A blood protein that increases in abundance as we age and has been linked to cognitive decline and memory loss, and researchers suspect that by blocking its activity, we could halt the kind of mental degeneration that leads to dementia.
The protein in question is known as beta-2 micro globulin (B2M), and its primary role is to identify potentially dangerous foreign cells in the blood and signal the immune system to attack them. But recent studies have found that the B2M proteins in the brain act a little differently - they can actually influence how the brain develops, how nerve cell communication is shaped, and possibly even behaviour. And now researchers in the US have found that by blocking B2M activity in old mice, they could restore their memory function and learning abilities to rival those of a young mouse.
The team, from UC San Francisco and Stanford University's School of Medicine, decided to follow up on the results of a separate Stanford study conducted in 2014 in which old mice were given the blood of new mice, and showed signs of improved learning ability. Further research revealed that prior to receiving the young blood, these old mice had 'pro-ageing factors' in their blood that blocked the process of neurogenesis, which facilitates memory function.
The idea was to investigate these pro-ageing factors, and figure out whether they could be blocked or reversed, to stop age-related mental decline. "I think there are two ways we can improve or reverse the hallmarks of ageing," one of the team, Saul A. Villeda from UC San Francisco, told Ian Sample at The Guardian. "One of them is to administer pro-youthful factors, but the other is to target these pro-ageing factors."
Villeda and his colleagues focussed on B2M because a number of studies in the past have linked high levels of the protein with cognitive dysfunction in Alzheimer's disease, HIV-associated dementia, and severe cases of kidney disease. It has also been confirmed that B2M levels increase with age in both the blood and brains of mice and humans.
To test its effect, they first injected B2M into the blood and brains of healthy, young mice, effectively mimicking levels of the protein seen naturally in old mice. The young mice were then put through a number of memory and cognitive ability tests, such as navigating a complex water maze. The team found that the increased levels of B2M significantly affected the young mice's ability to solve the maze, particularly when it was injected directly into the brain's circulatory system. The process of neurogenesis was also suppressed in these mice.
"Young animals are really good at this. They will make perhaps one or two mistakes over the course of three trials, Villeda told The Guardian. "But when you give them B2M, they'll make perhaps five mistakes. It's a striking difference."
Next, the team worked with mice that had been genetically engineered to block the activity of BSM in both the blood and the brain's circulatory system. They found that when these mice received the B2M injections and were put to the test, there was no negative effect on their cognitive or memory functions, or neurogenesis. And mice bred with no B2M at all actually performed better in the tests than the control group of young, healthy mice, and showed no signs of mental decline well into old age. "When we looked at the older animals, they were much smarter. They did not develop the same kinds of memory impairments. I was really surprised," Villeda told The Guardian.
Reporting the results in Nature Medicine, Villeda and his colleagues said the effect of heightened B2M could even be reversed, which is great news for the prospect of developing some sort of age-fighting drug in the future. Thirty days after the mice had their B2M injections and performed terribly in cognitive tests, they went back to performing just as well as the control group.
"From a translational perspective, we are interested in developing antibodies or small molecules to target this protein late in life," Villeda said in a press release. "Since B2M goes up with age in blood, CSF [cerebrospinal fluid in the brain], and also in the brain itself, this allows us multiple avenues in which to target this protein therapeutically."
The next step here is to figure out if there are other factors involved in age-related cognitive decline that might affect how successful B2M-blocking drugs can be, and if the effect of increased levels of B2M is as striking in humans as it appears to be in mice.