Guanfacine

Age-Related Memory Loss Reversed in Monkeys

Research uncovers the cellular defects that cause this type of forgetfulness.

• WEDNESDAY, JULY 27, 2011
• BY EMILY SINGER

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It happens to the best of us: you walk into the kitchen to get a cup of coffee but get distracted by the mail, and then forget what you were doing in the first place. Aging makes people particularly vulnerable to this kind of forgetfulness, where we fail to maintain a thought in the face of distractions.

New research from Yale University uncovers cellular changes that seem to underlie this type of memory loss in monkeys, and shows that it can be reversed with drugs. By delivering a certain chemical to the brain, researchers could make neurons in old monkeys behave like those in young monkeys. Clinical trials of a generic drug that mimics this effect are already underway.

The findings support the idea that some of the brain changes that occur with aging are very specific—rather than being caused by a general decay throughout the brain—and can potentially be prevented. "It helps us understand that the age-related changes in the brain are malleable," says Molly Wagster, chief of the Behavioral and Systems Neuroscience Branch at the National Institute on Aging, which funded the research. "That's a crucial piece of information, and extremely hopeful."

In the study, Amy Arnsten and collaborators recorded electrical activity from neurons in a part of the brain called the prefrontal cortex, a region especially vulnerable to aging in both humans and primates. It is vital for our most high-level cognitive functions, such as working memory and the ability to multitask and inhibit distractions. "The prefrontal cortex is a mental sketch pad, keeping things in mind even if nothing in the environment is telling us what to do," says Arnsten. "It's the building block of abstract thought."

Previous research has shown that neural circuits in this region are organized to create a sustained level of activity that is crucial for working memory. "By exciting each other, the neurons are able to maintain information that isn't currently in the environment," says Arnsten.

By analyzing activity recorded from young, middle-aged, and old monkeys, the researchers found that the firing rate of the neurons in this area declines with age. They found that other neurons, such as those that respond to cues in the environment, still fired normally even as the monkeys aged. The research was published today in the journal Nature.

Arnsten believes the problem is a stress response gone wrong. During stress, even in young animals, these brain cells are flooded with a signaling molecule called cAMP, which dampens activity by opening potassium channels. (She theorizes that this is an evolutionary adaption that allows the brain to quickly flip control from the prefrontal cortex, "a slow and thoughtful region," to a more primitive region in time of stress.) Normally, enzymes shut off the stress response and the brain goes back to normal. "But we think that in normal aging, the stress signaling pathway becomes disregulated," says Arnsten.

The researchers were able to rein in the problem by treating the cells with a drug that blocks the potassium channels. After treatment, brain cells in old monkeys fired more rapidly—just like those in their younger counterparts.

The researchers already knew that giving monkeys this drug systemically, rather than delivering it directly into the brain, could reverse age-related deficits in working memory. A clinical trial of the compound, a generic drug called guanfacine, originally used to treat hypertension, is underway at Yale.

The findings bode well for the prospect of slowing age-related cognitive decline in humans. "The more we learn about the synaptic basis of aging, the more we learn it affects very specific elements of what these neurons can do," says John Morrison, a neurologist at Mount Sinai School of Medicine. Morrison was not involved in the research. "Once we understand it, we can identify targets and deal with it," he says.

Now that researchers understand how guanfacine works, they may be able to design drugs that are more powerful or have fewer side effects. Guanfacine can act as a sedative, so people need to slowly build up their tolerance to the drug to avoid this effect.

It's not yet clear if the work has implications for the more serious memory and brain changes that occur in Alzheimer's disease and other types of dementia. (Monkeys don't get Alzheimer's, so researchers know the memory changes they see in these animals are part of the typical aging process.)

However, Morrison believes that these subtle cellular changes may make the brain more vulnerable to the cell death that occurs in Alzheimer's. And as researchers begin to explore ways to intervene earlier with Alzheimer's patients, it may be useful to target these changes early on.

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