Alzheimer’s: How do tau tangles grow?

New research in the Journal of Biological Chemistry breaks down the process through which tau tangles grow as long as they do. The findings may lead to new therapies that target the formation of tau aggregates in Alzheimer’s disease.
scientist looking at something through microscope
Researchers knew that Alzheimer’s-related tau aggregates consisted of a small number of long tau fibrils.

One of the hallmarks of Alzheimer’s disease is the so-called tau tangles. Tau is a protein contained within the axons of the nerve cells.

More specifically, tau helps form microtubules — essential structures that transport nutrients within nerve cells.

In a healthy brain, the tau protein helps these microtubules remain straight and strong. But in Alzheimer’s, tau collapses into aggregates called tangles. When this happens, the microtubules can no longer sustain the transport of nutrients and other essential substances in the nerve cells, which eventually leads to cell death.

How toxic and damaging these tau tangles can be, and how far they can spread, depends on their length. However, until now, scientists did not know why some tau tangles are longer than others in Alzheimer’s, or how these aggregates grow so long in the first place.

But now, scientists at the Ohio State University in Columbus have devised a mathematical model that has helped them explain what biological processes lie behind the formation of tau tangles.

The new research, conducted by Carol Huseby, Jeff Kuret, and Ralf Bundschuh, explains how the tangles grow and reach various lengths.

How tau fibrils elongate

Huseby and colleagues started with a basic two-step model of tau aggregation. Step one consists of two tau proteins slowly binding together, and step two involves additional tau molecules attaching themselves to the two proteins.

The researchers expanded this basic model to include additional ways in which tau fibrils behave. Scientists have previously described fibrils as “the tangles untangled.”

The amended model predicted that the tau protein would break down into several short fibrils. However, the researchers knew that under the microscope, tau tangles reveal long fibrils, not short ones.

So, in an attempt to explain the discrepancy between what the model predicted and the microscopic reality, the researchers wondered whether shorter fibrils joined together to form long fibrils, in a similar way to hair extensions.

Further experiments in which the scientists labeled tau fibrils with fluorescent colors revealed that indeed long fibrils were made up of shorter, differently-colored fibrils that had joined at the ends.

To the authors’ knowledge, these findings show for the first time that tau fibrils can grow in size by adding more than just a single protein at a time. Rather, shorter fibrils can attach to each other, elongating a fibril more quickly.

Study co-author Kuret explains that the findings may shed light on how tau tangles — and implicitly the disease itself — can spread from one cell to another. Once a long fibril is “broken up into little pieces, those can diffuse, facilitating their movement from cell to cell,” he says.

Furthermore, say the researchers, the findings help elucidate how tau fibrils can grow to be hundreds of nanometers long. Also, such knowledge can lead to a new class of drugs, which could stop tau from aggregating.

In the future, the scientists plan on amending their model to account for the many nuances that make the tau protein so complex. For instance, this series of experiments only used one type of tau, but there are six isoforms of the protein. Also, chemical processes, such as phosphorylation, can further change the structure of the protein.