- By adapting a standard tau aggregation biosensor assay, researchers at Massachusetts General Hospital examined the kinetics of tau aggregation across post-mortem brain tissue samples from patients with sporadic Alzheimer's disease
- Tau aggregation followed a consistent pattern in all cases, with a lag phase, a growth phase and a plateau phase; the lag and plateau phases were strongly dependent on the amount of tau seed initially added
- The slope of the growth phase correlated with morphological differences in the tau aggregates, which may reflect underlying differences in tau seed structure
- Treatment with anti-tau antibodies reduced the plateau phase as well as the size of resulting aggregates
- The results confirm the researchers' previous report of heterogeneity in the characteristics of tau among individuals with Alzheimer's disease and reinforce their earlier conclusion that individualized anti-tau immunotherapy might someday be possible
Massachusetts General Hospital previously observed in individuals with sporadic Alzheimer's disease (AD) that tau is heterogeneous in its biochemical properties and its ability to initiate aggregation, a hallmark of the disease. In Nature Medicine, they also reported that more aggressive seeding correlated with a more aggressive clinical course.
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The team reasoned that tau aggregation involves four steps: uptake of tau seeds by cells, delivery of the seeds to the cytoplasm, interaction of the seeds with endogenous tau protein and formation of the aggregate.
Expanding on the earlier research, Bradley T. Hyman, MD, PhD, director of the Alzheimer's Disease Research Unit at the MassGeneral Institute for Neurodegenerative Disease (MIND), and Simon Dujardin, PhD, instructor in the Department of Neurology, and colleagues recently determined that the kinetics of each step differ between patients with Alzheimer's disease. Published in Brain Communications, their experiments confirm and extend the concept of heterogeneity in the characteristics of proteopathic tau seeds in these individuals.
The research team tagged cells overexpressing tau with a fluorescent protein and incubated them with post-mortem brain tissue from patients with AD. They adapted a standard tau aggregation biosensor assay so they could continuously monitor the cells using an in vitro imaging chamber.
Thus, they were able to directly observe the kinetics of tau aggregation, focusing on the rate and extent to which different tau seeds generated aggregates.
- Tau aggregation followed a consistent pattern in all cases, with a lag phase, a growth phase and a plateau phase
- The length of the lag phase and the magnitude of the plateau phase were both strongly associated with the amount of seeding-competent tau, which differed among patients
- The slope of the growth phase was not correlated with the amount of seed, but rather with the size and circularity of tau aggregates, which may reflect dependence on the initial seed structure
- Treatment with anti-tau antibodies reduced the plateau phase as well as the size and circularity of resulting aggregates
These experiments uncovered some of the intracellular molecular processes that give rise to a characteristic tau seeding shape and reveal more about what influences tau aggregation. The kinetics assay will be useful in future studies that characterize changes over time in tau aggregation and the cellular processes that may underlie those changes.
Intriguingly, the study findings reinforce the research team's earlier conclusion that individualized anti-tau immunotherapy might someday be possible.
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