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Hometown U: Researchers' work seems to help rats remember

Kathleen McCoy
Dr. Colin McGill, on the left, and Dr. Eric S. Murphy are now preparing two papers for publication and are seeking research funds to answer questions about dosage and duration of the malate treatment.
Photo by Philip Hall
A specially bred albino rat is seen in its container on Tuesday in the lab in UAA’s Social Science Building where Dr. Eric S. Murphy and Dr. Colin McGill performed their experiment about the effects of malate on behavioral abilities in rats. A $10,000 Innovate grant let them buy 24 rats that had been bred for aging, and the researchers designed and built a black T-maze for the rats.
Photo by Philip Hall

Strangely enough, there's a link between Sweet Tart candy and the uber-healthy Alaska bog blueberry. They share malic acid, that mouth-puckering sourness identified with rhubarb and tart green apples. In fact, malic is Latin for apple.

For 15 years, malate-rich blueberries have been known to improve lab rat memory, as long as the rat ate the whole berry. Human memories improved too when subjects drank concentrated blueberry juice, according to results from a 2010 study. But every attempt to finally identify and isolate the single heroic blueberry ingredient failed.

Until last year. That's when UAA biochemist Colin McGill, working with cells under a microscope, proved that malate from Alaska bog blueberries successfully tamped down chemical processes that drive physical and mental decline -- all those sorry events that happen as we age, or develop illnesses like Alzheimer's and Parkinson's.

Seeing it under a microscope, though, is a world away from seeing it in a living, breathing animal.

"Every time I presented this," McGill said, "the first hand up was, 'Do you think this is actually going to be absorbed, dietarily? Will it make it through the blood-brain barrier?' "

Now he and UAA behavioral psychologist Eric Murphy can confidently answer yes. They've just completed a study on lab rats specially bred for old age. Malate, dissolved in water, gave these cranky, forgetful seniors a tremendous boost; after just six weeks, they regained their sharp-as-a-tack memories.

Murphy had been skeptical when McGill approached him, looking for a way to test his cell-model results on live animals.

"I thought, there's no way in you-know-where that this is ever going to happen," Murphy said. "I give you a 50-50 chance." They both called it "high risk, high reward."

Still, they persisted. A $10,000 grant from UAA's research stimulus Innovate fund provided money to purchase 24 NIH rats bred for aging. In McGill's garage, they designed and built their own black T-maze to run cognition tests.

Once half the rats were dosed on malate, trials began between those with and those without. The process dragged on; the geriatric rats were cranky and slow.

Sometimes they just sat in the maze and refused to move, much less explore the T. After five minutes, a test timed out. For old rats with no malate, it could take 15 trials to get 10 good runs. The scientists say they appreciate the four undergraduates who worked through these painstaking trials.

The memory test worked like this: A rat deposited at the bottom of the T was allowed to explore. Next, an arm of the T was closed off randomly, so the rat could choose only one arm.

Next, the rat was re-deposited at the bottom of the T, this time with both T arms open.

A healthy young rat will remember where it went last, and choose fresh territory. Impaired rats (the hippocampus, center of memory in the brain, is removed) randomly alternate, 50-50, between the two arms of the T.

Showing their decline, the geriatric rats with no malate did barely better, alternating 57.14 percent of the time.

Now here's where results get exciting. Healthy young rats with functional memories alternate 85 percent of the time. The malate-supplemented geriatric rats alternated 84.29 percent of the time.

"To put this in lay language," Murphy said, "by treating these geriatric animals with malate, they're behaving as if they were young and vibrant. You get a biochemical event that manifests itself behaviorally; these data are utterly remarkable."

The colleagues are preparing two papers for publication and looking for research money to answer their next questions: dosage and duration. Then, hopefully, comes testing on humans.

This initial round, they delivered a lot of malate -- the equivalent of about 2.5 pounds of dry blueberries (imagine eating that many Sweet Tarts). Could smaller doses deliver the same dramatic results?

They also need to do longitudinal studies, Murphy said: "Malate helps older rats enhance their memory but could it prevent decline? And at what age?"

Though more study is needed, McGill thinks malate may do both. The culprit in decline is the biochemical processes -- oxidative stress -- that McGill first saw under the microscope, and tamped down with malate.

All living organisms produce malate, he explained, which regulates chemical processes in cells. As we age, our malate production drops off, allowing oxidative stress to increase and lead to inflammation and decline.

He suspects that by supplementing the rats with malate, they simply restored the chemical compound to levels capable of temporarily stalling or constraining biochemical processes that drive our aging.

In other words, you can't turn back the clock, McGill said.

"When I first started working on this," he said, "I'd get emails from colleagues whose parents had Alzheimer's, asking where they could get malate. But it's not going to intervene in the progression of Alzheimer's. It's not going to stop aging. It might only provide a larger window of higher function.

"Not a miracle," McGill said, "but pretty cool."

Kathleen McCoy works at UAA, where she highlights campus life through social and online media.


Kathleen McCoy
Hometown U