A Molecular Signature of Cognitive Decline

Where did I leave my car keys? Did I come into this room to get something? And what was that person's name again?

Getting old often means getting a little forgetful. Now researchers working with mice think they have found a new reason why. They've identified molecular changes in the brains of aging mice that prevent learning and memory genes from being switched on as they are in younger animals. If the findings translate to humans, they may one day lead to drugs that stave off dementia or even the normal cognitive declines of old age. Indeed, a certain class of drugs already in development for treating cancer might fit the bill.

Previous studies had found age-related changes in gene expression in the hippocampus, a crucial memory center in the brain. Other work implicated histones—tiny protein spools that control gene expression by winding or unwinding DNA—in learning and memory. Neuroscientist André Fischer of the European Neuroscience Institute in Göttingen, Germany, and colleagues wanted to probe the histone connection further. They hypothesized that aging might change how histones function, causing alterations in gene expression that contribute to memory problems.

To test the idea, Fischer and colleagues compared old and young mice. Old mice don't have car keys to lose track of, but they do struggle to remember a place where they once received a nasty shock or a hidden platform in a pool of murky water. The team found staggering differences in gene expression between juvenile 3-month-old mice and 16-month-old mice (equivalent to late middle age in humans). An hour after being trained to associate a particular chamber with an impending shock to the foot, nearly 2000 genes in the hippocampus became more active in the younger mice compared with just six genes in the older mice.

The reason appears to be that in the younger mice the association between the chamber and the electric shock results in a type of chemical modification, called acetylation, at a specific site on histone protein H4K12. Acetylation causes histones to unspool their DNA, thereby allowing gene expression to proceed—so decreased acetylation generally reduces gene expression.

Indeed, when the researchers injected a drug into the hippocampus of older mice to restore acetylation, the gene expression profiles of these mice looked similar to those of their younger counterparts. Moreover, this treatment improved the ability of old mice to remember a foot shock, as evidenced by more fearful "freezing" behavior when they revisited the chamber a day later, the team reports in tomorrow's issue of Science.

"These studies bring us one step closer to understanding age-related memory loss and closer to developing a drug that might help boost memory in aging-associated memory loss," says David Sweatt, a neuroscientist at the University of Alabama, Birmingham. Sweatt notes that recent studies by his group and by Ottavio Arancio and colleagues at Columbia University have found that drugs that boost histone acetylation can improve memory in mouse models of Alzheimer's disease. Some of these drugs, known as histone deacetylase inhibitors, are already approved for treating cancer, and more are in the pipeline, says Arancio. But he cautions that it remains to be seen whether they are specific enough to work as memory enhancers without causing serious side effects. Fischer suggests that drugs that specifically enhance H4K12 acetylation, if they can be developed, might do the trick.

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