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Mark P. Mattson, Ph.D. Mark P. Mattson, Ph.D., Senior Investigator
Chief, Cellular and Molecular Neurosciences Section and
Chief, Laboratory of Neurosciences

Biography: Dr. Mattson received his Ph.D. in Biology from the University of Iowa in 1986. After 3 years of postdoctoral studies in Developmental Neuroscience at Colorado State University, Dr. Mattson took a faculty position at the Sanders-Brown Research Center on Aging at the University of Kentucky Medical Center where he was promoted to Full Professor in 1997. Dr. Mattson is currently Chief of the Laboratory of Neurosciences at the National Institute on Aging, and Professor of Neuroscience at Johns Hopkins University. He is Editor-in-Chief of the Ageing Research Reviews, and a Managing or Associate Editor of the Journal of Neurochemistry and Journal of Neuroscience Research. In addition, he has edited 10 volumes in the areas of mechanisms of cell death, aging and age-related neurodegenerative disorders. Dr. Mattson has received numerous awards including the Metropolitan Life Foundation Award and the Alzheimer's Association Zenith Award. He is considered a leader in the area of cellular and molecular mechanisms underlying neuronal plasticity and neurodegenerative disorders, and has made major contributions to understanding of the pathogenesis of Alzheimer's disease, and to its prevention and treatment. Dr. Mattson has published more than 340 original research articles and more than 70 review articles.
Research Overview: A multifaceted array of experimental models of aging and age-related neurodegenerative disorders are being employed in Dr. Mattson's laboratory in order to establish the molecular and biochemical changes that occur during aging and in disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and stroke. Data obtained in these experimental models are integrated with data obtained in studies of both normal elderly humans and patients with neurodegenerative disorders to arrive at conclusions as to why neuronal dysfunction and degeneration occur in the disorders. In addition to identifying the molecular and cellular alterations that lead to neuronal degeneration in age-related neurological disorders, investigators are elucidating the cellular signaling mechanisms that allow successful brain aging.
Although specific brain regions are more severely affected in a given age-related neurodegenerative disorder (e.g., hippocampus in AD and substantia nigra in PD), each disorder appears to involve similar biochemical and cellular cascades that ultimately lead to dysfunction and death of the neurons. Specific components of such cascades include oxidative damage to proteins, lipids and DNA; metabolic compromise resulting from impaired glucose metabolism and mitochondrial dysfunction; and overactivation of glutamate receptors and disruption of neuronal calcium homeostasis. Each of these cascades is implicated in the pathogenesis of AD, PD and stroke. Dr. Mattson's laboratory has played a major role in elucidating such neurodegenerative cascades, and is currently working to advance our understanding of the molecular and biochemical underpinnings of age-related neurodegenerative disorders. They have shown that genetic mutations that cause AD predispose neurons to apoptosis. Ongoing work is identifying the specific molecular triggers and executioners of neuronal apoptosis in different neurodegenerative disorders with the aim of developing drugs that interact with and block the cell death cascade. Several different experimental models have proven valuable in elucidating cellular and molecular mechanisms, and in developing novel preventative and therapeutic strategies. Models of AD being employed include transgenic mice that have been engineered to express mutant genes known to cause early-onset inherited AD, or PD, Huntingtin mutant mice, and models of stroke include transient occlusion of the middle cerebral artery in rats and mice.
Perhaps of equal importance to knowledge of the molecular and cellular mechanisms that result in neuronal dysfunction and death in age-related neurodegenerative disorders, is a better understanding of successful brain aging at the cellular and molecular levels. It is clear that such "anti-aging" signaling mechanisms exist because some individuals can live for more than a century with very little decline in their cognitive or motor capabilities. A major goal of research in Dr. Mattson's laboratory is to identify the cellular signaling mechanisms that promote the survival and plasticity of neurons during aging. They have shown that signaling pathways activated by neurotrophic factors and certain cytokines can increase resistance of neurons to degeneration in experimental models of neurodegenerative disorders. The specific molecular and biochemical changes that participate in such beneficial signaling mechanisms are currently under study.
Synapses are sites of where neurotransmission and trophic factor signaling occurs. Synaptic signaling pathways play fundamental roles in both immediate brain functions such as visual recognition and responses, and body movements, and long-term changes such as learning and memory. Recent findings in Dr. Mattson's laboratory suggest that alterations in synaptic signaling occur very early in the course of AD and other age-related neurodegenerative disorders. The impact of oxidative stress, neurotrophic factor and cytokine signaling, and genetic lesions on synaptic physiology are being examined. Work is currently focussing on synaptic physiology, molecular biology and biochemistry in experimental animal models of neurodegenerative disorders.
In studies aimed at identifying preventative and therapeutic strategies for neurodegenerative disorders, the laboratory has shown that rats and mice maintained on a dietary restriction (DR) regimen exhibit increased resistance to degeneration of hippocampal neurons in models of AD, increased resistance of substantia nigra dopaminergic neurons in models of PD, and increased resistance of cortical and striatal neurons in stroke models. Interestingly, DR increases neurogenesis in the hippocampus which may possibly contribute to enhanced cognitive function and resistance to injury. The cellular and molecular mechanisms that mediate the beneficial effects of DR on brain plasticity and resistance to injury are being studied.
DNA damage increases in brain cells during aging and may be an important trigger of cell death in neurodegenerative disorders. A better understanding of mechanisms of DNA damage and repair may therefore provide a foundation for developing novel approaches for preventing neuronal degeneration. Investigators in Dr. Mattson's laboratory have identified genetic and environmental factors that may promote or prevent DNA damage and its adverse consequences in the nervous system. An example of recent findings include the demonstration that folic acid deficiency can sensitize neurons to DNA damage and death in experimental models of Alzheimer's disease and Parkinson's disease. Low levels of dietary folic acid result in an elevation of homocysteine levels. Homocysteine impairs the ability of neurons to repair DNA damage resulting in increased uracil misincorporation and oxidatively modified DNA bases. In another set of studies LNS scientists have shown that telomerase, a reverse transcriptase that prevents chromosome shortening in mitotic cells, can protect neurons against DNA damage-induced apoptosis. Additional studies have established roles for telomerase in brain development where it appears to promote neuroblast proliferation and the survival of early postmitotic neurons. Telomerase is not normally expressed in neurons in the adult brain, but LNS scientists have generated transgenic mice that do express the telomerase protein in neurons and are testing the hypothesis that their neurons will be protected against damage in experimental models of age-related neurodegenerative disorders.
Stroke is the major neurological cause of disability and death worldwide. Research in Dr. Mattson's laboratory is revealing the molecular mechanisms responsible for neuronal death after a stroke, and is developing novel therapeutic strategies for improving outcome in stroke patients. A mouse stroke model in which the middle cerebral artery is occluded resulting in highly reproducible damage to the cerebral cortex and associated sensory-motor dysfunction is employed in combination with studies of cultured brain cells. Two examples of ongoing major efforts are projects that target the tumor suppressor protein p53 and mitochondrial ATP-sensitive potassium (Mito-KATP) channels. Using molecular and biochemical analyses it has been established that p53 plays a critical role in a form of programmed cell death that occurs in neurons after a stroke. In collaboration with the Drug Design and Development Section, a panel of chemical inhibitors of p53 has been synthesized and screened for efficacy in protecting neurons against ischemic injury in culture and against stroke-induced damage in mice. Several highly effective p53 inhibitors have been identified, two of which readily cross the blood-brain barrier and are effective when given intraperitoneally. The lead agent is being moved toward phase I clinical trials. In a second project, it was discovered that a drug called diazoxide, which opens Mito-KATP channels, is very effective in reducing brain damage and improving functional recovery following a stroke in mice. This drug has already been approved by the FDA for other indications, and it is therefore hoped that it can be used in clinical trials in human stroke patients. By studying mice with targeted disruption of specific genes believed to play a role in the pathogenesis of stroke, investigators are working to identify additional therapeutic targets.
A major effort is underway to determine whether abnormalities in the process of neurogenesis, the production of new nerve cells from neural stem cells, occur in aging and age-related neurodegenerative disorders. The proliferation, differentiation and survival of neural stem cells in the hippocampus and subventricular zone/cerebral cortex are being assessed in mouse models of Alzheimer's disease, Parkinson's disease and stroke. Studies of transgenic mice expressing mutant forms of amyloid precursor protein and presenilin-1, which cause inherited forms of Alzheimer's disease in humans, exhibit defects in neurogenesis. These abnormalities appear to result from increased production of the amyloid beta-peptide and perturbed calcium regulation in the neural stem cells and their progeny. In other studies, the signals that regulate the differentiation and survival of neural stem cells are being elucidated. Investigators in the Cellular and Molecular Neurosciences Section have shown that nitric oxide and brain-derived neurotrophic factor can promote neurogenesis. Interestingly, neurogenesis can be affected by diet - caloric restriction and dietary supplementation with folic acid stimulate neurogenesis suggesting a mechanism whereby dietary factors may modify brain aging and risk of neurodegenerative disorders.
Sphingomyelin and cholesterol are important components of the plasma membrane of neurons where it functions in cellular signal transduction and cellular responses to stress. By analyzing spinal cord and brain tissues from human patients and mouse models, investigators in this section of the LNS have shown that profound abnormalities in sphingomyelin metabolism occur in amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. The alterations, which include accumulation of long-chain ceramides and cholesterol esters, occur prior to neuronal degeneration and functional deficits in the mouse models. Moreover, agents that inhibit sphingomyelin synthesis or metabolism can protect neurons from being damaged and killed in experimental models of ALS and Alzheimer's disease, suggesting that the abnormalities in lipid metabolism are central to the disease process.
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Updated: Thursday November 29, 2012