Not just a harmless accessory, tau’s ‘fuzzy coat’ contributes to Alzheimer’s progression

Alzheimer’s disease is a neurodegenerative disorder that over time interferes with memory, thinking and the ability to perform day-to-day tasks.

It is the most common type of dementia. An estimated 7.2 million Americans aged 65 and older have Alzheimer’s.

“There is no cure for Alzheimer’s, and we still don’t fully understand what causes it,” said Michael Henderson, Ph.D., an associate professor at Van Andel Institute. “By deepening our understanding of how the disease develops, we hope to make strides toward better treatments. One particularly promising area of research focuses on a protein called tau.”

Tau is found in the brain, where it helps stabilize the internal structure of nerve cells. However, when things go wrong, tau can misfold and form sticky filaments that disrupt nerve cell function and contribute to Alzheimer’s development.

The presence of misfolded tau also can initiate a snowball effect, recruiting normal tau to misfold and form filaments — a process known as “seeding.”

Until recently, many scientists believed tau’s structured core was solely responsible for driving this snowball effect. But Henderson’s lab, along with the lab of Sjors H. W. Scheres, Ph.D. at MRC Laboratory Molecular Biology, found that the core alone is not sufficient to cause the level of misfolding seen in Alzheimer’s.

To dig deeper, the team shifted their focus to a different region of the protein: tau’s “fuzzy coat,” a loose, unstructured layer that surrounds the core.

They discovered that the fuzzy coat is not just a harmless accessory — it is an essential component in the seeding process.

On its own, the fuzzy coat plays a protective role, preventing tau from aggregating too quickly. But when negative charges are added by signaling molecules, the protein can form long fibers like those seen in diseases like Alzheimer’s.

The findings, which were published in the journal Nature Communications, improve our understanding of how tau contributes to Alzheimer’s disease and highlight a potential disease-modifying strategy to slow its progression.

“Our work reframes how we think about tau aggregation,” Henderson said. “It’s not just the core —it’s the interaction between the core and the fuzzy coat that drives this process. Additional work will be necessary to determine the molecular mechanisms of this interaction, but it’s a step in the right direction.”

The authors thank the individuals and families who participated in this research, without whom this work would not have been possible. Brain tissue was provided by the VAI Brain Bank.

Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health under award nos. F31AG084199 (Kasen) and R01AG077573 (Henderson); and by the MRC, as part of U.K. Research and Innovation (UKRI) under award no. MC_UP_A025_1013 (Scheres). This content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other funding organizations.