- Mark Mattson
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Mark Mattson 2009
Mark P. Mattson is Chief of the Laboratory of Neurosciences at the National Institute on Aging Intramural Research Program National Institute on Aging. He is also professor of Neuroscience at Johns Hopkins University.
Mark P. Mattson was born in 1957 in Rochester Minnesota. His wife Joanne and he are the parents of son Elliot and a daughter Emma.
After receiving his PhD degree from the University of Iowa, Dr. Mattson completed a postdoctoral fellowship in Developmental Neuroscience at Colorado State University. He then joined the Sanders-Brown Center on Aging and the Department of Anatomy and Neurobiology at the University of Kentucky College of Medicine as an Assistant Professor. Dr. Mattson was promoted to the rank of Associate Professor with tenure and then to Full Professor. In 2000, Dr. Mattson took the position of Chief of the Laboratory of Neurosciences at the National Institute on Aging in Baltimore, where he leads a multi-faceted research team that applies cutting-edge technologies in research aimed at understanding molecular and cellular mechanisms of brain aging and the pathogenesis of neurodegenerative disorders. He is also a Professor in the Department of Neuroscience at Johns Hopkins University School of Medicine.
Dr. Mattson 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 the pathogenesis of Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and stroke, and to their prevention and treatment. He has published more than 700 peer-reviewed articles in leading journals and books, and has edited 10 books in the areas of neuronal signal transduction, neurodegenerative disorders and mechanisms of aging. Dr. Mattson is the most highly cited neuroscientist in the world according to the ISI information database (http://www.in-cites.com/top/2006/second06-neu.html), and he has an h index of over 130 (i.e., he has authored more than 130 articles that have each been cited at least 120 times; see http://scholar.google.com/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22MP+Mattson%22&as_publication=&as_ylo=&as_yhi=&as_sdt=1.&as_sdtp=on&as_sdts=21&hl=en).
Profiles of Dr. Mattson have been published in numerous forums including: Science Watch (http://archive.sciencewatch.com/sept-oct2003/sw_sept-oct2003_page3.htm). Nature Medicine (http://www.nature.com/nm/journal/v10/n4/full/nm0404-324.html).
Dr. Mattson has received many awards including the Metropolitan Life Foundation Medical Research Award, the Alzheimer’s Association Zenith Award, the Jordi Folch Pi Award, the Santiago Grisolia Chair Prize, and several Grass Lectureship Awards. He was elected as a Fellow of the American Association for the Advancement of Science. He is Editor-in-Chief of NeuroMolecular Medicine and Ageing Research Reviews, and has been/is a Managing or Associate Editor of the Journal of Neuroscience, Trends in Neurosciences, the Journal of Neurochemistry, the Neurobiology of Aging, and the Journal of Neuroscience Research. Dr. Mattson has served on several NIH study sections and on scientific advisory boards for many research foundations. He has trained more than 70 postdoctoral and predoctoral scientists, and has made major contributions to the education of undergraduate, graduate and medical students.
Contributions to Neuroscience Research Research by Dr. Mattson in the area of molecular and cellular mechanisms that regulate neuronal plasticity and survival, in the contexts of brain development and aging, has established a new conceptual framework for understanding the pathogenesis of neurodegenerative disorders. He showed that perturbations of cellular signaling mechanisms that regulate developmental neuroplasticity are responsible for synaptic dysfunction and cell death in neurodegenerative disorders. In particular, he has been a leader in advancing an understanding of the molecular events that destabilize cellular calcium homeostasis and ultimately cause the death of neurons in AD, Parkinson’s disease, ALS and stroke. Here are 9 specific examples of seminal findings of Dr. Mattson that represent major advances in the fields of neuroscience and neurodegenerative disorders.In his early research Dr. Mattson discovered that the neurotransmitter glutamate, previously believed to function only at synapses, plays a key role in regulating dendrite outgrowth and synaptogenesis. He then showed that neurotrophic factors can modify the effects of neurotransmitters on neurite outgrowth, synaptogenesis and cell survival. Glutamate and neurotrophic factors exert their effects on neuronal plasticity and survival by modulating cellular calcium homeostasis. These findings revealed the molecular basis for activity-dependent regulation of neuronal plasticity. Importantly, Dr. Mattson’s discovery that neurotrophic factors such as bFGF, BDNF and IGFs can protect neurons against dysfunction and degeneration in experimental models of stroke and Alzheimer’s disease led to clinical trials of neurotrophic factor delivery in patients with stroke and neurodegenerative disorders. His seminal and highly cited findings in this area were published in multiple articles in the Journal of Neuroscience and Neuron.
A major contribution to the fields of neuroscience and neurology were Dr. Mattson’s studies that elucidated mechanisms of synaptic dysfunction and degeneration in AD. He showed that Ab induces membrane-associated oxidative stress which disrupts calcium homeostasis and renders neurons vulnerable to excitotoxicity and apoptosis. The latter work showed that the lipid peroxidation product 4-hydroxynonenal mediates Ab toxicity by covalently modifying ion-motive ATPases, and glucose and glutamate transporters. He also showed that presenilin mutations endanger neurons by perturbing endoplamic reticulum calcium regulation. Hes work also revealed a physiological role for the secreted form of amyloid precursor protein generated by alpha-secretase activity (sAPPalpha). He showed that sAPPalpha suppresses neuronal excitability and protects neurons against excitotoxicity by a mechanism involving activation of receptors coupled to cyclic GMP production and activation of potassium channels. The findings described above were published over a period of 10 years in multiple articles in journals such as Nature, Science, Neuron, PNAS and the Journal of Neuroscience.
Dr. Mattson was the first to report that TNF and NF-kB can promote neuronal survival, and he went on to show that the mechanism involves up-regulation of the expression of manganese superoxide dismutase and Bcl-2, and stabilization of cellular calcium homeostasis. These provocative findings led to a 180 degree turn in the view of pro-inflammatory cytokines and NF-kB in neuronal injury by establishing that activation of NF-kB in neurons is part of an adaptive response aimed at protecting the neurons. These findings were published in Nature Medicine, Neuron, PNAS and the Journal of Neuroscience.
A series of findings by Dr. Mattson during the 1990s and 2000s established links between diet and the pathogenesis of neurodegenerative disorders. He has shown that dietary energy restriction can increase the resistance of neurons in the brain to dysfunction and degeneration in animal models of Alzheimer’s, Parkinson’s and Huntington’s diseases and stroke. The underlying mechanism was shown to involve increased production of neurotrophic factors and protein chaperones, suggesting an adaptive response of brain cells to the stress associated with dietary energy restriction. Findings from studies of rodent models were published in the Annals of Neurology, PNAS and the Neurobiology of Disease. Findings from a study using a monkey model of Parkinson’s disease were published in PNAS. Collectively, these findings provide an example of how Dr. Mattson’s basic research into the biochemistry and biology of neuronal plasticity and death has provided information that can be directly applied to improving the human condition.
Discoveries made in Dr. Mattson’s laboratory led to a new view of apoptotic biochemical cascades in the physiological regulation of synaptic plasticity and structural remodeling, and introduced the neuroscience field to the concept of “synaptic apoptosis”. He showed that, by cleaving specific glutamate receptor subunits, caspases play important roles in regulating synaptic plasticity, an entirely new and unexpected function of apoptotic proteases. These findings were published in the Journal of Neuroscience, the JBC and Experimental Neurology.
Dr. Mattson’s work has revealed mechanisms by which diabetes adversely affects hippocampal plasticity and cognitive function. In a study published in Nature Neuroscience he showed that, in both insulin-deficient rats and insulin-resistant mice, diabetes impairs hippocampus-dependent memory, perforant path synaptic plasticity and adult neurogenesis, and the adrenal steroid corticosterone contributes to these adverse effects. Changes in hippocampal plasticity and function in both models were reversed when normal physiological levels of corticosterone were maintained, suggesting that cognitive impairment in diabetes may result from glucocorticoid-mediated deficits in neurogenesis and synaptic plasticity. In a related study published in Hippocampus, Mattson showed that rats fed with a high-fat, high-glucose diet supplemented with high-fructose corn syrup exhibit alterations in energy and lipid metabolism similar to clinical diabetes, with elevated fasting glucose and increased cholesterol and triglycerides. Rats maintained on this diet for 8 months exhibited impaired spatial learning ability, reduced hippocampal dendritic spine density, and reduced long-term potentiation at Schaffer collateral—CA1 synapses. These changes occurred concurrently with reductions in levels of BDNF in the hippocampus. Dr. Mattson also investigated whether manipulations that enhance neurotrophin levels will also restore neuronal structure and function in diabetes. He found that running wheel activity, caloric restriction, or the combination of the two treatments increased levels of BDNF in the hippocampus of db/db mice. Enhancement of hippocampal BDNF was accompanied by increases in dendritic spine density on the secondary and tertiary dendrites of dentate granule neurons. These studies suggest that diabetes exerts detrimental effects on hippocampal structure, and that this state can be attenuated by increasing energy expenditure and decreasing energy intake. The implications of these findings for cognitive aging are clear – dietary moderation and regular exercise will enhance cognitive function.
The key roles of toll-like receptors (TLRs) as mediators of the detection and responses of immune cells to invading pathogens are well known. However, Dr. Mattson recently discovered that neurons also express a subset of TLRs and that their activation promotes neuronal degeneration in experimental models of stroke and AD. He has also provided evidence that TLRs play roles in regulating the processes of neurogenesis and neurite outgrowth, suggesting roles in neuronal plasticity. TLR2 and TLR4 levels are increased in cerebral cortical neurons in response to ischemia/reperfusion injury, and the amount of brain damage and neurological deficits caused by a stroke are significantly less in mice deficient in TLR2 or -4 compared with WT control mice. Mattson found that TLR4 expression increases in neurons when exposed to Ab or the lipid peroxidation product 4-hydroxynonenal (HNE). Neuronal apoptosis triggered by Ab and HNE is mediated by jun N-terminal kinase (JNK); neurons from TLR4 mutant mice exhibit reduced JNK and caspase-3 activation and were protected against apoptosis induced by Ab and HNE. Levels of TLR4 are decreased in inferior parietal cortex tissue specimens from end-stage AD patients compared to aged-matched control subjects, possibly as the result of loss of neurons expressing TLR4. These findings, which were published in PNAS, the Journal of Neuroscience and the Journal of Neurochemistry suggest that TLR4 signaling increases the vulnerability of neurons to Ab and oxidative stress in AD, and identify TLR4 as a potential therapeutic target for stroke and AD.
Glucagon-like peptide-1 (GLP-1) is an endogenous insulinotropic peptide secreted from the gastrointestinal tract in response to food intake. It enhances pancreatic islet beta-cell proliferation and glucose-dependent insulin secretion, and lowers blood glucose and food intake in patients with type 2 diabetes mellitus (T2DM). A long-acting GLP-1 receptor (GLP-1R) agonist, exendin-4 (Ex-4), is the first of this new class of antihyperglycemia drugs approved by the FDA to treat T2DM. Mattson and his colleagues at the National Institute on Aging have shown that GLP-1Rs are expressed in neurons where they are coupled to the cAMP second messenger pathway resulting in neurotrophic actions. For example, he showed that Ex-4 can protect neurons from being damaged and killed by Ab. Administration of Ex-4 reduced brain damage and improved functional outcome in a transient middle cerebral artery occlusion stroke model, and also protected dopaminergic neurons against degeneration, preserved dopamine levels, and improved motor function in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Moreover, Ex-4 treatment ameliorated abnormalities in peripheral glucose regulation and suppressed cellular pathology in both brain and pancreas in a mouse model of Huntington's disease. The treatment also improved motor function and extended the survival time of the Huntington's disease mice. The preclinical findings from their studies of GLP-1 and Ex-4 were published in PNAS and Diabetes. Because Ex-4 improves glucose regulation and exerts direct neuroprotective actions on neurons in the brain, Dr. Mattson is working with a neurologist at the NIA Intramural Clinical Program to test the efficacy of Ex-4 in patients with Alzheimer’s disease.
Life Outside the Laboratory
Dr. Mattson is an off-road motorcycle rider, having raced motocross and competed in observed trials in the 1970s; he continues to ride a trials bike for pleasure. Taught by his father DeWayne, Mark learned how to train and drive standardbred race horses (trotters and pacers), and was well known for his achievements on race tracks in Minnesota, Wisconsin, Iowa and Michigan during the 1970s and 1980s. He has also been a competitive runner and is currently a varsity cross country coach at Patterson Mill High School in Bel Air, Maryland. In addition, Dr. Mattson is a Master Gardener and also enjoys raising egg-laying chickens.
References
Mattson MP, Murrain M, Guthrie PB, Kater SB (1989) Fibroblast growth factor and glutamate: Opposing actions in the generation and degeneration of hippocampal neuroarchitecture. J. Neurosci. 9:3728-3740.
Mattson MP (1990) Antigenic changes similar to those seen in neurofibrillary tangles are elicited by glutamate and calcium influx in cultured hippocampal neurons. Neuron 4:105-117.
Cheng B, Mattson MP (1991) NGF and bFGF protect rat and human central neurons against hypoglycemic damage by stabilizing calcium homeostasis. Neuron 7:1031-1041.
Mattson MP, Cheng B, Davis D, Bryant K, Lieberburg I, Rydel RE (1992) b-amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J. Neurosci. 12:376-389.
Cheng B, Christakos S, Mattson MP (1994) TNFs protect neurons against excitotoxic/metabolic insults and promote maintenance of calcium homeostasis. Neuron 12:139-153.
Furukawa K, Barger SW, Blalock E, Mattson MP (1996) Activation of K+ channels and suppression of neuronal activity by secreted b-amyloid precursor protein. Nature 379: 74-78.
Bruce AJ, Boling W, Kindy MS, Peschon J, Kraemer PJ, Carpenter MK, Holtsberg FW, Mattson MP (1996) Altered neuronal and microglial responses to brain injury in mice lacking TNF receptors. Nature Medicine 2: 788-794.
Mark RJ, Pang, Z, Geddes JW, Uchida K, Mattson MP (1997) Amyloid b-peptide impairs glucose uptake in hippocampal and cortical neurons: involvement of membrane lipid peroxidation. J. Neurosci. 17: 1046-1054.
Guo Q, Fu W, Sopher BL, Miller MW, Ware CB, Martin GM, Mattson MP (1999) Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knockin mice. Nature Medicine 5: 101-107.
Glazner GW, Chan SL, Lu C, Mattson MP (2000) Caspase-mediated degradation of AMPA receptor subunits: a mechanism for preventing excitotoxic necrosis and ensuring apoptosis. J. Neurosci. 20: 3641-3649.
Duan W, Guo Z, Jiang H, Ware M, Li XJ, Mattson MP (2003) Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice. Proc. Natl. Acad. Sci. U.S.A. 100: 2911-2916.
Cutler RG, Kelly J, Pedersen WA, Tammara A, Hatanpaa K, Troncoso JC, Mattson MP (2004) Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer’s disease. Proc. Natl. Acad. Sci. U.S.A. 101: 2070-2075.
Kruman II, Wersto RP, Cardozo-Pelaez F, Smilenov L, Chan SL, Chrest FJ, Emokpae R, Gorospe M, Mattson MP (2004) Cell cycle activation linked to neuronal cell death initiated by DNA damage. Neuron 41:549-561.
Wang Y, Chan SL, Miele L, Yao PJ, Mackes J, Ingram DK, Mattson MP, Furukawa K (2004) Involvement of Notch signaling in hippocampal synaptic plasticity. Proc. Natl. Acad. Sci. U.S.A. 101: 9458-9462.
Mattson MP (2004) Pathways towards and away from Alzheimer's disease. Nature 430:631-639.
Maswood N, Young J, Tilmont E, Zhang Z, Gash DM, Gerhardt GA, Grondin R, Roth GS, Mattison J, Lane MA, Carson RE, Cohen RM, Mouton PR, Quigley C, Mattson MP, Ingram DK (2004) Caloric restriction increases GDNF levels and attenuates neurochemical and behavioral deficits in a primate model of Parkinson's disease. Proc. Natl. Acad. Sci. U.S.A. 101:18171-18176.
Arumugam TV, Chan SL, Jo DG, Yilmaz G, Tang SC, Gleichmann M, Cheng A, Okun E, Dixit VD, Chigurupati S, Mughal M, Ouyang X, Miele L, Magnus T, Poosala S, Granger DN, Mattson MP (2006) Gamma secretase-mediated notch signaling worsens brain damage and functional outcome in ischemic stroke. Nature Medicine 12:621-623.
Tang SC, Arumugam TV, Xu X, Cheng A, Mughal MR, Jo DG, Lathia JD, Siler DA, Chigurupati S, Ouyang X, Magnus T, Camandola S, Mattson MP. (2007) Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits. Proc. Natl. Acad. Sci. U.S.A. 104:13798-13803.
Stranahan AM, Arumugam TV, Cutler RG, Lee K, Egan JM, Mattson MP (2008) Diabetes impairs hippocampal function via glucocorticoid-mediated effects on new and mature neurons. Nature Neurosci. 11:309-317.
Mattson MP, Gleichmann M, Cheng A (2008) Mitochondria in neuroplasticity and neurological disorders. Neuron 60:748-766.
Martin B, Golden E, Carlson OD, Pistell P, Zhou J, Kim W, Frank BP, Thomas S, Chadwick WA, Greig NH, Bates GP, Sathasivam K, Bernier M, Maudsley S, Mattson MP, Egan JM (2009) Exendin-4 improves glycemic control, ameliorates brain and pancreatic pathologies, and extends survival in a mouse model of Huntington's disease. Diabetes 58:318-328.
Arumugam TV, Phillips TM, Cheng A, Morrell CH, Mattson MP, Wan R (2010) Age and energy intake interact to modify cell stress pathways and stroke outcome. Ann Neurol. 67:41-52.
Martin B, Ji S, Maudsley S, Mattson MP (2010) "Control" laboratory rodents are metabolically morbid: Why it matters. Proc. Natl. Acad. Sci. U.S.A. 107: 6127-6133.
Okun E, Griffioen K, Barak B, Roberts NJ, Castro K, Pita MA, Cheng A, Mughal MR, Wan R, Ashery U, Mattson MP (2010) Toll-like receptor 3 inhibits memory retention and constrains adult hippocampal neurogenesis. Proc. Natl. Acad. Sci. U.S.A. 107:15625-15630.
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- Johns Hopkins University faculty
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