Professor, Neurology and Neuroscience
Weill Cornell Medical College
The elderly are at a greater risk for many neurodegenerative diseases. The most common of these age-related diseases are Alzheimer's, Parkinson's and Huntington’s diseases. The goals of our laboratory are to discover the underlying cause of age-related neurodegenerative diseases and to develop effective therapies.
The brain is very dependent on oxygen and glucose (sugar). Our research shows that many age-related diseases and stroke may share similar fundamental mechanisms of damage, i.e., a reduced ability to use glucose and oxygen, which either causes the disease(s) or is a critical clinically relevant change. We are trying to determine why this reduction occurs and its consequences for brain function.
Our studies show that oxidative stress induced post-translational modification of key glucose metabolic enzymes is likely to contribute to the reduced glucose utilization. Abnormalities in the use of glucose and oxygen cause an dysregulation of calcium and the production of excess free radicals, which in turn, may lead to the brain dysfunction. Thus, reversing diminished use of glucose, preventing the free radical damage, or a change in calcium with specific drugs should protect the brain. Cells from patients, genetically modified cells and animal models are being used to test these possibilities and to evaluate the effectiveness of drugs.
Dr. Gary E. Gibson received his B.S. degree in Zoology and Chemistry from the University of Wyoming. He received his Ph.D. in Physiology with emphasis in Biochemistry and Neuroscience at Cornell University. He did his postdoctoral work at UCLA He was on the faculty at UCLA He then moved to Cornell University Medical College and Burke Medical Research Institute, where he has been ever since. He is currently Professor of Neuroscience (with tenure), and is also a member of the graduate program in Neuroscience at Cornell Medical College and teaches graduate students in that program. He also served as the Associate Director of the Dementia Research Service.
Dr. Gibson received the American Society for Neurochemistry award for outstanding young investigator. He has given lectures at many institutions and honorary lectures including the Deans hour at Cornell University Medical College, the NIH Director’s Talk and the Visek Lectureship at the University of Illinois. He has served on over 20 NIH review panels for reviewing grants. He regularly reviews grants for the Alzheimer’s Association and the American Federation for Aging Research. He is a member of numerous scientific societies including the American Society for Neurochemistry (past secretary, 2005-2006), the Society for Neuroscience, the International Society for Neurochemistry, International Society for Cerebral Blood Flow and Metabolism, American Institute of Nutrition and American Society for Pharmacology and Experimental Therapeutics. He has three U.S. patents for his work. He has been continuously funded by NIH grants for his whole academic career at Cornell/Burke. He has and does serve on numerous committees at Burke and Cornell. He has served on the editorial board of several journals. He is currently on the editorial board of Neurochemical Research, Neurochemical International (Associate Editor) and Journal of Neurochemistry. He serves as an editorial advisor for many other journals. Numerous undergraduate students and postdocs have trained in his laboratory.
Research Papers since 2000
Kiss, G., Konrad, C., Doczi, J., Starkov, A. A., Kawamata, H., Manfredi, G., Zhang, S. F., Gibson, G. E., Beal, M. F., Adam-Vizi, V., Chinopoulos, C . 2013. The negative impact of alpha-ketoglutarate dehydrogenase complex deficiency on matrix substrate-level Phosphorylation. FASEB J 27:2392-2406.
Gibson GE, Chen HL, Xu H, Qiu L, Xu Z, Denton TT, Shi, Q. 2012. Deficits in the mitochondrial enzyme α-ketoglutarate dehydrogenase lead to Alzheimer’s disease-like calcium dysregulation. Neurobiology of Aging. 33: Pages 1121.e13–1121.e24. PMCID: PMC3321099. NIHMSID: NIHMS345041
Shi Q, Gibson GE. 2011. Up-regulation of the mitochondrial malate dehydrogenase by oxidative stress is mediated by miR-743a. J. Neurochem. 118: 440-448. PMCID 3135703
Shi Q, Xu H, Yu H, Zhang N, Ye Y, Estevez AG, Deng H, Gibson GE. 2011. Inactivation and reactivation of the mitochondrial α-ketoglutarate dehydrogenase complex. J. Biological Chemistry. 286: 17640-17648.
Nilsen LH, Shi Q, Gibson GE, Sonnewald U. (2011) Brain [U-13C]glucose metabolism in mice with decreased α-ketoglutarate dehydrogenase complex activity. J. Neuroscience Research. 89(12):1997-2007.
Bubber P, Haroutunian V, Gibson GE, Blass JP. 2011. Abnormalities in the tricarboxylic acid (TCA) cycle in brain of schizophrenia patients. European Neuropsychopharmacology. 21:254-260. PMCID 3033969
Huang HM, Chen HL, Gibson GE (2010) Thiamine and Oxidants Interact to Modify Cellular Calcium Stores. Neurochem Res. 35:2107–2116. PMCID 3085841
Area-Gomez E, de Groof JD, Boldogh I, Bird TD, Gibson GE, Koehler CM, Duff KE, Naini A, Bonilla E, Yaffe MP, Pon LA, Schon EA. (2009) Presenilins Are Enriched in Endoplasmic Reticulum Membranes Associated with Mitochondria. Am J Pathol. 175:1810-1816. PMCID 2774047
Yang L, Shi Q, Ho DJ, Starkov AA, Wille EJ, Xu H, Chen HL, Zhang S, Cliona M, Stack CM, Calingason NY, Gibson GE, Beal MF. (2009) Mice deficient in dihydrolipoyl succinyltransferase show increased vulnerability to mitochondrial toxins. Neurobiology of Disease. 36:320-330.
Dumont M, Ho DJ, Calingasan NY, Xu H, Gibson GE, Beal MF. 2009. Mitochondrial dihydrolipoyl succinyltransferase deficiency accelerates amyloid pathology and memory deficit in a transgenic mouse model of amyloid deposition. Free Radical Biology and Medicine. 47:1019-1027. PMCID 2761144
Shi Q, Risa Ø, Sonnewald U, Gibson GE. 2009. Mild reduction in the activity of the α-ketoglutarate dehydrogenase complex elevates GABA shunt and glycolysis. J Neurochem. 54:111-8. PMCID 2750872
Karuppagounder SS, Pinto JT, Xu H, Chen LH, Beal MF, Gibson GE. 2009. Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model of Alzheimer’s Disease. Neurochemistry International. 54:111-118. PMCID 2892907
Karuppagounder SS, X H, Shi Q, Chen LH, Pedrini S, Pechman DP, Baker, HA, Beal MF, Gandy SE, Gibson GE. 2009. Thiamine deficiency induces oxidative stress and exacerbates the plaque pathology in Alzheimer’s mouse model. Neurobiology of Aging. 30:1587-1600. PMCID 2782730
Karuppagounder SS, Xu H, Pechman D, Chen LH, Degiorgio LA and Gibson G E. (2008) Translocation of amyloid precursor protein C-terminal fragment(s) to the nucleus precedes neuronal death due to thiamine deficiency-induced mild impairment of oxidative metabolism. Neurochemical Research. 33, 1365-1372. PMCID:2870991
Calingasan NY, Ho DJ, Wille EJ, Campagna MV, RuanJ, Dumont M, Yang L, Shi Q, Gibson GE, Beal MF. (2008) Influence of mitochondrial enzyme deficiency on adult neurogenesis in mouse models of neurodegenerative diseases. Neuroscience. 153:986-996. PMCID 18423880
Shi Q, Xu H, Kleinman WA, Gibson GE. 2008. Novel functions of the α-ketoglutarate dehydrogenase complex may mediate diverse oxidant-induced changes in mitochondrial enzymes associated with Alzheimer’s disease. Biochim Biophys ActA Molecular Basis of Disease. 1782:229-238. PMCID: PMC3106300
Shi Q, Karuppagounder SS, Xu H, Pechman D, Chen H-L, Gibson GE. 2007. Responses of the mitochondrial alpha-ketoglutarate dehydrogenase complex to thiamine deficiency may underlie regional selective vulnerability. Neurochemistry International. 50:921-931. PMCID 2753422
Karuppagounder SS, Shi Q, Xu H, Gibson GE. 2007. Changes in inflammatory processes associated with selective vulnerability following mild impairment of oxidative metabolism. Neurobiology of Disease. 26:353-362. PMCID 2753424.
Zhang L, Cooper AJL, Krasnikov BF, Xu H, Bubber P, Pinto JT, Gibson GE, Hanigan MH. 2006. Cisplatin-Induced Toxicity Is Associated with Platinum Deposition in Mouse Kidney Mitochondria in Vivo and with Selective Inactivation of the α-Ketoglutarate Dehydrogenase Complex in LLC-PK1 Cells. Biochemistry. 45:8959-8971.
Ke Z, Bowen WM, Gibson GE. 2006 Peripheral inflammatory mechanisms modulate microglial activation in response to mild impairment of oxidative metabolism. Neurochemistry International. 49:548-556.
Santos SS, Gibson GE, Cooper AJL, Denton TT, Thompson CM, Bunik VI, Alves PM and Sonnewald U. 2006. Inhibitors of a-Ketoglutarate Dehydrogenase Complex Alter [1-13C]Glucose and [U-13C]Glutamate Metabolism in Cerebellar Granule Neurons. Journal of Neuroscience Research. 83:450-458.
Murphy EJ, Huang H-M, Cowburn RF, Lannfelt L, Gibson GE. 2006. Phospholipid mass is increased in fibroblasts bearing the Swedish amyloid precursor mutation. Brain Research Bulletin. 69:79-85.
Kim SY, Marekov L, Bubber P, Browne SE, Stavrovskaya I, Lee J, Steinert PM, Blass JP, Beal MF, Gibson GE and Cooper AJL. 2005. Mitochondrial aconitase is a transglutaminase 2 substrate: transglutamination is a probable mechanism contributing to high-molecular-weight aggregates of aconitase and loss of aconitase activity in Huntington disease brain. Neurochemical Research. 30:1245-1255.
Waagepetersen HS, Hansen GH, Fenger K, Lindsay JG, Gibson G, Schousboe A. 2006. Cellular mitochondrial heterogeneity in cultured astrocytes as demonstrated by immunogold labeling of α-ketoglutarate dehydrogenase. Glia. 52:225-231.
Bunik VI, Denton TT, Xu H, Thompson CM, Cooper AJL, Gibson GE 2005. Phosphonate analogues of α-ketoglutarate inhibit the activity of the α-ketoglutarate dehydrogenase complex isolated from brain and in cultured cells. Biochemistry. 44:10552-10561.
Huang HM, Chen HL, Xu H and Gibson GE. 2005. Modification of endoplasmic reticulum Ca2+ stores by select oxidants produces changes reminiscent of those in cells from patients with Alzheimer’s disease. Free Radical Biol. Med. 39:979-989.
Ke ZJ, Calingasan NY, Karuppagounder SS, DeGiorgio LA, Volpe BT, Gibson GE. 2005. CD40L deletion delays neuronal death in a model of neurodegeneration due to mild impairment of oxidative metabolism. J. Neuroimmunology. 164:85-92.
Krasnikov BF, Kim SY, McConoughey SJ, Ryu H, Xu H, Stavrovskaya I, Iismaa S, Mearns, B, RatanRR, Blass JP, Gibson GE, Cooper AJL. (2005) Transglutaminase activity is present in highly purified non-synaptosomal mouse brain and liver mitochondria. Biochemistry. 44(21):7830-7843. PMCID 2597021.
Ke ZJ, Calingasan NY, DeGiorgio LA, Volpe BT, Gibson GE. 2005. CD40-CD40L Interactions promote Neuronal Death in a Model of Neurodegeneration Due to Mild Impairment of Oxidative Metabolism. Neurochemistry International. 47:204-215.
Bubber P, Haroutunian V, Fisch G, Blass JP, Gibson GE. 2005. Mitochondrial abnormalities in Alzheimer brain: mechanistic implications. Ann Neurology. 57:695-703.
Shi Q, Chen HL, Xu H, and Gibson GE. 2005. Reduction in the E2k subunit of the alpha-ketoglutarate dehydrogenase complex has effects independent of complex activity. Journal of Biological Chemistry. 280:10888-10896.
Jeitner TM, Xu H, Gibson GE. 2005. Inhibition of α-ketoglutarate dehydrogenase complex by the myeloperoxidase products, hypochlorous acid and mono-N-chloramine. J. Neurochem. 92:302-310.
Huang HM, Fowler C, Xu H, Zhang H, Gibson GE. 2005. Mitochondrial function in fibroblasts with aging in culture and/or Alzheimer’s disease. Neurobiology of Aging. 29:651-658.
HuangHM, Zhang H, OuHC, Chen HL and Gibson GE. 2004. α-Keto-ß-methyl-n-valeric acid diminishes reactive oxygen species and alters endoplasmic reticulum Ca2+ stores. Free Radical Biology and Medicine. 37:1779-1789.
Bubber P, Ke ZJ, and Gibson GE. 2004. Tricarboxylic acid cycle enzymes following thiamine deficiency. Neurochemistry International. 45:1021-1028.
Bubber P, Tang J, Haroutunian V, Xu H, Davis KL, Blass JP, Gibson GE. 2004. Mitochondrial enzymes in schizophrenia. Journal of Molecular Neuroscience. 24:315-321.
Klivenyi P, Starkov AA, Calingasan NY, Gardian G, Browne SE, Yang L, Bubber P, Gibson G E, Patel MS and Beal MF. 2004. Mice deficient in dihydrolipoamide dehydrogenase show increased vulnerability to MPTP, malonate and 3-nitropropionic acid neurotoxicity. J Neurochem. 88:1352-60.
Huang HM, Fowler C, Zhang H, Gibson GE. 2004. Mitochondrial heterogeneity within and between different cell types. Neurochemical Research. 29:651-658.
Huang HM, Ou HC, Xu H, Chen HL, Fowler C, Gibson GE. 2003. Inhibition of alpha-ketoglutarate dehydrogenase complex promotes cytochrome c release from mitochondria, caspase-3 activation, and necrotic cell death. J. Neuroscience Research. 74:309-317.
Ke ZJ, DeGiorgio LA, Volpe BT, Gibson GE. 2003. Reversal of thiamine deficiency induced neurodegeneration. J Neuropathology and Experimental Neurology. 62:195-207.
Gibson GE, Kingsbury AE, Xu H, Lindsay JG, Daniel S, Foster OJF,LeesAJ, Blass JP. 2003. Deficits In tricarboxylic acid cycle enzyme in brains from patients with Parkinson’s Disease. Neurochemistry International. 43:129-135.
Huang HM, Zhang H, Xu H and Gibson GE 2003. Inhibition of the a-Ketoglutarate Dehydrogenase Complex Alters Mitochondrial Function and Cellular Calcium Regulation. Biochimica et Biophysica Acta Molecular Basis of Disease. 1637:119-126.
Gibson GE, Zhang H, Xu H, Park LCH, Jeitner TM. 2002. Oxidative stress increases internal calcium stores and reduces a key mitochondrial enzyme. Biochim Biophys Acta. 1586:177-189.
Andreassen OA, Ferrante RJ, Huang H-M, Dedeoglu A , Park LP, Ferrante KL, Kwon JK, Borchelt DR, Ross CA, Gibson GE and Beal MF. 2001. Dichloroacetate stimulates pyruvate dehydrogenase and exerts therapeutic effects in transgenic mouse models of HD. Annals of Neurology. 50:112-117.
Zhang H, Huang HM, Carson R, Mahmood J, Thomas H, Gibson GE. 2001 Assessment of Membrane Potentials of Mitochondrial Populations In Living Cells. Analytical Biochemistry. 298:170-180.
Park LCH, Albers DS, Xu H, Lindsay JG, Beal MF, Gibson GE. 2001. Mitochondrial Impairment in the Cerebellum of the Patients with Progressive Supranuc-lear Palsy. Journal of Neuroscience Research. 66:1028-1034.
Park LCH, Zhang H and Gibson GE 2001. Co-culture with astrocytes or microglia protects metabolically impaired neurons. Mechanisms of Aging and Development. 123:21-27.
Simon DK, Lin MT, Ahn CH, Liu G-J, Gibson GE, Beal MF, Johns DR. 2001. Low mutational burden of individual acquired mitochondrial DNA mutations in brain. Genomics.73:113-116.
Chun HS, Gibson GE, DeGiorgio LA, Kidd V, Son JH. 2000. Dopaminergic cell death induced by MPP+, oxidant and specific neurotoxicants shares the common molecular mechanism. J. Neurochemistry. 76:1-13.
Calingasan NY and Gibson GE 2000. Dietary restriction attenuates the neuronal loss, induction of heme oxygenase-1 and blood brain barrier breakdown induced by impaired oxidative metabolism. Brain Research. 885:62-69
Gibson GE, Zhang H, Sheu K-FR and Park LCH. 2000. Differential alterations in antioxidant capacity in cells from Alzheimer patients. Biochimica Biophysica Acta. 1502:319-329.
Murphy EJ, Zhang H, Sorbi S, Rapoport SI, Gibson GE. 2000. Phospholipid composition and levels are not altered in fibroblasts bearing presenilin-1 mutations. Brain Res Bull. 52:207-212.
Gibson GE, Haroutunian V, Zhang H, Park LCH, Shi Q, Lesser M, Mohs RC, Sheu RK and Blass, JP 2000. Mitochondrial damage in Alzheimer's disease varies with apolipoprotein E genotype. Annals of Neurology. 48(3)297-303.
Albers DS, Augood SJ, Park LCH, Browne SE, Martin DM, Adamson J, Hutton M, Standaert DG, Vonsatte JPJ, Gibson GE and Beal MF. 2000. Frontal lobe dysfunction in PSP: Evidence for oxidative stress and mitochondrial impairment. J. Neurochem. 74: 878-881.
Park LCH, Calingasa NY, Sheu K-FR, Gibson GE. 2000. Quantitative "aketoglutarate dehydrogenase activity in brain sections and cultured cells. Analytical Biochemistry. 277:86-93.
Calingasan NY, Huang PL, Chun HS, Gibson GE. 2000. Vascular factors are critical in selective neuronal loss in an animal model of impaired oxidative metabolism. J. Neuropathology and Experimental Neurology. 59:207-217.
Park LCH, Calingasan NY, Uchida K, Zhang H, and Gibson GE 2000. Metabolic impairment induces brain cell-type selective changes in oxidative stress and cell death in culture. J. Neurochem. 74:114-124.
Chapter & Reviews since 2000
Gibson GE, Hirsch JA, Cirio RT, Jordan BD, Fonzetti P, Elder J.. 2013. Abnormal Thiamine-Dependent Processes in Alzheimer’s Disease. Lessons from Diabetes. Molecular and Cellular Neuroscience. 55:17-25. NIHMS 431588.
Gibson GE, Starkov A, Shi Q, Beal MF. 2012. α-Ketoglutarate Dehydrogenase Complex in Neurodegeneration. Mitochondria and Cell Signaling in Health and Disease. Edited by Sten Orrenius, Enrique Cadenas, and Lester Packer. CRC Press.
Gibson GE, Shi Q 2010. A mitocentric view of Alzheimer’s disease suggests multi faceted treatments. Journal of Alzheimer’s Disease. 20 (Supp 2): S591-S607. NIHMS289121. PMCID: PMC3085842
Gibson GE, Starkov A, Blass JP, Ratan RR, Beal MF. 2010. Cause and consequence: mitochondrial dysfunction initiates and propagates neuronal dysfunction, neuronal death and behavioral abnormalities in age associated neurodegenerative diseases. Biochimica et Biophysica Acta Molecular Basis of Disease (Special Issue: Mitochondrial Dysfunction). 1802:122–134. PMCID 2790547
Gibson GE, Karuppagounder SS, Shi Q. 2008. Oxidant induced changes in mitochondria and calcium dynamics in the pathophysiology of Alzheimer’s disease. (IN: Mitochondria and Oxidative Stress in Neurodegenerative Disorders. Editors Gibson GE, Ratan RR, Beal MF) Ann. N.Y. Acad. Sci. 1147: 221–232. PMCID 2744687
Karuppagounder SS and Gibson GE. 2008. Thiamine deficiency: a model of metabolic encephalopathy and of selective neuronal vulnerability. Metabolic Encephalopathy. Editor David W. McCandless. Springer Press. pp 235-260.
Shi Q and Gibson GE. 2007. Oxidative stress and transcriptional regulation in Alzheimer’s disease. Alzheimer Disease & Associated Disorders - An International Journal. 21(4):276-291.
Gibson GE, Blass JP 2007. Thiamine-dependent processes and treatment strategies in neurodegenerations. Antioxidants and Redox Signaling. 9(10) 1-15.
BunikVI, SchlossJV, PintoJT, Gibson GE, CooperAJL. 2007. Enzyme-catalyzed side reactions with molecular oxygen may contribute to cell signaling and neurodegenerative diseases. Neurochemical Research. 32(4-5):871-892.
Joseph JA and Gibson GE. 2007. Chapter 4.2. Coupling of neuronal function to oxygen and glucose metabolism through changes in neurotransmitter dynamics as revealed with aging, hypoglycemia and hypoxia. Handbook of Neurochemistry and Molecular Biology. 3rd Edition Volume 5. Brain energetics from genes to metabolites to cells: Integration of molecular and cellular processes. Edited by Gary E. Gibson and Gerald Dienel. pp 297-320.
Blass JP and Gibson GE. 2006. Correlations of disability and biologic alterations in Alzheimer brain and test of significance by a therapeutic trial in humans. Journal of Alzheimer’s Disease. 9:207–218.
Gibson GE, Huang HMH 2005. Commentary. Oxidative stress in Alzheimer’s disease. Neurobiology of Aging. 26:575-578.
Gibson GE, Blass JP, Beal MF, Bunik V 2005. The α-Ketoglutarate dehydrogenase complex: a mediator between mitochondria and oxidative stress in neurodegeneration. Molecular Neurobiology. 31:1-31.
Gibson GE and Huang 2004. Mitochondrial enzymes and endoplasmic reticulum calcium stores as targets of oxidative stress in neurodegenerative diseases. J. Bioenergetics and Biomembranes. 36:335-341.
Ke ZJ and Gibson GE. 2004. Selective Response of Various Brain Cell Types During Neurodegeneration Induced by Mild Impairment of Oxidative Metabolism. Neurochemical Intl. 45:361-369.
Gibson GE and Huang HM. 2002. Oxidative processes in the brain and non-neuronal tissues biomarkers of Alzheimer’s disease. Frontiers in Bioscience. 7:d1007-1015.
Blass JP, Gibson GE and Hoyer S. 2002. The role of the metabolic lesion in Alzheimer’s Disease. J. Alzheimer’s Disease. 4:225-232.
Gibson GE. 2002. Interactions of oxidative stress with cellular calcium dynamics -and Glucose Metabolism In Alzheimer’s Disease. Free Radical Biology and Medicine. 32:1061-1070.
Gibson GE and Zhang H. 2002. Interactions of oxidative stress with thiamine homeostasis promote neurodegeneration. Neurochemistry International. 40:493-504.
Gibson GE and Zhang H. 2001. Abnormalities in oxidative processes in non-neuronal tissues from patients with Alzheimer’s disease. The Journal of Alzheimer’s Disease. 3:329-338.
Gibson GE and Zhang H. 2000. Effects of Ginkgo biloba (EGb761) on metabolism of reactive oxygen species in fibroblasts from Alzheimer’s Disease patients and controls. In Advances in Ginkgo Biloba Extract Research Vol 8. ginkgo biloba Extract (EGB 761) as a neuroprotective agent from basic studies to clinical trials. edited by Y Christen. Salal editeur. Marseille IPSEN Foundation. pp 108-121.
Our current research can be divided into four areas:
1) KGDHC and neurodegenerative disease.
Mitochondrial dysfunction and oxidative stress are consistent features of multiple neurodegenerative diseases including Alzheimer’s disease (AD). Reductions in the α-ketoglutarate dehydrogenase complex (KGDHC), oxidative stress, diminished metabolism and neurodegeneration appear closely linked. The activity of KGDHC, a key mitochondrial enzyme complex that consists of three proteins, is markedly reduced in brains in several neurodegenerative diseases. The overall goals of this research are to assess the cause of the reduction in KGDHC in brains from patients with neurodegenerative disease and to use cell and animal models to determine the consequences of the decline, and how the decline in activity or the consequences might be ameliorated. The reduction in KGDHC activity is not simply secondary to neurodegeneration, since the decline occurs in brain areas vulnerable to degeneration, and in regions without overt neuropathology. Future studies will test the closely associated hypotheses that: (i) the diminished KGDHC activity in AD is due to the sensitivity of KGDHC to post-translational modifications including oxidative stress; (ii) mitochondrial function including the response to oxidant stress and release of pro-apoptotic proteins is sensitive to reductions in the KGDHC activities; (iii) neurons are particularly sensitive to diminished KGDHC; (iv) the proteins that make up the complex serve alternative functions. The experiments will determine if the reductions in KGDHC activity in brains of patients with neurodegenerative diseases are due to post-translational changes by using a combination of antibodies that detect common modifications and mass spectrometry. Experiments to determine the consequences of reduced KGDHC activities on cell function will utilize a specific inhibitor, as well as genetic manipulation of individual KGDHC subunits in multiple cell models and cell types from transgenic mice. The research will test the role of each subunit and determine if neurons are more vulnerable than other brain cells. These experiments will test the relation of diminished KGDHC to mitochondrial membrane potentials, to the stimulation of the release of cytochrome c and to the response to oxidant challenge. Further experiments will test whether thioredoxin mediates the consequences of an inhibition of KGDHC through a linkage with cellular thiol metabolism. In summary, the sensitivity of KGDHC to multiple oxidative stressors and its importance to cellular function suggest that multiple factors converge at KGDHC to cause neurodegeneration. Successful completion of these studies will provide new understanding of the molecular mechanisms underlying AD and other neurodegenerative diseases, and are likely to suggest new therapeutic strategies.
2) Enzymes of the tricarboxylic acid cycle in neurodegeneration.
Diminished brain metabolism and oxidative stress are characteristic features of Alzheimer's disease (AD). The mechanisms underlying these changes are as yet poorly defined. Our recent studies indicate that a marker of mitochondrial damage, the α‑ketoglutarate dehydrogenase complex (KGDHC), correlates at least as well with clinical disability as do plaque and tangle counts. KGDHC and several other mitochondrial enzymes are known to be sensitive to reactive oxygen species (ROS). These studies test the hypothesis that: impairment of select mitochondrial enzymes by ROS is an important component of the cascade of events that leads to diminished metabolism and to the cognitive deficits in AD. This hypothesis will be tested on human autopsy brains collected by our collaborators at the Mt Sinai (N.Y.) ADRC, who have collected several hundred samples of brain from patients whose pre‑terminal neuropsychological status has been determined using the Clinical Dementia Rating (CDR). Quantitative markers of oxidative stress and activities of specific mitochondrial enzymes will be compared to clinical status (CDR) and to markers of AD pathology including plaque and tangle counts, by refined statistical methods. Tissue culture models will also be used, so as to do mechanistic experiments on the effects of specific ROS on the activities of the same mitochondrial enzymes examined in the necessarily co-relational studies of human autopsied brain. The models will be: (1) cultured fibroblasts from AD patients, to test the effects of ROS on cells which have the same genetic background as that in which the disease is expressed; (2) culture models of neurons, the most vulnerable cell type in AD brains. These models will also provide systems to test the efficacy of approaches to limit or reverse the changes in mitochondrial enzymes due to ROS. Thus, these studies will not only help clarify mechanisms in AD, but also have direct implications for the development of new therapies.
3) Thiamine deficiency.
Thiamine (vitamin B1) deficiency (TD) produces a mild, chronic impairment of oxidative metabolism that models the diminished metabolism and reduced activities of the thiamine-dependent mitochondrial enzymes that occur in brain in several common age-related neurodegenerative disorders. Regionally selective neuro- degeneration and activation of astrocytes, microglia and endothelial cells occur in TD and in these diseases. Vascular changes, inflammatory responses, oxidative stress and neuronal death are present in brains from TD mice and in brains from patients who die from common neurodegenerative diseases. A mechanistic sequence of events cannot be discovered in autopsied human brain, but can be studied effectively in experimental animals. Several features of the TD model make it amenable to analysis of the interactions leading to neurodegeneration: (1) The time course of the events leading to neuronal death is prolonged (11 days); (2) The death occurs in a discrete nucleus with a well-defined number of neurons; (3) The model exists in mice so transgenic animals can be used to test mechanism. The proposed experiments will test the following hypothesis: TD-induced abnormalities in metabolism increase neural production of cytokines, which activate microglia and astrocytes and stimulate endothelial cells to promote entry of peripheral immune cells. Cytotoxic compounds that are released from these activated cells combine to produce neurodegeneration. The underlying mechanisms will be tested in vivo by the strategy successfully used in our ongoing experiments. The sequences of responses of cell-specific changes in markers of inflammation, vascular responses and oxidative stress will be established. Specific drug treatments and, where feasible, transgenic animals will be used to test whether each specific step is critical in the cascade leading to neurodegeneration. An understanding of these mechanisms will likely suggest new ways to overcome the consequences of the mild, chronic impairment of oxidative metabolism that accompanies numerous age-related neurodegenerative disorders.
4) Fibroblasts studies.
The continuing goal of our research is to understand the molecular basis of demonstrated abnormalities in calcium regulation and their clinical relevance to Alzheimer’s disease. Calcium regulation is closely linked to the metabolism of reactive oxygen species (ROS) and oxygen-dependent pathways of energy production, both of which are altered in AD brain. However, interpretation of observations in brain has been hampered by the difficulty in determining whether an alteration is causative or secondary to neurodegeneration. Abnormalities in calcium regulation persist in fibroblasts cultured from patients with either familial or non-familial forms of AD compared to controls including patients with other neurodegenera tive disorders. Properties that persist in cultured fibroblasts are inherent traits of AD cells that are independent of diet, drugs or neurodegeneration. Our completed studies with fibroblast cell lines from multiple members of one presenilin-1 AD family provide evidence of increased oxidative stress in AD cells. To determine the role of ROS in the production of the abnormalities of calcium regulation and oxygen-dependent pathways of energy production in cells from AD patients, the proposed experiments will use cultured fibroblasts to test a three-part hypothesis: (a) cells from AD patients produce excessive ROS and are more sensitive to oxidants than controls, (b) abnormalities in cellular ROS metabolism underlie AD-related changes in cellular calcium regulation and mitochondrial function, (c) AD/control differences in calcium and ROS are diagnostic and predictive for AD. The results of these experiments will reveal whether various AD gene mutations alter the interactions of oxidative stress, oxidative metabolism and calcium. Demonstration that alterations in specific oxidant species or their cognate antioxidant systems are a triggering event that lead to abnormalities in calcium signaling and mitochondrial function would have pathological, therapeutic and diagnostic significance.
Gary Gibson, Ph.D.
Qingli Shi, Ph.D.
Dr. Gary Gibson and his research group are trying to discover the underlying cause of age-related neurodegenerative diseases and to develop effective therapies. The most common age-related neurodegenerative diseases are Alzheimer’s, Parkinson’s and Huntington’s diseases. The research shows that fundamental mechanisms of damage may be similar in many age-related diseases and stroke. The brain is very dependent on oxygen and glucose. Our research suggests that a reduced ability to use glucose and oxygen either causes the disease(s) or is a critical clinically relevant change. We are trying to determine why this reduction occurs and its consequences for brain function. Abnormalities in the use of glucose and oxygen cause abnormal regulation of calcium and production of excess free radicals, and these may lead to the brain dysfunction. Thus, preventing the free radical damage or change in calcium with specific drugs should protect these proteins and thus save the brain. Cells from patients, genetically modified cells and animal models are used to test these possibilities and to evaluate the effectiveness of drugs.
The following techniques are routinely used in our laboratory:
Resource Sharing Plan for Mitochondrial Dysfunction in Neurodegeneration of Aging
The investigators on the program project have two mechanisms for Resource Sharing:
1) Dr. Anatoly Starkov maintains a web site that has “everything you want to know about mitochondria” including multiple protocols. The address is http://oxphos.org.
2) Information on the program project is available in a downloadable PDF. This document includes:
Preliminary data are discussed in group meetings. They will not be posted on a public site because they are preliminary.