell health in the mice over a two-month period. Finally, the investigators will inject portions of disease-related human tau into the brains of mice and assess, over a two-month period, how these tau “seeds” promote tau clumps and affect brain cell survival.    


The results of this project could shed new light on the role of early-stage tau clumps in Alzheimer’s and other brain disorders. They could also lead to novel therapies against tau that prevent brain cell loss. 

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