How a carbohydrate-rich mesh protects our brain

As we age, things don’t quite work the way they used to. Now Stanford researchers have identified how the breakdown of a sugary layer in the blood vessels that feed the brain could result in aging related cognitive decline (Nature 2025, DOI: 10.1038/s41586-025-08589-9).

The body has numerous ways to protect itself against harm. One of those, the blood brain barrier (BBB), controls how molecules pass from the bloodstream to the brain. But this barrier breaks down with age, allowing toxins and pathogens to pass through, causing disease.

When chemistry PhD student Sophia Shi did a rotation into the lab of neuroscientist Tony Wyss-Coray, she says “it felt personally very meaningful” to think about the molecular mechanisms of dementia and aging.

After spending time in Carolyn Bertozzi’s lab getting excited about the world of glycans, Shi realized there might be a way to understand how these complex molecules could be involved in dementia. So she pitched the idea of studying glycans and how they change in the brain with aging and disease to both Bertozzi and Wyss-Coray. Her PhD project was born.

“Initially, I was just looking at glycans in the brain,” Shi recalls. But then she realized that while every cell in the body has sugars on its surface, the sugar layer on the inside of those brain-feeding blood vessels is especially large. “I was like, ‘wow, this is the place I feel like would be really exciting to study.’ ”

Shi was able to demonstrate that in this sugary layer called the glycocalyx, branched glycoproteins called mucins are an important component. Shi also observed that the number of mucins compared to other glycocalyx components decreases with age.

As the mucins disappear, the whole layer becomes leaky, which is associated with reduced cognition. Shi then repaired that layer in mice using gene therapy and stopped the leakiness, proving a causal link.

Neuroscientist Shelly Erickson at the University of Washington says “it's a pretty compelling study” that highlights the importance of mucins in the BBB and in age-related illness. She says she would be interested in understanding what's contributing to the mucin’s selective decrease when other glycoproteins and proteoglycans in the glycocalyx seem to be increased with aging. “Getting at those mechanisms may also provide some level of therapeutic insight,” she says.

Shi already has some hypotheses about the mechanisms behind the mucin loss and is actively trying to understand what is going on. Historically, she adds, there hasn’t been a lot of overlap with glycobiology and neuroscience. “I'm hoping to really help open up this space and continue research,” she says. Shi will be doing that when she starts up her own lab at Harvard in the fall.