By ANDREW JOSEPH @DrewQJoseph

Scientists have shown that delivering blood from an old mouse into a young mouse or vice versa prompts a sort of “Freaky Friday” effect: The brains of the young mice exposed to the old blood lose vitality, while the young blood rejuvenates some brain function in the older mice.

What they don’t know, however, is what makes those transformations occur. On Monday, scientists reported they had latched on to a protein made by the blood vessels as a key player in how older blood seems to induce cellular damage inside the brain.

What’s more, they found that disabling the protein in older mice improved the function of their brain cells and the mice’s performance on cognitive tests. Their study, published in the journal Nature Medicine, points to the protein, called VCAM1, as a possible target for a therapy for neurocognitive disorders.

As both humans and mice get older, cells in the brain called microglia — a type of nervous system immune cell — become more active, producing neuroinflammation. At the same time, the activity of neural stem cells, which are involved in making more neurons, gets tamped down. Together, these two shifts are thought to play a key role in the structural and functional deterioration that happens as we age.

Injecting blood from an old mouse into a young mouse triggers these same cellular responses to aging, suggesting that certain factors in the plasma — the protein-rich, fluid part of blood — signal for these changes to happen inside the brain. But unlike other organs, a healthy brain is sealed off from the blood by a barrier, leaving open the question of how the components of blood can influence what’s going on inside the brain.

“What was completely not understood was how circulating factors in the blood can communicate given that we have an intact blood-brain barrier,” said Hanadie Yousef, the lead author of the paper, who conducted the study as a postdoctoral researcher at Stanford.

For the study, Yousef and her colleagues turned to brain endothelial cells — those that make up the blood vessels that run along the brain. They focused on the cells in the hippocampus, a region of the brain key to learning and memory. They figured that these cells, which help make up the blood-brain barrier, might act as intermediaries in the interplay between the two sides. And when they looked at the levels of different proteins in people as they aged, they discovered that the one that increased the most over time was VCAM1, which is made by and found on the surface of these endothelial cells.

Endothelial cells throughout the body express the protein VCAM1, which lassos immune cells circulating in the blood and helps escort them into a tissue when it is damaged or injured. Their directive is different in the endothelial cells in the brain. Here, they similarly tether immune cells, but the cells can’t cross into the brain because of the barrier. But through different signals, that binding still sets off the brain’s immune response.

Researchers have noticed, however, that too much VCAM1 might be a sign of or be involved in a waning brain. In one study of almost 700 older adults, a team found that higher VCAM1 levels correlated to worse cognitive impairment.

In the new study in mice, the researchers dismantled VCAM1 in two ways to figure out whether the high levels of the protein helped cause cognitive impairment, or whether they were simply a byproduct of aging.

First, they deleted the gene (called Vcam1) that encodes the protein, and found that these mice were protected against the effects of the transferred aged blood.

They also blocked VCAM1 with an antibody, leaving immune cells in the blood unable to tether to the endothelial cells. These older mice had more neural stem cell activity and reduced microglial activity than untreated older mice, demonstrated improvement on cognitive measures, and solved a maze test as if they were spring chickens.

“In old mice, if we gave them the antibody against VCAM1 or deleted Vcam1 for most of their lifetimes, it basically blocks the bad effects of this aged plasma,” said Tony Wyss-Coray, a professor of neurology and neurological sciences at Stanford and senior author of the paper.

The researchers don’t know exactly what was occurring, but they propose that certain components in older plasma promote the expression of VCAM1. With more VCAM1 on the surface of the endothelial cells, there’s more tethering of immune cells to the blood brain barrier. That in turn produces signals that promote inflammation and the other cellular — and, eventually, cognitive — problems associated with aging.

Julie Andersen, a neuroscientist at the Buck Institute, who was not involved in the work, said she thought it was significant that the Stanford researchers had identified something in the endothelial cells that appears to be involved in the mechanisms of aging. Oftentimes, she said, research tends to overlook these cells.

She raised the question, though, about whether the process described in the paper might just be one way aging wears on a brain. If, for example, the blood-brain barrier starts to “leak” a bit over time — if it allows cells or proteins into the brain that shouldn’t be there — then that might be another aging process that hurts the brain. Just targeting VCAM1 might not be able to overcome that and the other ways time erodes the health of the brain.

“Clearly this is a potential mechanism that can play a role in the impact you see in terms of microglial activation and reduction in stem cell proliferation, but I would contend in aging, there are other things that could be at play here,” Andersen said. “But I do think that this is cool that they’ve actually identified an endothelial cell marker that’s altering with age and really have come up with a viable hypothesis for how the increase in that marker could be driving some of these age-related phenomena, and how the use of an antibody can restore some of the changes.”

Yousef is done with her postdoc and is now CEO of Juvena Therapeutics, a tissue regeneration startup. But Wyss-Coray and his lab are still at work trying to discover more about VCAM1. They’ve also started exploring whether blocking it with an antibody is effective in animal models of vascular dementia.

About the Author

Andrew Joseph

General Assignment Reporter

Andrew is a general assignment [email protected]@DrewQJoseph