Mark Mattson Discusses the Relationship Between Energy Metabolism & Alzheimer's
Special Topic of Alzheimer's Disease Interview, July 2011
In our Special Topic on Alzheimer's Disease, the work of Dr. Mark P. Mattson ranks at #6 by total cites and #18 by total papers, based on 176 papers cited 11,195 times during the analysis period. Two of these papers appear on the top 20 lists and one is part of the Research Front Map, "Alzheimer's Beta-Amyloid Fibrils."
Mattson is among the top 1% of researchers in the fields of Neuroscience & Behavior, Clinical Medicine, Biology & Biochemistry, Molecular Biology & Genetics, and Social Sciences Essential Science IndicatorsSM from Thomson Reuters. His overall record in the database includes 340 papers cited a total of 14,276 times between January 1, 2001 and February 28, 2011.
Mattson is the Chief of the Laboratory of Neurosciences at the National Institute on Aging, part of the National Institutes of Health, in Baltimore, Maryland. He is also the Editor-in-Chief of both Ageing Research Reviews and NeuroMolecular Medicine.
When did your Alzheimer's work begin to pay off and lead to findings that are meaningful today in how we think about this disease?
That was in the early 1990s. We started studying what might be responsible for the death of nerve cells in Alzheimer's disease. That was when the amyloid story was taking off, because the amyloid beta peptide had been identified and the amino acid sequence was known. Shortly after that, the amyloid precursor protein was cloned, and so on. Bruce Yankner at Harvard was the first to show that the amyloid beta peptide can damage and kill neurons, and we followed up closely on his findings and started to elucidate the molecular mechanism responsible for the damaging effects of this peptide.
We found two main processes going on. One was that this peptide, when it's self-aggregating, causes oxidative stress, and this seems to be particularly bad when the peptide is aggregating on the surface of nerve cells. We showed that the oxidative stress caused by amyloid disrupts calcium regulation in the neurons and makes them very vulnerable to, for example, the damaging effects of glutamate receptor activation or to reduced energy levels.
"There is pretty good epidemiologic evidence that people who keep their minds active and engaged during midlife are at reduced risk for Alzheimer's."
Some think that during normal aging, the ability of nerve cells to maintain energy levels is reduced. So if amyloid is accumulating along with the changes induced by normal aging, the amyloid might tip the neurons over the edge and cause them to degenerate.
How did you follow up on those findings?
It was about that time that we developed some pretty reasonable animal models for Alzheimer's disease, as well as Huntington's disease and Parkinson's, based on genetic defects that cause those diseases in humans—for instance, defects in the gene that codes for the amyloid precursor protein or for presenilin-1, both of which will increase production of amyloid beta peptide and the accumulation of amyloid in the brain.
So various mouse models were developed that get age-related amyloid accumulation, learning and memory impairment, and even, in some models, changes in the cytoskeleton. And we got interested in what kind of lifestyle or environmental factors might modify the disease process in these models.
What did you learn? What lifestyle or environmental factors play an important role?
One factor we discovered that had a beneficial effect was dietary energy restriction. A dietary regimen that we used with our animal models was alternative day fasting. If we maintain our mouse models on alternative day fasting diet, the age of onset of symptoms, whether the cognitive impairment in the Alzheimer's model, or the movement problems in the Huntington's or Parkinson's models, was shifted. There was a delay in the onset of these diseases.
The mice live to an older age without developing symptoms, and the progress, for example, in the Alzheimer's model, of the amyloid deposition was slowed down. Learning and memory impairment were delayed. They weren't completely prevented, but highly significantly delayed. We've been doing that research since the late 1990s and we're still doing it. We're trying to understand what changes are occurring in the brain that confer this effect of dietary energy restriction.
One thing we've found that's been holding up really well is that dietary energy restriction results in the increased production of neurotrophic factors, including brain-derived neurotrophic factor (BDNF), and that's proven to be really interesting because other laboratories have shown that BDNF plays critical roles in learning and memory.
It also plays an important role in neurogenesis, the production of new nerve cells from stem cells in the brain. What's also been shown by many labs, and we've found this also to be true, is that BDNF can protect neurons from being damaged and killed by adverse conditions of the kind we think occur in aging and Alzheimer's disease. For example, BDNF will increase glucose uptake in the nerve cells and increase ATP levels in these cells, which is a good thing. So that's one way in which we think the calorie restriction can benefit the brain.
Are there other mechanisms through which dietary restriction might play a role in delaying symptoms and slowing disease progression?
We've also found that dietary energy restriction increases production of a class of proteins called chaperones. These are the proteins that function to protect cells against stress. Some of these are called heat-shock proteins. And these could also be playing a role.
Related to this is work done by other scientists here—Josephine Egan and Nigel Greig—on the role of GLP-1, glucagon-like peptide one. When you eat a meal, this peptide is released from the gut and it will promote insulin production and release from pancreatic beta cells. But perhaps more importantly, from the diabetic standpoint, GLP-1 acts on muscle and liver cells to increase sensitivity to insulin. GLP-1 has a very short half-life of about two minutes. The reason is that there's a protease in the blood that cleaves GLP-1 and inactivates it.
What we discovered is that nerve cells have GLP-1 receptors and that GLP-1 in the blood gets into the brain. Moreover, there's a diabetes drug called Byetta (exenatide), which is a genetically modified version of GLP-1 and is not cleaved by the protease and so has a longer half-life. When we give Byetta to Alzheimer's mice or Huntington's Disease mice, it has beneficial effects in delaying the disease onset and slowing down the disease process. We published papers on that in the past few years.
Are you considering trying Byetta on Alzheimer's disease in humans in a clinical trial?
Yes. We recruited a neurologist named Dimitrios Kapogiannis here at NIA, and he is now conducting a clinical trial of Byetta in patients who are in an early stage of Alzheimer’s disease. We know this drug will improve their glucose regulation, and we have done some studies and others have, as well, that have indicated that diabetes, particularly long-standing diabetes, can impair cognitive function. It's not good to be insulin resistant and have diabetes and it's particularly bad for the brain.
"...we got interested in what kind of lifestyle or environmental factors might modify the disease process in these models."
So we know this drug will improve glucose regulation and lower insulin levels. And based on the animal studies, we also think Byetta will get into the brain and have a direct effect slowing down the disease process. We will see what happens.
What would you say is the most exciting research to come out of your laboratory in the last five years?
That's it. This is the most exciting. We've gone all the way from the basic research discovering the effects of the peptide GLP-1 on energy metabolism in the brain to clinical trials of an improved version of GLP-1 (Byetta) in patients.
What would you say are the most significant results outside your own work that is effecting where Alzheimer's research stands today?
There are a lot of interesting projects going on in different areas, but the most significant findings recently are the failure of clinical trials with drugs that target amyloid production. For a long time, those drugs were the most exciting thing being pursued. If we could inhibit production of the amyloid beta peptide, that would decrease amyloid levels in the brain and slow down or stop amyloid, or so we thought.
If we put the amyloid-targeted approaches aside, we're not left with a heck of a lot. There are a lot more clinical trials ongoing, and I hate to be somewhat pessimistic, but they're not really with drugs that would be expected to have a very dramatic effect on the disease—anti-inflammatory agents, for instance, or anti-oxidants.
So my view is that prevention is the key, and the most exciting thing happening is the emerging evidence that one's risk factor for Alzheimer's can be decreased by modification of diet and lifestyle. And the same things that reduce risk for other age-related diseases—cardiovascular disease, cancer, diabetes—such as regular exercise, moderation in dietary energy intake, exercising the brain in a challenging way, seem to be very important. There is pretty good epidemiologic evidence that people who keep their minds active and engaged during midlife are at reduced risk for Alzheimer's.
Another area that's significantly affecting research and our hopes for the future is early diagnosis. One could make a parallel with cancer research. Beginning in the early 1970s, intensive work conducted and supported by the National Cancer Institute (NCI) resulted in development of methods used today for early diagnosis for many cancers, and treatments that, in many cases, either cure the cancer or at least stop for a meaningful time period the growth or spread of the tumors.
In Alzheimer's disease, a similar approach has begun, although the current budget climate may constrain funding of such efforts. We're making progress through several efforts funded and conducted by NIA, but we have to keep working on ways to identify people at increased risk for Alzheimer's and people in the preclinical stages so that we can start interventions early enough. Unfortunately at this point we don't really have drugs that clearly will have a preventive effect. Quite a bit of the work is still in animal models. We need studies in humans and we need to understand how to diagnose this disease early and prevent it.
Mark P. Mattson, Ph.D.
Laboratory of Neurosciences
National Institute on Aging
Baltimore, MD, USA
MARK P. MATTSON'S MOST CURRENT MOST-CITED PAPER IN ESSENTIAL SCIENCE INDICATORS:
Oddo S, et al., "Triple-transgenic model of Alzheimer’s disease with plaques and tangles: Intracellular A beta and synaptic dysfunction," Neuron 39(3): 409-21, 31 July 2003 with 742 cites. Source: Essential Science Indicators from Thomson Reuters.
- Fast Moving Front, September 2010
- Fast Breaking Paper, August 2005
- Science Watch® Newsletter Classic Interview, September 2003
KEYWORDS: ALZHEIMER’S DISEASE, NEURONS, AMYLOID BETA PEPTIDE, MOLECULAR MECHANISM, SELF-AGGREGATING, OXIDATIVE STRESS, CALCIUM REGULATION, GLUTAMATE RECEPTOR ACTIVATION, REDUCED ENERGY LEVELS, NEURONAL DEGENERATION, ANIMAL MODELS, HUNTINGTON’S, PARKINSON’S, GENETIC DEFECTS, AMYLOID PRECUSOR PROTEIN, PRESENILIN-1, LEARNING, MEMORY, CYTOSKELETON, LIFESTYLE, ENVIRONMENTAL FACTORS, DIETARY ENERGY RESTRICTION, NEUROTROPHIC FACTORS, BDNF, NEUROGENESIS, GLUCOSE UPTAKE, ATP LEVELS, CHAPERONE PROTEINS, GLP-1, BYETTA, DISEASE ONSET, DIABETES, INSULIN, CLINICAL TRIALS, PREVENTION, RISK FACTORS, EARLY DIAGNOSIS.