Michael P. McDonald, PhD

Associate Professor
Department of Neurology
Department of Anatomy & Neurobiology

Office: 415 Link Building
Tel: (901) 448-4648
mike@tennessee.edu

Education

  • PostDoc, National Institute of Mental Health, Bethesda, MD, Behavioral Neuroscience
  • Ph.D., University of Minnesota, Minneapolis, MN, Experimental Psychology
  • M.A., New York University, New York, NY, General Psychology
  • B.A., Arizona State University, Tempe, AZ, Psychology

Research interest/specialty

Behavioral and neuropathological analyses of mouse models of Alzheimer's and Parkinson's diseases.

Research keywords

Memory, Learning, Behavior, Psychology, Genetics, Genomics, Neuroscience, Pathology, Pharmacology, Receptor, Apoptosis, Gene therapy, Knockout, Membrane, Mouse, Mutation, Alzheimer's disease, Parkinson's disease, Amyloid, Synuclein, Oxidative stress, Cognition, Akinesia, Bradykinesia, Tremor

Research description

Our lab studies the involvement of gangliosides in the behavioral and cognitive impairments, protein misfolding, and neurodegeneration of Alzheimer's and Parkinson's diseases. Gangliosides are glycolipids richly expressed in neuronal membranes. Although the functions of gangliosides are not completely understood, converging evidence clearly demonstrates a critical role for membrane gangliosides in the binding and aggregation of amyloid-beta (Abeta), the toxic peptide that aggregates into plaques in Alzheimer's disease. Our previous research showed that elimination of the GD3 synthase (GD3S) gene significantly reduces Abeta binding and Abeta-induced cell death in primary neuronal cultures. In a mutant mouse model of Alzheimer's disease, knocking out GD3S nearly eliminates plaque formation and Abeta-associated neuropathology, and reverses memory deficits. Because GD3 ganglioside is a critical mediator of the ceramide/sphingomyelin-dependent apoptotic pathway, we expect that inhibiting GD3S will also be neuroprotective in models of Parkinson's disease. In addition to targeted mutation of GD3S, ongoing experiments involve injection of viral-vector-mediated small-interfering RNA (siRNA) constructs to "silence" GD3S, and intracranial infusion of v. cholerae sialidase (VCS), an enzyme that hydrolyzes specific sialic acid residues on gangliosides. Both of these manipulations have the effect of reducing levels of the more-complex brain gangliosides, which have a high affinity for Abeta, and increasing levels of the less-complex brain gangliosides, which have a lower affinity for Abeta and are neuroprotective. We expect this line of research to provide insight into new therapeutic targets for Alzheimer's and Parkinson's diseases.

Publications

  1. Dhanushkodi, A, McDonald, MP. Intracranial V. cholerae sialidase protects against excitotoxic neurodegeneration. PLoS One, 6 (12), e29285, 2011.
  2. Casadesus, G, Arendash, G, Laferla, F, McDonald, M. Animal models of Alzheimer's disease. Int J Alzheimers Dis, 2010, 606357, 2010.
  3. Ariga, T, Yanagisawa, M, Wakade, C, Ando, S, Buccafusco, JJ, McDonald, MP, Yu, RK. Ganglioside metabolism in a transgenic mouse model of Alzheimer's disease: expression of Chol-1α antigens in the brain. ASN Neuro, 2 (4), e00044, 2010.
  4. Harrison FE, May JM, McDonald MP. Vitamin C deficiency increases basal exploratory activity but decreases scopolamine-induced activity in APP/PSEN1 transgenic mice. Pharmacol Biochem Behav, 4 (94), 543-52, 2010.
  5. Harrison, FE, Allard, J, Bixler, R, Usoh, C, Li, L, May, JM, McDonald, MP. Antioxidants and cognitive training interact to affect oxidative stress and memory in APP/PSEN1 mice. Nutr Neurosci, 12 (5), 203-18, 2009.
  6. Harrison, FE, Hosseini, AH, McDonald, MP, May, JM. Vitamin C reduces spatial learning deficits in middle-aged and very old APP/PSEN1 transgenic and wild-type mice. Pharmacol Biochem Behav, 93 (4), 443-50, 2009.
  7. Harrison, FE, Hosseini, AH, McDonald, MP. Endogenous anxiety and stress responses in water maze and Barnes maze spatial memory tasks. Behav Brain Res, 198 (1), 247-51, 2009.
  8. Ding, Y, Qiao, A, Wang, Z, Goodwin, JS, Lee, ES, Block, ML, Allsbrook, M, McDonald, MP, Fan, GH. Retinoic acid attenuates beta-amyloid deposition and rescues memory deficits in an Alzheimer's disease transgenic mouse model. J Neurosci, 28 (45), 11622-34, 2008.
  9. Harrison, FE, Yu, SS, Van Den Bossche, KL, Li, L, May, JM, McDonald, MP. Elevated oxidative stress and sensorimotor deficits but normal cognition in mice that cannot synthesize ascorbic acid. J Neurochem, 106 (3), 1198-208, 2008.
  10. Ariga, T, McDonald, MP, Yu, RK. Role of ganglioside metabolism in the pathogenesis of Alzheimer's disease--a review. J Lipid Res, 2008.
  11. Bernardo, A, Harrison, FE, McCord, M, Zhao, J, Bruchey, A, Davies, SS, Jackson Roberts, L, Mathews, PM, Matsuoka, Y, Ariga, T, Yu, RK, Thompson, R, McDonald, MP. Elimination of GD3 synthase improves memory and reduces amyloid-beta plaque load in transgenic mice. Neurobiol Aging, 2008.
  12. Bernardo, A, McCord, M, Troen, AM, Allison, JD, McDonald, MP. Impaired spatial memory in APP-overexpressing mice on a homocysteinemia-inducing diet. Neurobiol Aging, 28 (8), 1195-205, 2007.
  13. Bazalakova, MH, Wright, J, Schneble, EJ, McDonald, MP, Heilman, CJ, Levey, AI, Blakely, RD. Deficits in acetylcholine homeostasis, receptors and behaviors in choline transporter heterozygous mice. Genes Brain Behav, 6 (5), 411-24, 2007.
  14. Reiserer, RS, Harrison, FE, Syverud, DC, McDonald, MP. Impaired spatial learning in the APPSwe + PSEN1DeltaE9 bigenic mouse model of Alzheimer's disease. Genes Brain Behav, 6 (1), 54-65, 2007.
  15. Harrison, FE, Reiserer, RS, Tomarken, AJ, McDonald, MP. Spatial and nonspatial escape strategies in the Barnes maze. Learn Mem, 13 (6), 809-19, 2006.
  16. Siesser, WB, Zhao, J, Miller, LR, Cheng, SY, McDonald, MP. Transgenic mice expressing a human mutant beta1 thyroid receptor are hyperactive, impulsive, and inattentive. Genes Brain Behav, 5 (3), 282-97, 2006.
  17. Siesser, WB, Cheng, SY, McDonald, MP. Hyperactivity, impaired learning on a vigilance task, and a differential response to methylphenidate in the TRbetaPV knock-in mouse. Psychopharmacology (Berl), 181 (4), 653-63, 2005.
  18. Keller, NR, Diedrich, A, Appalsamy, M, Miller, LC, Caron, MG, McDonald, MP, Shelton, RC, Blakely, RD, Robertson, D. Norepinephrine transporter-deficient mice respond to anxiety producing and fearful environments with bradycardia and hypotension. Neuroscience, 139 (3), 931-46, 2005.
  19. de Paulis, T, Commers, P, Farah, A, Zhao, J, McDonald, MP, Galici, R, Martin, PR. 4-Caffeoyl-1,5-quinide in roasted coffee inhibits [3H]naloxone binding and reverses anti-nociceptive effects of morphine in mice. Psychopharmacology (Berl), 176 (2), 146-53, 2004.
  20. Khuchua, Z, Wozniak, DF, Bardgett, ME, Yue, Z, McDonald, M, Boero, J, Hartman, RE, Sims, H, Strauss, AW. Deletion of the N-terminus of murine map2 by gene targeting disrupts hippocampal ca1 neuron architecture and alters contextual memory. Neuroscience, 119 (1), 101-11, 2003.
  21. Howard, HC, Mount, DB, Rochefort, D, Byun, N, Dupré, N, Lu, J, Fan, X, Song, L, Rivière, JB, Prévost, C, Horst, J, Simonati, A, Lemcke, B, Welch, R, England, R, Zhan, FQ, Mercado, A, Siesser, WB, George, AL, McDonald, MP, Bouchard, JP, Mathieu, J, Delpire, E, Rouleau, GA. The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. Nat Genet, 32 (3), 384-92, 2002.
  22. de Paulis, T, Schmidt, DE, Bruchey, AK, Kirby, MT, McDonald, MP, Commers, P, Lovinger, DM, Martin, PR. Dicinnamoylquinides in roasted coffee inhibit the human adenosine transporter. Eur J Pharmacol, 442 (3), 215-23, 2002.
  23. McDonald, MP, Miller, KM, Li, C, Deng, C, Crawley, JN. Motor deficits in fibroblast growth factor receptor-3 null mutant mice. Behav Pharmacol, 12 (6-7), 477-86, 2001.
  24. Schramm, NL, McDonald, MP, Limbird, LE. The alpha(2a)-adrenergic receptor plays a protective role in mouse behavioral models of depression and anxiety. J Neurosci, 21 (13), 4875-82, 2001.
  25. Sung, KW, Kirby, M, McDonald, MP, Lovinger, DM, Delpire, E. Abnormal GABAA receptor-mediated currents in dorsal root ganglion neurons isolated from Na-K-2Cl cotransporter null mice. J Neurosci, 20 (20), 7531-8, 2000.
  26. Zhu, XG, Kaneshige, M, Parlow, AF, Chen, E, Hunziker, RD, McDonald, MP, Cheng, SY. Expression of the mutant thyroid hormone receptor PV in the pituitary of transgenic mice leads to weight reduction. Thyroid, 9 (11), 1137-45, 1999.
  27. McDonald, MP, Wong, R, Goldstein, G, Weintraub, B, Cheng, SY, Crawley, JN. Hyperactivity and learning deficits in transgenic mice bearing a human mutant thyroid hormone beta1 receptor gene. Learn Mem, 5 (4-5), 289-301, 1999.
  28. Davis, JA, Paylor, R, McDonald, MP, Libbey, M, Ligler, A, Bryant, K, Crawley, JN. Behavioral effects of ivermectin in mice. Lab Anim Sci, 49 (3), 288-96, 1999.
  29. Liu, Y, Wada, R, Kawai, H, Sango, K, Deng, C, Tai, T, McDonald, MP, Araujo, K, Crawley, JN, Bierfreund, U, Sandhoff, K, Suzuki, K, Proia, RL. A genetic model of substrate deprivation therapy for a glycosphingolipid storage disorder. J Clin Invest, 103 (4), 497-505, 1999.
  30. McDonald, MP, Gleason, TC, Robinson, JK, Crawley, JN. Galanin inhibits performance on rodent memory tasks. Ann N Y Acad Sci, 863, 305-22, 1998.
  31. Cheng, CM, Joncas, G, Reinhardt, RR, Farrer, R, Quarles, R, Janssen, J, McDonald, MP, Crawley, JN, Powell-Braxton, L, Bondy, CA. Biochemical and morphometric analyses show that myelination in the insulin-like growth factor 1 null brain is proportionate to its neuronal composition. J Neurosci, 18 (15), 5673-81, 1998.
  32. McDonald, MP, Willard, LB, Wenk, GL, Crawley, JN. Coadministration of galanin antagonist M40 with a muscarinic M1 agonist improves delayed nonmatching to position choice accuracy in rats with cholinergic lesions. J Neurosci, 18 (13), 5078-85, 1998.
  33. Norflus, F, Tifft, CJ, McDonald, MP, Goldstein, G, Crawley, JN, Hoffmann, A, Sandhoff, K, Suzuki, K, Proia, RL. Bone marrow transplantation prolongs life span and ameliorates neurologic manifestations in Sandhoff disease mice. J Clin Invest, 101 (9), 1881-8, 1998.
  34. McDonald, MP, Overmier, JB. Present imperfect: a critical review of animal models of the mnemonic impairments in Alzheimer's disease. Neurosci Biobehav Rev, 22 (1), 99-120, 1998.
  35. McDonald, MP, Crawley, JN. Galanin-acetylcholine interactions in rodent memory tasks and Alzheimer's disease. J Psychiatry Neurosci, 22 (5), 303-17, 1997.
  36. Lijam, N, Paylor, R, McDonald, MP, Crawley, JN, Deng, CX, Herrup, K, Stevens, KE, Maccaferri, G, McBain, CJ, Sussman, DJ, Wynshaw-Boris, A. Social interaction and sensorimotor gating abnormalities in mice lacking Dvl1. Cell, 90 (5), 895-905, 1997.
  37. Liu, Y, Hoffmann, A, Grinberg, A, Westphal, H, McDonald, MP, Miller, KM, Crawley, JN, Sandhoff, K, Suzuki, K, Proia, RL. Mouse model of GM2 activator deficiency manifests cerebellar pathology and motor impairment. Proc Natl Acad Sci U S A, 94 (15), 8138-43, 1997.
  38. Sweeney, WA, Luedtke, J, McDonald, MP, Overmier, JB. Intrahippocampal injections of exogenous beta-amyloid induce postdelay errors in an eight-arm radial maze. Neurobiol Learn Mem, 68 (1), 97-101, 1997.
  39. McDonald, MP, Wenk, GL, Crawley, JN. Analysis of galanin and the galanin antagonist M40 on delayed non-matching-to-position performance in rats lesioned with the cholinergic immunotoxin 192 IgG-saporin. Behav Neurosci, 111 (3), 552-63, 1997.
  40. Sango, K, McDonald, MP, Crawley, JN, Mack, ML, Tifft, CJ, Skop, E, Starr, CM, Hoffmann, A, Sandhoff, K, Suzuki, K, Proia, RL. Mice lacking both subunits of lysosomal beta-hexosaminidase display gangliosidosis and mucopolysaccharidosis. Nat Genet, 14 (3), 348-52, 1996.
  41. McDonald, MP, Crawley, JN. Galanin receptor antagonist M40 blocks galanin-induced choice accuracy deficits on a delayed-nonmatching-to-position task. Behav Neurosci, 110 (5), 1025-32, 1996.
  42. Schaal, DW, McDonald, MP, Miller, MA, Reilly, MP. Discrimination of methadone and cocaine by pigeons without explicit discrimination training. J Exp Anal Behav, 66 (2), 193-203, 1996.
  43. McDonald, MP, Overmier, JB, Bandyopadhyay, S, Babcock, D, Cleary, J. Reversal of beta-amyloid-induced retention deficit after exposure to training and state cues. Neurobiol Learn Mem, 65 (1), 35-47, 1996.
  44. Sango, K, Yamanaka, S, Hoffmann, A, Okuda, Y, Grinberg, A, Westphal, H, McDonald, MP, Crawley, JN, Sandhoff, K, Suzuki, K, Proia, RL. Mouse models of Tay-Sachs and Sandhoff diseases differ in neurologic phenotype and ganglioside metabolism. Nat Genet, 11 (2), 170-6, 1995.
  45. McDonald, MP, Dahl, EE, Overmier, JB, Mantyh, P, Cleary, J. Effects of an exogenous beta-amyloid peptide on retention for spatial learning. Behav Neural Biol, 62 (1), 60-7, 1994.