'Old-age protein' may cause memory loss

All in the mind. A brain protein that declines with age could hold the clue to memory loss.

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The next time you forget where you left your car keys, you might be able blame an immune protein that builds up in your blood as you age. The protein impairs the formation of new brain cells and contributes to age-related memory loss—at least in mice, according to a new study. Blocking it could help prevent run-of-the-mill memory decline or treat cognitive disorders, the researchers say.

“The findings are really exciting,” says neurologist Dena Dubal of the University of California, San Francisco (UCSF), who was not involved in the study. “The importance of this work cannot be underestimated as the world’s population is aging rapidly.”

Multiple groups of scientists have shown that adding the blood of older mice to younger animals’ bodies makes them sluggish, weaker, and more forgetful. Likewise, young blood can restore the memory and energy of older mice. Neuroscientist Saul Villeda of UCSF homed in on one actor he thought might be responsible for some of that effect: β2 microglobulin (B2M), an immune protein normally involved in distinguishing one’s own cells from invading pathogens. B2M has also been found at increased levels in patients with Alzheimer’s disease and other cognitive disorders.

Villeda and his colleagues first measured B2M levels in the blood of both people and mice of different ages; they found that those levels increased with age. When the researchers injected B2M into 3-month-old mice, the young animals suddenly had trouble remembering how to complete a water maze, making more than twice as many errors after they’d already been trained to navigate the maze. Moreover, their brains had fewer new neurons than other mice. Thirty days later, however, when the protein had been cleared from their bodies, the animals' memory troubles were gone as well, and the number of newly formed brain cells was back to normal.

To see whether reducing B2M levels could treat or prevent memory impairment as the rodents aged, Villeda’s group genetically engineered mice to lack the gene for B2M. Compared to control mice, older animals with no B2M were better at learning and memory tasks, nearly as good as young animals at completing the water maze, for instance, the scientists report online today in Nature Medicine. They got similar results when they engineered mice to lack another immune molecule, suggesting that B2M is part of a pathway that affects the brain.

“What this shows is that you can manipulate the blood, rather than the brain, to potentially treat memory problems,” Villeda says. “And that’s so much easier and more tractable in terms of thinking of human patients.”

The study is a solid confirmation of previous papers that showed B2M's important role in aging and memory, says biologist Irina Conboy of the University of California, Berkeley, who recently published a scientific paper showing that targeting a separate molecule can lower levels of B2M and restore brain cell formation. The real test, Conboy says, will come in clinical trials that aim to block B2M—or other related molecules—to treat or prevent memory disorders in humans.

“In my opinion, age is just a number, and it’s not a chronological number of years, but a number representing the strength of signaling pathways within cells,” Conboy says. “Which means we can start with an old cell, change its signaling, and make it behave like new again.”