More than a century ago, scientists discovered that when staining various tissues and organs throughout the body, dye molecules transported through the blood could not enter the brain tissue. There was a mysterious barrier between the blood and the brain tissue. Today, with the help of advanced labeling and imaging techniques, we already know that this blood - brain barrier is composed of endothelial cells of brain capillaries and astrocytes in the brain tissue. It is a key barrier that protects the brain from circulating inflammatory factors, pathogens, and other harms.

Professor Tony Wyss - Coray, a well - known neuroscientist at Stanford University, has extensively studied the changes that occur in the blood - brain barrier during the aging process for many years. In particular, during aging and age - related neurodegenerative diseases (such as Alzheimer's disease), there is a close association between the change in the permeability of the blood - brain barrier and the decline of cognitive function in the brain. They also found through animal experiments that repairing the blood - brain barrier of old mice and blocking the influence of aging blood on the brain could make the aging brain “return to youth”.

In a recent paper published in the top academic journal Nature, Professor Wyss - Coray collaborated with Professor Carolyn Bertozzi, the 2022 Nobel laureate in chemistry. They made an important new discovery about the changes in the blood - brain barrier during the aging process, which in turn brought new clues for promoting brain health. In the words of the researchers, the crucial and previously unknown large - scale structural changes in the process of brain aging have been hiding in plain sight.

This discovery benefits from Professor Bertozzi's pioneering work in the field of glycosylation modification. Over the years, researchers have found that many sugar - chain - containing molecules (including glycoproteins, glycolipids, and even sugar RNAs) are distributed on the cell surface and affect various biological processes. In this study, they paid attention to the surface of endothelial cells that form the blood - brain barrier.

Specifically, it is the glycocalyx on the surface of these endothelial cells, which is mainly composed of proteoglycans, glycoproteins, and glycolipids. Since the sugar chains all face the outside of the cell, the outer layer of the cell seems to be coated with a layer of sugar, just like a calyx enclosing a petal. Therefore, the glycocalyx is also called the “glycocalyx”.

When examining the brains of mice of different ages, the researchers observed through special metal stains and electron microscopes that the “sugar coating” of the blood - brain barrier in healthy young mice was thick and uniform, while in the brains of old mice, this “sugar coating” became thin and fragmented. Along with the changes in the “sugar coating”, the blood - brain barrier leaked, allowing neurotoxic factors and inflammatory factors in the blood to easily enter the brain tissue. These are the key pathological signs of aging and neurodegenerative diseases.

The researchers further found that the reduction of mucin - type O - sugar chains, the main structural component of the glycocalyx, was the key factor leading to the damage of the “sugar coating” of the blood - brain barrier. Mucin - type O - glycosylation is a post - translational modification of proteins. Under the action of enzymes, mucin family or glycoproteins containing mucin domains on the cell surface add sugar chains through serine and threonine residues.

Mucin - type O - glycosylation in brain endothelial cells not only decreases during aging. Data analysis of population cohorts shows that in patients with different neurodegenerative diseases such as Alzheimer's disease and Huntington's disease, mucin - type O - glycosylation in brain endothelial cells is generally down - regulated.

Since this down - regulation of glycosylation is not due to the loss of the glycoprotein scaffold of the mucin domain but mainly due to the decrease in the level of O - glycosylation biosynthetic enzymes, in order to reverse the defect of the glycocalyx, the researchers tried to use adeno - associated virus as a vector to deliver the genes expressing two key mucin - type O - glycosylation synthases into the cerebral blood vessels of old mice. The experimental results showed that in the old mice treated with this gene therapy, the leakage of the blood - brain barrier was significantly improved. In addition, as the “sugar coating” of the blood - brain barrier was restored more completely, the neuroinflammation in old mice was reduced, and they showed significant improvement in memory and learning ability in tests such as maze - running.

Based on these results, the authors of the study summarized in the paper that “Our results provide a detailed composition and structural map of the aging brain endothelial glycocalyx and reveal that the dysregulation of the glycocalyx related to aging and diseases has an important impact on the integrity of the blood - brain barrier and brain health.”

Professor Bertozzi, the co - corresponding author, further pointed out in a Stanford University press release that it is crucial to next understand whether a similar mechanism is at work in humans and to translate these findings into therapies. Given that the low permeability of the blood - brain barrier is not only a protection for the brain but also a challenge for drug delivery, the discovery of this “sugar coating” may also bring new and better methods to help us deliver drugs to the brain, offering hope for the treatment of various brain diseases such as multiple sclerosis and brain tumors.