Scientists reverse age-related memory loss in mice

Scientists reversed memory loss in mice after disabling a single molecule in the cerebral blood vessels.

The tests, performed at Stanford University School of Medicine, allowed aging rodents to tear through a maze with the vim and vigor of a mouse half their age. 

They saw internal transformations, too: the treatment rejuvenated the mice’s ability to generate new nerve cells, and dampened inflammation. 

The findings add weight to the theory that there’s something in our blood which is responsible for cognitive decline – and that there could be a way to stop it.

Tests on mice, performed at Stanford University School of Medicine, allowed aging rodents to tear through a maze with the vim and vigor of a mouse half their age

The new research does not identify what it is about old blood that causes our brains to slow down.  

However, by blocking one molecule the team found they could control the traffic that flows through blood vessels, and thereby control how the brain inflames. 

‘We may have found an important mechanism through which the blood communicates deleterious signals to the brain,’ senior author Tony Wyss-Coray, PhD, professor of neurology and neurological sciences, co-director of the Stanford Alzheimer’s Disease Research Center, said.  

The study showed there could one day be treatments that curb or even reverse cognitive decline decline without having to perform invasive techniques. 

‘We can now try to treat brain degeneration using drugs that typically aren’t very good at getting through the blood-brain barrier — but, in this case, would no longer need to,’ lead author Hanadie Yousef, PhD, a former postdoctoral scholar in the Wyss-Coray lab, said.

The researchers focused on the mouse hippocampus, a well-studied brain structure that’s essential to memory and learning and whose architecture and function are similar in mice and humans. 

The hippocampus is also one of the very few sites in the adult mammalian brain where neurogenesis, the creation of new nerve cells, occurs; those new cells are critical to the formation of new memories.

Since his lab first began reporting several years ago that unknown factors in old blood can accelerate cognitive decline and, conversely, that factors in young blood can rejuvenate old brains, Wyss-Coray, the D.H. Chen Professor II, has sought to identify those factors. 

But he and his colleagues took a different tack in the new study.

He said the roughly 400 miles of blood vessels that pass through the human brain differ from those elsewhere in the body in one important respect: they’re much more selective about what gets in and what comes out.

‘The blood-brain barrier excludes most bloodborne cells and substances,’ he said. ‘We wondered if, instead of entering the brain and monkeying with brain cells directly, something in circulating blood could be communicating directly with the brain’s endothelial cells.’

A few years ago, Wyss-Coray and his colleagues compared blood from young and old people to pinpoint substances whose abundance changes with age. 

In the new study, they narrowed their search to just those age-associated bloodborne substances that are in some way directly related to vascular function. 

Topping the list was a circulating form of a protein constantly produced within endothelial cells and displayed on their surfaces.

The protein, VCAM1, is well known to immunologists. 

It’s a docking station for circulating cells of the immune system — a first stop in a passport-punching process that under certain relatively rare conditions grants those immune cells permission to migrate across the brain’s otherwise tightly closed border.

This protein gets sawed off of endothelial-cell surfaces and dumped into the bloodstream by lawnmowerlike enzymes at pretty much the same rate it gets produced, so its population size on blood vessels remains relatively constant. 

But VCAM1’s abundance on blood-vessel surfaces jumps markedly in the event of local injury or infection. That snags immune cells, which combat infectious pathogens and are essential to the healing process.

‘At any given time, levels of circulating VCAM1 are a good proxy for the total amount of VCAM1 on the body’s blood-vessel endothelial cell surfaces,’ Wyss-Coray said. Previous studies have linked high circulating VCAM1 levels to cancer, heart disease, stroke, Alzheimer’s disease, epilepsy and other inflammatory disorders. 

In the study, the researchers showed that VCAM1’s abundance on the endothelial cells comprising blood-vessel walls in the mouse brains rises in old age, as well as in the brains of younger mice that are given infusions of older mice’s plasma, the cell-free, liquid portion of blood. 

Likewise, the researchers observed increased signs of inflammation in the older mice’s cells.

Wyss-Coray suspects that the tethering of immune cells to blood-vessel surfaces — particularly if immune cells are in an activated state due to an existing condition, such as injury or infection, or to old age — enhances the release of inflammatory proteins that penetrate blood vessel walls via specialized receptors on endothelial-cell surfaces.

Circulating VCAM1, though, wasn’t the source of brain dysfunction. 

When the investigators depleted old mice’s plasma of the protein before giving the plasma to young mice, they observed the same damaging effects in the hippocampus — reduced neurogenesis, increased microglial inflammation — they’d previously seen when young mice received old plasma.

Deleting the gene encoding VCAM1 in mice brains prevented the protein’s production in the brain’s endothelial cells. 

If this deletion was performed in young adulthood, the mice no longer suffered reduced neurogenesis or increased microglial inflammation when they grew older.

The researchers achieved the same results with monoclonal antibodies, specialized proteins that bind avidly and exclusively to their target. 

Three weeks of treatment with a monoclonal antibody directly targeting and blocking VCAM1 was enough to increase neurogenesis and diminish microglial reactivity in older mice’s hippocampi.

These mice aced a battery of mental-acuity tests. 

One test, the Barnes maze, involves a table from which mice want to escape. 

The table has lots of holes through which the mouse can fall a short distance onto the floor (although not far enough to cause an injury). 

But one hole connects to a tube mounted horizontally under it, providing a comforting escape to the mice. The mouse must learn and remember how to get to the ‘safety’ hole.

Once they were fully trained, older mice treated with this antibody reached the escape hole in the Barnes maze as quickly as young mice.

‘Blocking VCAM1 in the brain wound up making these mice smarter,’ Wyss-Coray said. ‘In all the time I’ve been working on this, I’ve never seen such performance before.’