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Research profile
Therapeutic approaches for maintaining cognitive function in ageing
Dr Debbie Young
Gene Therapy Research Group
Department of Molecular Medicine & Pathology
Faculty of Medical and Health Sciences
University of Auckland
Challenging the brain with stimulating intellectual activity and/or physical activity throughout life maintains cognitive function in old age and reduces the risk for developing neurodegenerative disease in humans. In 1999, we were one of the first groups to show that this effect can be reproduced in rats housed in an enriched environment, comprising of opportunities for social interaction and physical activity (Young et al., 1999). Enriched rats showed resistance to brain insult and increased neurogenesis (birth of new neurons) in the hippocampus, a brain region that plays a pivotal role in learning and memory. Increased hippocampal neurogenesis is associated with improved learning and memory, while conversely, decreased neurogenesis, such as that which occurs with ageing, is associated with impaired learning and memory function. Treatments that maintain neurogenesis throughout life and into senescence may be effective approaches for maintaining cognitive function in ageing but potentially also in treating diseases associated with cognitive impairment such as Alzheimer’s disease.
Identifying the cell signals and molecular events involved in hippocampal neurogenesis will be pivotal to developing these therapeutic strategies. In an extension of our enrichment studies, we used adeno-associated viral (AAV) vector-mediated gene transfer approaches to provide definitive evidence that vascular endothelial growth factor (VEGF) is a key mediator of neurogenesis (Cao et al., 2004). Currently, we are investigating whether gene therapy approaches based on VEGF-mediated stimulation of neurogenesis may have potential for maintaining cognitive function. Furthermore, we are also investigating whether a combination of environmental and genetic influences can synergistically enhance neurogenesis and associated learning and memory function. If successful, the efficacy of this strategy will be determined in aged rats and novel genetic rat models of Alzheimer’s disease that we are also developing in our lab using AAV-mediated gene transfer technology.
Young D, Lawlor PA, Leone P, Dragunow M, During MJ. (1999) Environmental enrichment inhibits spontaneous apoptosis, prevents seizures and is neuroprotective. Nature Medicine. 5, 448-453.
Cao L, Jiao X, Zuzga DS, Liu Y, Fong DM, Young D, During MJ. (2004) VEGF links hippocampal activity with neurogenesis, learning and memory. Nat Genetics. 36(8):827-35.
Website
http://www.health.auckland.ac.nz/molmedpath/research/during.html
Publications
| 2005. | Klugmann M, Leichtlein CB, Symes CW, Serikawa T, Young D, During MJ. Restoration of aspartoacylase activity in CNS neurons does not ameliorate motor deficits and demyelination in a model of Canavan disease. Mol Ther. 11(5):745-53. |
| 2005. | Klugmann M, Symes WC, Leichtlein CB, Klaussner B, Dunning J, Fong D, Young D, During MJ. AAV-mediated hippocampal expression of short and long Homer 1 proteins differentially affect cognition and seizure activity in adult rats. Mol. Cell. Neurosci. 28(2):347-60 |
| 2004. | Cao L, Jiao X, Zuzga DS, Liu Y, Fong DM, Young D, During MJ. VEGF links hippocampal activity with neurogenesis, learning and memory. Nat Genet. 36(8):827-35. |
| 2004. | Kells AP, Fong DM, Dragunow M, During MJ, Young D, Connor B. AAV-mediated gene delivery of BDNF or GDNF is neuroprotective in a model of Huntington disease. Mol Ther. 9(5):682-8. |
| 2003. | Lin EJ, Richichi C, Young D, Baer K, Vezzani A, During MJ. Recombinant AAV-mediated expression of galanin in rat hippocampus suppresses seizure development. Eur J Neurosci. 18(7):2087-92. |
| 2003. | Klugmann M, Symes CW, Klaussner BK, Leichtlein CB, Serikawa T, Young D, During MJ. Identification and distribution of aspartoacylase in the postnatal rat brain. Neuroreport. 14(14):1837-40. |
| 2001. | Xu R, Janson CG, Mastakov M, Lawlor P, Young D, Mouravlev A, Fitzsimons H, Choi KL, Ma H, Dragunow M, Leone P, Chen Q, Dicker B, During MJ. Quantitative comparison of expression with adeno-associated virus (AAV-2) brain-specific gene cassettes. Gene Ther. 8(17):1323-32. |
| 2000. | During MJ, Symes CW, Lawlor PA, Lin J, Dunning J, Fitzsimons H, Poulsen D, Leone P, XU R, Dicker BL, Lipski J, Young D. An oral vaccine against NMDAR1 with efficacy in experimental stroke and epilepsy. Science 287, 1453-1460. |
| 2000. | Dragunow M, Xu R, Walton M, Woodgate A-M, Lawlor P, MacGibbon GA, Young D, Gibbons H, Lipski J, Muravlev A, Pearson A, During M. c-Jun promotes neurite outgrowth and survival in PC12 cells. Molecular Brain Res., 83(1-2):20-33. |
| 1999. | Young D, Lawlor PA, Leone P, Dragunow M, During MJ. Environmental enrichment inhibits spontaneous apoptosis, prevents seizures and is neuroprotective. Nature Medicine. 5, 448-453. |
| 1998. | During M, Xu R, Young D, Kaplitt MG, Sherwin RA, Leone P. Peroral gene therapy of lactose intolerance using an adeno-associated virus vector. Nature Medicine. 4. 1131-1135. |
| 1998. | Walton M, Saura J, Young D, MacGibbon G, Hansen W, Lawlor PA, Sirimanne E, Gluckman P, Dragunow M. CCAAT-enhanced binding protein- expressed in activated microglial cells after brain injury. Mol. Brain Res. 61, 11-22. |
| 1998. | Walton M, MacGibbon G, Young D, Sirimanne E, Williams C, Gluckman P, Dragunow M. Do c-Jun, c-Fos and amyloid precursor protein play a role in neuronal death or survival? J. Neurosci. Res. 53, 330-342. |
| 1998. | Hughes PE, Young D, Preston KM, Yan Q, Dragunow M. Differential regulation by MK-801 of immediate-early genes, brain-derived neurotrophic factor and trk receptor mRNA induced by a kindling after-discharge. Mol. Brain Res. 53, 138-151. |
| 1997. | Connor B, Young D, Yan Q, Faull RL, Synek B, Dragunow M. Brain-derived neurotrophic factor is reduced in Alzheimer's disease. Mol. Brain Res. 49(1-2), 71-81. |
| 1997. | MacGibbon GA, Lawlor PA, Sirimanne ES, Walton MR, Connor B, Young D, Williams C, Gluckman P, Faull RL, Hughes P, Dragunow M. Bax expression in mammalian neurons undergoing apoptosis, and in Alzheimer's disease hippocampus. Brain Res. 750(1-2), 223-34. |
| 1996. | Connor B, Young D, Lawlor P, Gai W, Waldvogel H, Faull RL, Dragunow M. Trk receptor alterations in Alzheimer's disease. Mol. Brain Res. 42(1), 1-17. |
| 1996. | Walton M. Young D. Sirimanne E. Dodd J. Christie D. Williams C. Gluckman P. Dragunow M. Induction of clusterin in the immature brain following a hypoxic-ischemic injury. Mol. Brain Res. 39(1-2), 137-52. |
| 1995. | MacGibbon GA. Lawlor PA. Hughes P. Young D. Dragunow M. Differential expression of inducible transcription factors in basal ganglia neurons. Mol. Brain Res. 34(2), 294-302. |
| 1995. | Dragunow M. Preston K. Dodd J. Young D. Lawlor P. Christie D. Clusterin accumulates in dying neurons following status epilepticus. Mol. Brain Res. 32(2), 279-90. |
| 1995. | Young D. Dragunow M. Neuronal injury following electrically induced status epilepticus with and without adenosine receptor antagonism. Exp. Neurol. 133(2), 125-37. |
| 1994. | Young D. Dragunow M. MK-801 and NBQX prevent electrically induced status epilepticus. Neuroreport. 5(12), 1481-4. |
| 1994. | Young D. Dragunow M. Status epilepticus may be caused by loss of adenosine anticonvulsant mechanisms. Neuroscience. 58(2), 245-61. |
| 1993. | Dragunow M. Young D. Hughes P. MacGibbon G. Lawlor P. Singleton K. Sirimanne E. Beilharz E. Gluckman P. Is c-Jun involved in nerve cell death following status epilepticus and hypoxic-ischaemic brain injury? [published erratum appears in Mol Brain Res 20(1-2), 179]. Mol. Brain Res. 18(4), 347-52. |
| 1993. | Young D. Dragunow M. Non-NMDA glutamate receptors are involved in the maintenance of status epilepticus. Neuroreport. 5(1), 81-3. |
| 1993. | Hughes P. Young D. Dragunow M. MK-801 sensitizes rats to pilocarpine induced limbic seizures and status epilepticus. Neuroreport. 4(3), 314-6. |
| 1993. | Paxton JW. Young D. Robertson IG. Pharmacokinetics of acridine-4-carboxamide in the rat, with extrapolation to humans. Cancer Chemother. Pharmacol. 32(4), 323-5. |
| 1993. | Paxton JW. Young D. Evans SM. Robertson IG. Kestell P. Tumour profile of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide after intraperitoneal administration in the mouse. Cancer Chemother. Pharmacol. 32(4), 320-2. |
| 1993. | Cornford EM. Young D. Paxton JW. Hyman S. Farrell CL. Elliott RB. Blood-brain glucose transfer in the mouse. Neurochem. Res. 18(5), 591-7. |
| 1993. | Smillie AC. Rodda JC. Young D. The protein of pigmented Polynesian dental enamel. Arch. Oral Biology.38(8), 717-24. |
| 1992. | Cornford EM. Young D. Paxton JW. Sofia RD. Blood-brain barrier penetration of felbamate. Epilepsia. 33(5), 944-54. |
| 1992. | Cornford EM. Young D. Paxton JW. Comparison of the blood-brain barrier and liver penetration of acridine antitumor drugs. Cancer Chemother. Pharmacol. 29(6), 439-44. |
| 1992. | Evans SM. Young D. Robertson IG. Paxton JW. Intraperitoneal administration of the antitumour agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide in the mouse: bioavailability, pharmacokinetics and toxicity after a single dose. Cancer Chemother. Pharmacol. 31(1), 32-6. |
| 1992. | Paxton JW. Young D. Evans SM. Kestell P. Robertson IG. Cornford EM. Pharmacokinetics and toxicity of the antitumour agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide after i.v. administration in the mouse. Cancer Chemother. Pharmacol. 29(5), 379-84. |
| 1992. | Cornford EM. Young D. Paxton JW. Finlay GJ. Wilson WR. Pardridge WM. Melphalan penetration of the blood-brain barrier via the neutral amino acid transporter in tumor-bearing brain. Cancer Res. 52(1), 138-43. |
| 1990. | Young D, Evans PC, Paxton JW. Quantitation of the antitumour agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide in plasma by high-performance liquid chromatography. J. Chromat. 528(2), 385-94. |
| 1990. | Kestell P. Paxton JW. Evans PC. Young D. Jurlina JL. Robertson IG. Baguley BC. Disposition of amsacrine and its analogue 9-([2-methoxy-4 [(methylsulfonyl)amino]phenyl]amino)-N,5-dimethyl-4- acridinecarboxamide (CI-921) in plasma, liver, and Lewis lung tumors in mice. Cancer Res. 50(3), 503-8. |
| 1987. | Grigor MR. Allan JE. Carrington JM. Carne A. Geursen A. Young D. Thompson MP. Haynes EB. Coleman RA. Effect of dietary protein and food restriction on milk production and composition, maternal tissues and enzymes in lactating rats. J. Nutrition. 117(7), 1247-58. |
Books or book chapters:
| 2004. | Young D, During MJ. Using the immune system to target epilepsy. In Molecular mechanisms of epileptogenesis. DK Binder, H. Scharfman eds. Adv Exp Med Biol. 548:134-44. |
| 2004. | Young D. and Dragunow M. The role of adenosine in status epilepticus. In Status epilepticus CG Wasterlain, D Treiman eds. (in press). |
| 2003. | During, MJ, Young D, Baer K, Lawlor PA and Klugmann M. Development and optimization of adeno-associated virus vector transfer into the central nervous system. In virus vectors for gene therapy: methods and protocols. CA Machida (ed) Methods Mol Med. 76:221-36.. |
| 1996. | Young D., Glass M and Dragunow M. Pathophysiology of seizures. In Pediatrics and Perinatology: the scientific basis. P.D. Gluckman and M.A. Heymann (eds). Edward Arnold. NY pp 440-443. |
| 1996. | Young D. and Dragunow M. c-Fos antisense: infusion and effects. In Antisense strategies for the study of receptor mechanisms. R.B. Raffa and F. Porreca (eds). R.G. Landes pp 111-133. |
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