Running Boosts Brain Cells in A-T Mutated Mice

Researchers at the Salk Institute for Biological Studies in La Jolla, Calif., have shown that running can boost brain-cell survival in mice with the neurodegenerative disorder Ataxia-telangiectasia (A-T).1 Surprisingly, during the course of the study, they also discovered that the Atm gene--which is absent in those with the disease--appears to play a critical role in neural stem cell development. A-T is a rare disease characterized by the death of brain cells, which results in a progressive loss of motor control that typically, by adolescence, confines patients to wheelchairs. While the cell death appears first in the cerebellum, the brain region that directs movement, it eventually occurs throughout the brain. Courtesy of JThe Salk InstituteCarrolee Barlow By monitoring the number of revolutions each mouse lapped on a running wheel that was placed in its cage, the researchers actually discovered that the miles logged by these mice appeared to correlate directly with increased cell numbers. "We were stunned by that," says Salk assistant professor Carrolee Barlow, the study's lead author. "It's almost as if they were wearing pedometers, and those that ran more grew more cells," she says. In the sedentary A-T mice, however, the team found that most newly born brain cells died. "We don't understand that fully, but it probably has something to do with an inability to cope with oxidative stress," she suggests. "But, by exposing these mutant animals to a running wheel, many more of those cells, instead of dying or hanging around to die later, actually became neurons, and so the running appears to rescue many cells that would otherwise die." Although decreased cell survival in the sedentary A-T mice was expected, Barlow and colleagues were struck by another bolt from the gray matter. "We found [in this mutated breed] that if you're missing the Atm gene, neural stem cells seem to be incapable of becoming an oligodendrocyte or a neuron, although they can become astrocytes without any problem," she explains. "We didn't expect that there would be a defect in the cell's decision on what kind of cell it could become. That was very unexpected." It indicates, she adds, that there is something going on in a stem cell--in the absence of the Atm gene--that causes both neurons and oligodendrocytes to become abnormal. This discovery has caused Barlow and colleagues to alter their approach in researching A-T. "From the disease perspective, it tells us that we should be focusing on both neurons and oligodendrocytes, which we really haven't been doing in the past," she comments. "We've mainly focused on neurons. From a bigger perspective, it also makes us think that astrocytes just might be the default of what a neural stem cell becomes if it can't become a neuron or an oligodendrocyte." Courtesy of JThe Salk InstituteFred Gage The work builds on research directed by Salk professor and coauthor Fred Gage. During the last several years, Gage and others at the institute have shown that running leads to increased brain cell numbers in normal adult mice, elderly "senior citizen" mice and a genetically "slow-learning" strain of mice.2, 3 In addition, Gage's research has shown that new cell growth also occurs in human brains.4 The cumulative results emanating out of Salk and other institutions hint that running and/or exercise might help delay the onset and progression of some neurodegenerative diseases. "A-T is rare, but at the cellular level it shares properties with more common neurodegenerative diseases such as Alzheimer's and, in fact, looks a lot like aging," says Barlow. The cell-boosting effects of running were found in the hippocampus, a region of the brain linked to learning and memory and known to be affected by Alzheimer's disease. Research in Barlow's laboratory now is focusing on identifying exactly how exercise is helping these brain cells survive. "It must be altering brain chemistry--altering levels of particular hormones or growth factors, perhaps," she proposes. "If we can identify the specific molecules responsible for [the effect of running], those molecules should point to new drug strategies to treat A-T and other neurodegenerative diseases ... [and] a medication that would do the same thing." In the meantime, clinicians might pick up the ball and run with trials monitoring active and inactive patients and the progression of the disease state "to clarify whether or not exercise really is helpful in humans." A.J.S. Rayl (ajsrayl@loop.com) is a contributing editor for The Scientist. References 1. D.R. Allen et al., "Ataxia telangiectasia mutated is essential during adult neurogenesis," Genes & Development, 15:554-66, March 1, 2001. 2. H. van Praag et al., "Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus," Nature Neuroscience, 2:266-70, 1999. 3. H. van Praag et al., "Running enhances neurogenesis, learning, and long-term potentiation in mice," Proceedings of the National Academy of Sciences, 96:13427-31, 1999. 4. A.J.S. Rayl, "Research turns another 'fact' into myth," The Scientist, 13[4]:16, Feb. 15, 1999.

Running Boosts Brain Cells in A-T Mutated Mice

Interested in reading more?

Become a Member of