To stay at the forefront of this research requires an ability to work across an array of experimental disease models and to effortlessly make the transition from cell cultures to animals and from animals to humans. This adaptability is one reason why the name of neuroscientist Mark P. Mattson, of the National Institute on Aging (NIA) in Baltimore, Maryland, is now perched comfortably atop the ISI Essential Science Indicators Web product rankings of hot researchers in neuroscience & behavior over the last decade. Mattson has published upwards of 250 neuroscience papers in Thomson ISI-indexed journals since 1993; collectively, these papers have now been cited more than 13,000 times. In all, in the last 10 years Mattson has published more than 40 articles that have collected over 100 cites each, and 8 papers each cited more than 300 times. His seminal article on beta amyloid peptides and calcium homeostasis in the February 1992 issue of the Journal of Neuroscience (M.P. Mattson, et al., "Beta-amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity," J. Neurosci., 12(2): 376-89, 1992) has racked up a remarkable 800+ citations.

Mattson, now 46, received his bachelor’s degree in zoology from Iowa State University in 1979, where he originally hoped to pursue a career in veterinary science. Instead he went on to get a Master’s at North Texas State University in 1982 and then a Ph.D. in biology at the University of Iowa in 1986. After a three-year post-doc at Colorado State University, Mattson moved to the University of Kentucky, where he became a full professor of anatomy and neurobiology in 1997. In 2000, he became chief of the Laboratory of Neurosciences at NIA and a professor in the department of neuroscience at Johns Hopkins University School of Medicine.

  One of your papers from 2001, on NF-kappaB and neurodegenerative disorders, has enjoyed a pretty hot streak of citations recently (M.P. Mattson and S. Camandola, J. Clin. Invest., 107[3]: 247-54, 2001). What makes NK-kappaB so important, and why now?

Well, NF-kappaB was discovered by David Baltimore, who received the Nobel Prize for his reverse transcriptase. We began to study NF-kappaB in neurons for a couple of reasons. One is that various investigators had shown that it’s present in neurons and, unlike in some other cell types, it’s normally present in the active form in neurons. Even in the absence of any imposed stimulation of the nerve cells, this transcription factor is active. We were interested in seeing if NF-kappaB played a role in some of the effects of these neurotrophic factors we were studying. What we discovered was that if we activated NF-kappaB in nerve cells, that was sufficient to protect the cells from being killed by these different insults. One of the major discoveries here, and it was very controversial at the time, was described in a 1995 paper in PNAS in which we showed that a cytokine called tumor necrosis factor, or TNF, can activate NF-kappaB and can protect neurons from being killed by several different insults (S.W. Barger, et al., PNAS, 92[20]: 9328-32, 1995). It was controversial because TNF was discovered precisely due to its ability to kill some types of tumor cells—that’s why it got its name. So we found that TNF promoted the survival of neurons, which are very different from tumor cells. Then we discovered that NF-kappaB, this transcription factor, plays a critical role in TNF’s ability to promote the survival of neurons. Interestingly, in 1996, the next year, three papers appeared in the same issue of Science, one from David Baltimore’s lab, which showed that although TNF kills tumor cells, if you block NF-kappaB in those cells, they are killed even more easily. The bottom line there was that NF-kappaB also promotes survival of tumor cells, but that it can’t overcome the killing effect of TNF. We then went on to a number of studies identifying the genes that are stimulated by NF-kappaB and that are responsible for promoting the survival of neurons. The reason our work on NF-kappaB receives so much attention now is mainly that it was some of the first work on NF-kappaB in neurons and, second, that it revealed cell-survival-promoting function of NF-kappaB, which had not been previously recognized by anyone, including David Baltimore, the factor’s original discoverer.

  Lately, you’ve been doing a lot of work on calorie restriction and its effect on neurodegeneration. What got you into this area of research?

We’ve always been interested in trying to protect nerve cells in various models of neurodegenerative disorders, whether with growth factors or anti-oxidants. We did a lot of work studying different anti-oxidants, showing they could protect neurons. Right before I moved here to the NIA, I began studying the question of whether, by manipulating the diets of rats and mice, we could modify the vulnerability of neurons in models for Alzheimer’s, Parkinson’s, Huntington’s, and stroke. I was aware that the only known way to increase the life span of rats and mice—and it’s now being shown in monkeys—is to reduce calorie intake. In animals, caloric restriction not only increases life span but also decreases the incidence of age-related diseases, like cardiovascular disease, diabetes, and cancer.

So we did a set of studies with a very simple design. We took rats or mice, put them on a normal ad libitum diet, and compared them to an experimental group on which we used a diet strategy that’s called meal skipping. It’s essentially food deprivation. So one day a week, in the morning, you take food away and you don’t give them any food that day. It’s been shown that this meal-skipping diet extends the life span of rats and mice.

We now have a number of different animal models of neurodegenerative disorders: we have stroke, where we block off a blood vessel in the brain; we have Parkinson’s, which involves administering a toxin to mice that selectively damages dopamine-producing neurons; and we have a couple models related to Alzheimer’s. One involves a presenilin-mutant mouse. What we’ve found, and we’ve probably published 10 papers by now, is a very robust neuro-protective effect of the dietary-restriction regime, if we maintain the animals on the regimen for at least several weeks or a month. It improves functional outcomes in all these models.

  Do you have any idea what the mechanism is?

We think that the nerve cells become more resistant to being killed in these models. In these animals on dietary restriction, we see increased production of certain neurotrophic factors. One such factor, which increases the most of all the ones we’ve looked at so far, is known as BDNF, for brain-derived neurotrophic factor. We had previously shown that this BDNF growth factor can protect neurons from being killed by, for example, glutamate. And we have evidence that increase in BDNF levels makes an important contribution to the neuro-protective effect of dietary restriction. There’s another class of proteins that we’ve found at increased levels in nerve cells of dietary-restricted animals; we call these stress-resistance proteins—heat-shock proteins, for example. These play an important role in protecting cells under stressful conditions. So those are the two major types of changes we have seen: increased neurotrophic factors and increased stress-resistance proteins.

  Are there other circumstances that affect BDNF levels?

This is actually where it gets even more interesting, because increases in BDNF have been shown to occur, for instance, during physical exercise. If rats or mice are provided access, for example, to the running wheel every day, BDNF in the brain increases. The other manipulation that produces a similar elevation is what’s called environmental enrichment. Normally rats and mice are maintained in boring cages, where they have nothing to do. But if you put rats and mice in bigger cages, with lots of toys to play with, and they get more exercise as well—that hasn’t been completely sorted out yet—BDNF levels increase. It’s interesting, because if you look at some of the risk factors for Alzheimer’s, there aren’t a lot known yet, but one is that people who use their brains a lot seem to be protected, and the other is that exercise seems to reduce risk. It’s also been reported that levels of BDNF are decreased in brains of patients with Alzheimer’s disease.

  Does the research on BDNF extend beyond Alzheimer’s? What about other diseases?

We’ve also done some fascinating work with BDNF and Huntington’s. Reading the literature, you find out that Huntington’s disease patients essentially are all hyperglycemic. They have a diabetes-like condition. It’s also been shown from studying the brain tissue of individuals who die from Huntington’s that they have decreased BDNF levels. The same is true in transgenic mice with an abnormal Huntington’s gene: they are hyperglycemic and have reduced BDNF levels in the brain. As I mentioned, we found that dietary restriction increases BDNF levels. Well, one of the most striking and highly reproducible effects of dietary restriction is to increase insulin sensitivity, which means typically that blood glucose levels decrease somewhat as well. Huntington’s mutant mice have an abnormal glucose tolerance test. We had a paper on that in PNAS recently (W.Z. Duan, et al., PNAS, 100[5]: 2911-6, 2003). However, when you put them on dietary restriction, their blood glucose is greatly improved. Moreover, these mice at some point start to have motor dysfunction and can’t walk very well. On dietary restriction, the onset of motor dysfunction was delayed and they lived considerably longer—5% to 10% longer. And now we have evidence that the decreased BDNF levels in the brains of these mice are somehow causing, or at least contributing to, the inability of these animals to regulate blood glucose levels. We don’t know how it’s occurring, but we think that these decreased BDNF levels play an important role in the abnormal glucose regulation of these mice.

So right now we have a major effort going on to try to understand these signaling pathways in the brain that are involved not only in neuro-protection and resistance to age-related neurodegenerative disorders, but also in regulating blood glucose and in regulating life span.

  Can you give us a prediction of where your research might be going in the short term? Are there clinical implications we should know about?

I divide this issue into two different directions: One is coming up with recommendations for dietary changes that may prevent neurodegenerative disorders. In addition to dietary restriction, for example, we’re working on other dietary factors such as folic acid, and we have a lot of evidence that folic acid may be important in protecting nerve cells during aging. We’re also working on dietary lipids. Cholesterol is a hot topic now in the Alzheimer’s field. In fact, they’re now doing clinical trials of statins on Alzheimer’s patients. Evidence is emerging that there’s a role for cholesterol in the pathogenesis of Alzheimer’s. We’re starting to study the underlying mechanisms in nerve cells, and we’re finding that by manipulating cholesterol regulation in nerve cells we can affect their vulnerability in different models. So there may be some manipulations of dietary fats that might be beneficial. Since I’m not a clinician, the only way I can move things to the clinic is to work with clinicians. And one of the reasons I came to NIA is that they have a good clinical program.

In addition to these dietary manipulations, we also have some drugs designed and developed and in various preclinical stages. An example that is prominent right now is p53 inhibitors. The tumor-suppressor protein p53 was discovered because mutations in p53 may be important in certain types of cancer, and cells that are defective in p53 are very hard to kill. We and others found that p53 plays a role in the death of neurons, at least in cell culture and in animal models of neurodegenerative disorders. We now have a compound called PFT-alpha that is a selective p53 inhibitor. And we’ve shown that it is neuro-protective in some models. We’ve synthesized about 50 different analogs of this PFT-alpha and we’ve found a couple that are even more effective at inhibiting p53 and protecting neurons. We’ve published several papers, one in the Annals of Neurology, where we showed that p53 inhibitors are effective in Parkinson’s models (W.Z. Duan, et al., Ann. Neurol., 52[5]: 597-606, 2002). And now we’re at the stage where we’re doing safety studies in animals to make sure these compounds don’t have any obvious side effects.

  Do you think it will someday be possible to cure these neurodegenerative diseases? Or do you think the best we’ll be able to do is slow or stop the progress?

I am more and more convinced that we have to take this approach of trying to prevent age-related neurodegenerative diseases. Cures would be great, but the reality of these diseases is that unless we get some very early diagnosis for the most common cases, by the time the patients become symptomatic the process is in full swing and will be very difficult to control. I think the best we can hope for is to slow down the course of disease. With Alzheimer’s disease, for instance, I think it will be unlikely that we’ll ever be able to stop it in its tracks or reverse it. But preventing it may be a different story.