Skip to main content

Advertisement

SpringerLink
Log in

Transgenic mouse models of neurodegenerative disease: Opportunities for therapeutic development

  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Neurodegenerative diseases present an extraordinary challenge for medicine due to the grave nature of these illnesses, their prevalence, and their impact on individuals and caregivers. The most common of these age-associated chronic illnesses are Alzheimer’s disease (AD) and Parkinson’s disease (PD); other examples include the prion disorders, amyotrophic lateral sclerosis (ALS), and the trinucleotide (CAG) repeat diseases. All of these diseases are characterized by well-defined clinical syndromes with progressive courses that reflect the dysfunction and eventual loss of specific neuronal populations. Current therapies provide only symptomatic relief; none significantly alter the course of disease. We describe here how transgenic mice designed to model these diseases have substantially contributed to the identification and validation of many promising new therapies, and conversely how they have quickly and cost effectively eliminated several targets with unrealized expectations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Paulson HL: Protein fate in neurodegenerative proteinopathies: polyglutamine diseases join the (mis)fold. Am J Hum Genet 1999, 64:339–345.

    Article  PubMed  CAS  Google Scholar 

  2. Collinge J, Sidle KC, Meads J, Ironside J, Hill AF: Molecular analysis of prion strain variation and the aetiology of ‘new variant’ CJD. Nature 1996, 383:685–690.

    Article  PubMed  CAS  Google Scholar 

  3. Prusiner SB, Scott MR, DeArmond SJ, Cohen FE: Prion protein biology. Cell 1998, 93:337–348.

    Article  PubMed  CAS  Google Scholar 

  4. Butler DA, Scott MR, Bockman JM, et al.: Scrapie-infected murine neuroblastoma cells produce protease-resistant prion proteins. J Virol 1988, 62:1558–1564.

    PubMed  CAS  Google Scholar 

  5. Korth C, May BC, Cohen FE, Prusiner SB: Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Proc Natl Acad Sci U S A 2001, 98:9836–9841. This study utilized a cell culture model of prion disease to identify compounds that interfere with the generation of pathologic prion protein conformations.

    Article  PubMed  CAS  Google Scholar 

  6. Peretz D, Williamson RA, Kaneko K, et al.: Antibodies inhibit prion propagation and clear cell cultures of prion infectivity. Nature 2001, 412:739–743. Cell culture models of prion disease were used to demonstrate that antibodies to normal prion protein inhibit the production of pathologic prion protein and concordantly diminish the levels of transmissible prions.

    Article  PubMed  CAS  Google Scholar 

  7. Aguzzi A: Peripheral prion pursuit. J Clin Invest 2001, 108:661–662. A concise and comprehensive discussion of scientific literature relevant to the investigation of prion propagation outside of the nervous system and the mechanism by which prion infections spread to the central nervous system.

    Article  PubMed  CAS  Google Scholar 

  8. Brandner S, Klein MA, Frigg R, et al.: Neuroinvasion of prions: insights from mouse models. Exp Physiol 2000, 85:705–712. A concise and comprehensive discussion of scientific literature relevant to the investigation of prion propagation outside of the nervous system and the mechanism by which prion infections spread to the central nervous system.

    Article  PubMed  CAS  Google Scholar 

  9. Ross CA, Margolis RL, Rosenblatt A, et al.: Huntington disease and the related disorder, dentatorubral-pallidoluysian atrophy (DRPLA). Medicine 1997, 76:305–338.

    Article  PubMed  CAS  Google Scholar 

  10. Davies SW, Turmaine M, Cozens BA, et al.: Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 1997, 90:537–548.

    Article  PubMed  CAS  Google Scholar 

  11. DiFiglia M, Sapp E, Chase KO, et al.: Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 1997, 277:1990–1993.

    Article  PubMed  CAS  Google Scholar 

  12. Becher MW, Kotzuk JA, Sharp AH, et al.: Intranuclear neuronal inclusions in Huntington’s disease and dentatorubral and pallidoluysian atrophy: correlation between the density of inclusions and IT15 CAG triplet repeat length. Neurobiol Dis 1998, 4:387–397.

    Article  PubMed  CAS  Google Scholar 

  13. Mangiarini L, Sathasivam K, Seller M, et al.: Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 1996, 87:493–506.

    Article  PubMed  CAS  Google Scholar 

  14. Schilling G, Becher MW, Sharp AH, et al.: Intranuclear inclusions and neuritic pathology in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum Mol Genet 1999, 8:397–407.

    Article  PubMed  CAS  Google Scholar 

  15. Ross CA: When more is less: pathogenesis of glutamine repeat neurodegenerative diseases. Neuron 1995, 15:493–496.

    Article  PubMed  CAS  Google Scholar 

  16. Rosen DR, Siddique T, Patterson D, et al.: Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993, 362:59–62.

    Article  PubMed  CAS  Google Scholar 

  17. Borchelt DR, Guarnieri M, Wong PC, et al.: Superoxide dismutase 1 subunits with mutations linked to familial amyotrophic lateral sclerosis do not affect wild-type subunit function. J Biol Chem 1995, 270:3234–3238.

    Article  PubMed  CAS  Google Scholar 

  18. Ratovitski T, Corson LB, Strain J, et al.: Variation in the biochemical/biophysical properties of mutant superoxide dismutase 1 enzymes and the rate of disease progression in familial amyotrophic lateral sclerosis kindreds. Hum Mol Genet 1999, 8:1451–1460.

    Article  PubMed  CAS  Google Scholar 

  19. Price DL, Sisodia SS, Borchelt DR: Genetic neurodegenerative diseases: the human illness and transgenic models. Science 1998, 282:1079–1083.

    Article  PubMed  CAS  Google Scholar 

  20. Yim MB, Chock PB, Stadtman ER: Copper,zinc superoxide dismutase catalyzes hydroxyl radical production from hydrogen peroxide. Proc Natl Acad Sci U S A 1990, 87:5006–5010.

    Article  PubMed  CAS  Google Scholar 

  21. Beckman JS, Carson M, Smith CD, Koppenol WH: ALS, SOD and peroxynitrite. Nature 1993, 364:584.

    Article  PubMed  CAS  Google Scholar 

  22. Wiedau-Pazos M, Goto JJ, Rabizadeh S, et al.: Altered reactivity of superoxide dismutase in familial amyotrophic lateral sclerosis. Science 1996, 271:515–518.

    Article  PubMed  CAS  Google Scholar 

  23. Estévez AG, Crow JP, Sampson JB, et al.: Induction of nitric oxide-dependent apoptosis in motor neurons by zinc-deficient superoxide dismutase. Science 1999, 286:2498–2500.

    Article  PubMed  Google Scholar 

  24. Culotta VC, Klomp LW, Strain J, et al.: The copper chaperone for superoxide dismutase. J Biol Chem 1997, 272:23469–23472.

    Article  PubMed  CAS  Google Scholar 

  25. Wong PC, Waggoner D, Subramaniam JR, et al.: Copper chaperone for superoxide dismutase is essential to activate mammalian Cu/Zn superoxide dismutase. Proc Natl Acad Sci U S A 2000, 97:2886–2891.

    Article  PubMed  CAS  Google Scholar 

  26. Subramaniam JR, Lyons WE, Liu J, et al.: Mutant SOD1 causes motor neuron disease independent of copper chaperone-mediated copper loading. Nat Neurosci 2002, 5:301–307. Transgenic and knockout mice were generated to probe the role of copper-mediated chemistry in the pathogenesis of familial ALS linked to mutations in SOD1. Normally, SOD1 acquires an atom copper cofactor through interactions with a protein termed the copper chaperone for SOD1 (CCS). This paper demonstrates that eliminating CCS and dramatically reducing the incorporation of copper into mutant SOD1 does not proportionately diminish toxicity of the mutant enzyme.

    Article  PubMed  CAS  Google Scholar 

  27. Wang J, Xu G, Gonzales V, et al.: Fibrillar inclusions and motor neuron degeneration in transgenic mice expressing superoxide dismutase 1 with a disrupted copper-binding site. Neurobiol Dis 2002, in press. Transgenic mice were produced in which two of the four amino acid residues critical to the binding of copper to SOD1 were mutated to correspond to mutations found in familial ALS patients. This novel mutant, which lacked detectable levels of normal activity (copper dependent), was expressed in transgenic mice and found to cause an ALS-like disease.

  28. Terry R, Katzman R: Senile dementia of the Alzheimer type: defining a disease. In The Neurology of Aging. Edited by Katzman R, Terry R. Philadelphia: FA Davis; 1983:51–84.

    Google Scholar 

  29. Glenner GG, Wong CW: Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984, 120:885–890.

    Article  PubMed  CAS  Google Scholar 

  30. Masters CL, Simms G, Weinman NA, et al.: Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad SciU S A 1985, 82:4245–4249.

    Article  CAS  Google Scholar 

  31. Weidemann A, König G, Bunke D, et al.: Identification, biogenesis, and localization of precursors of Alzheimer’s disease A4 amyloid protein. Cell 1989, 57:115–126.

    Article  PubMed  CAS  Google Scholar 

  32. Haass C, Selkoe DJ: Cellular processing of beta-amyloid precursor and the genesis of amyloid beta-peptide. Cell 1993, 75:1039–1042.

    Article  PubMed  CAS  Google Scholar 

  33. Vassar R, Bennett BD, Babu-Khan S, et al.: Beta-secretase cleavage of Alzheimer’s amyloid precusor protein by the transmembrane aspartic protease BACE. Science 1999, 286:735–741.

    Article  PubMed  CAS  Google Scholar 

  34. Wolfe MS, Xia W, Ostazewski BL, et al.: Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and -secretase activity. Nature 1999, 398:513–517.

    Article  PubMed  CAS  Google Scholar 

  35. Jarrett JT, Berger EP, Lansbury PT Jr: The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer’s disease. Biochemistry 1993, 32:4693–4697.

    Article  PubMed  CAS  Google Scholar 

  36. Burdick D, Soreghan B, Kwon M, et al.: Assembly and aggregation properties of synthetic Alzheimer’s A4/b amyloid peptide analogs. J Biol Chem 1992, 267:546–554.

    PubMed  CAS  Google Scholar 

  37. Sherrington R, Froelich S, Sorbi S, et al.: Alzheimer’s disease associated with mutations in presenilin 2 is rare and variably penetrant. Hum Mol Genet 1996, 5:985–988.

    Article  PubMed  CAS  Google Scholar 

  38. Sherrington R, Rogaev EI, Liang Y, et al.: Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 1995, 375:754–760.

    Article  PubMed  CAS  Google Scholar 

  39. Murayama O, Tomita T, Nihonmatsu N, et al.: Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer’s disease. Neurosci Lett 1999, 265:61–63.

    Article  PubMed  CAS  Google Scholar 

  40. Games D, Adams D, Alessandrini R, et al.: Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 1995, 373:523–527.

    Article  PubMed  CAS  Google Scholar 

  41. Hsiao K, Chapman P, Nilsen S, et al.: Correlative memory deficts, AΒ elevation and amyloid plaques in transgenic mice. Science 1996, 274:99–102.

    Article  PubMed  CAS  Google Scholar 

  42. Sturchler-Pierrat C, Abramowski D, Duke M, et al.: Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci U S A 1997, 94:13287–13292.

    Article  PubMed  CAS  Google Scholar 

  43. Calhoun ME, Wiederhold KH, Abramowski D, et al.: Neuron loss in APP transgenic mice. Nature 1998, 395:755–756.

    Article  PubMed  CAS  Google Scholar 

  44. Irizarry MC, McNamara M, Fedorchak K, Hsiao K, Hyman BT: APPSw transgenic mice develop age-related AΒ deposits and neuropil abnormalities, but no neuronal loss in CA1. J Neuropathol Exp Neurol 1997, 56:965–973.

    PubMed  CAS  Google Scholar 

  45. Borchelt DR, Thinakaran G, Eckman CB, et al.: Familial Alzheimer’s disease-linked presenilin 1 variants elevate AΒ1-42/1-40 ratio in vitro and in vivo. Neuron 1996, 17:1005–1013.

    Article  PubMed  CAS  Google Scholar 

  46. Borchelt DR, Ratovitski T, Van Lare J, et al.: Accelerated amyloid deposition in the brains of transgenic mice co-expressing mutant presenilin 1 and amyloid precursor proteins. Neuron 1997, 19:939–945.

    Article  PubMed  CAS  Google Scholar 

  47. Holcomb L, Gordon MN, McGowan E, et al.: Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 1998, 4:97–100.

    Article  PubMed  CAS  Google Scholar 

  48. De Strooper B, Saftig P, Craessaerts K, et al.: Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 1998, 391:387–390.

    Article  PubMed  Google Scholar 

  49. Cai H, Wang Y, McCarthy D, et al.: BACE1 is the major Β-secretase for generation of AΒ peptides by neurons. Nat Neurosci 2001, 4:233–234. Article characterizes mice in which the gene for BACE1 has been deleted by homologous recombination. They demonstrate that animals lacking this enzyme appear outwardly normal and survive to adulthood with no significant phenotype except for the near-complete loss of Β-amyloid. These studies suggest that BACE1 may be an ideal therapeutic target for Alzheimer’s disease.

    Article  PubMed  CAS  Google Scholar 

  50. Luo Y, Bolon B, Kahn S, et al.: Mice deficient in BACE1, the Alzheimer’s beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nature 2001, 4:231–232. Article characterizes mice in which the gene for BACE1 has been deleted by homologous recombination. They demonstrate that animals lacking this enzyme appear outwardly normal and survive to adulthood with no significant phenotype except for the near-complete loss of Β-amyloid. These studies suggest that BACE1 may be an ideal therapeutic target for Alzheimer’s disease.

    CAS  Google Scholar 

  51. Schenk D, Barbour R, Dunn W, et al.: Immunization with amyloid-attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999, 400:173–177.

    Article  PubMed  CAS  Google Scholar 

  52. Morgan D, Diamond DM, Gottschall PE, et al.: AΒ peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature 2000, 408:982–985. Article confirms the earlier finding of Schenk et al. [51] that AΒ vaccination prevents the accumulation of amyloid plaques in APP transgenic mice. The lines of mice used for this study normally develop memory impairment with increasing amyloid burden, but this study demonstrated that behavioral decline is also ameliorated by peptide immunization. These findings support the hypothesis that abnormal amyloid production underlies the symptoms of Alzheimer’s disease and that preventing the deposition of this peptide may forestall cognitive decline.

    Article  PubMed  CAS  Google Scholar 

  53. Janus C, Pearson J, McLaurin J, et al.: AΒ peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature 2000, 408:979–982. Article confirms the earlier finding of Schenk et al. [51] that AΒ vaccination prevents the accumulation of amyloid plaques in APP transgenic mice. The lines of mice used for this study normally develop memory impairment with increasing amyloid burden, but this study demonstrated that behavioral decline is also ameliorated by peptide immunization. These findings support the hypothesis that abnormal amyloid production underlies the symptoms of Alzheimer’s disease and that preventing the deposition of this peptide may forestall cognitive decline.

    Article  PubMed  CAS  Google Scholar 

  54. Lim GP, Yang F, Chu T, et al.: Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer’s disease. J Neurosci 2000, 20:5709–5714. Authors used APP transgenic mice to show that ibuprofen may protect against Alzheimer’s disease by decreasing amyloid deposition. They further show that ibuprofen lowers brain interleukin-1Β levels and glial activation, providing a possible molecular/ cellular mechanism for its effect on AΒ.

    PubMed  CAS  Google Scholar 

  55. Haugabook SJ, Le T, Yager D, et al.: Reduction of AΒ accumulation in the Tg2576 animal model of Alzheimer’s disease after oral administration of the phosphatidyl-inositol kinase inhibitor wortmannin. FASEB J 2001, 15:16–18. This study demonstrates that chronic oral wortmanin administration can reduce AΒ accumulation in young APP transgenic mice by roughly 50%, and similarly lowers the number of plaques and the surface area they cover in older animals. The mechanism of this effect is not discussed.

    PubMed  CAS  Google Scholar 

  56. Cherny RA, Atwood CS, Xilinas ME, et al.: Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer’s disease transgenic mice. Neuron 2001, 30:665–676. Study characterizes the ability of clioquinol to solubilize Alzheimer’s disease amyloid in vitro, and then demonstrate that this copper/zinc chelator can reduce brain AΒ deposition in aged APP transgenic mice. By starting drug treatment in animals that had already developed substantial plaque burdens, they provide a stringent test of clioquinol’s ability to clear pre-existing aggregates. Importantly, clioquinol is a pharmacopia agent that has been used extensively as an oral antibiotic in the United States.

    Article  PubMed  CAS  Google Scholar 

  57. Ferrante RJ, Andreassen OA, Jenkins BG, et al.: Neuroprotective effects of creatine in a transgenic mouse model of Huntington’s disease. J Neurosci 2000, 20:4389–4397. Article describes a study in which creatine was tested for efficacy in transgenic mouse models of Huntington’s disease, a relatively rare fatal disease that is currently untreatable. This report describes a modest improvement in the motor function of the mice and moderate extension of life, a first step in the effort to find effect therapies for this severely debilitating disease.

    PubMed  CAS  Google Scholar 

  58. Andreassen OA, Dedeoglu A, Ferrante RJ, et al.: Creatine increase survival and delays motor symptoms in a transgenic animal model of Huntington’s disease. Neurobiol Dis 2001, 8:479–491. Article describes a study in which creatine was tested for efficacy in transgenic mouse models of Huntington’s disease, a relatively rare fatal disease that is currently untreatable. This report describes a modest improvement in the motor function of the mice and moderate extension of life, a first step in the effort to find effect therapies for this severely debilitating disease.

    Article  PubMed  CAS  Google Scholar 

  59. Chen M, Ona VO, Li M, et al.: Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 2000, 6:797–801. Article describes a study in which minocycline was tested for efficacy in transgenic mouse models of Huntington’s disease, a relatively rare fatal disease that is currently untreatable. This report describes a modest improvement in the motor function of the mice and moderate extension of life, a first step in the effort to find effect therapies for this severely debilitating disease.

    Article  PubMed  CAS  Google Scholar 

  60. Ferrante RJ, Andreassen OA, Dedeoglu A, et al.: Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington’s disease. J Neurosci 2002, 22:1592–1599. Article describes a study in which coenzyme Q10 and remacemide were tested for efficacy in transgenic mouse models of Huntington’s disease, a relatively rare fatal disease that is currently untreatable. This report describes a modest improvement in the motor function of the mice and moderate extension of life, a first step in the effort to find effect therapies for this severely debilitating disease.

    PubMed  CAS  Google Scholar 

  61. Andreassen OA, Ferrante RJ, Huang HM, et al.: Dichloroacetate exerts therapeutic effects in transgenic mouse models of Huntington’s disease. Ann Neurol 2001, 50:112–117. Article describes a study in which dichloroacetate was tested for efficacy in transgenic mouse models of Huntington’s disease, a relatively rare fatal disease that is currently untreatable. This report describes a modest improvement in the motor function of the mice and moderate extension of life, a first step in the effort to find effect therapies for this severely debilitating disease.

    Article  PubMed  CAS  Google Scholar 

  62. Schilling G, Coonfield ML, Ross CA, Borchelt DR: Coenzyme Q10 and remacemide hydrochloride amerliorate motor deficits in a Huntington’s disease transgenic mouse model. Neurosci Lett 2001, 315:149–153. Article describes a study in which coenzyme Q10 and remacemide were tested for efficacy in transgenic mouse models of Huntington’s disease, a relatively rare fatal disease that is currently untreatable. This report describes a modest improvement in the motor function of the mice and moderate extension of life, a first step in the effort to find effect therapies for this severely debilitating disease.

    Article  PubMed  CAS  Google Scholar 

  63. Andreassen OA, Ferrante RJ, Dedeoglu A, Beal MF: Lipoic acid improves survival in transgenic mouse models of Huntington’s disease. Neuroreport 2001, 12:3371–3373. Article describes a study in which lipoic acid was tested for efficacy in transgenic mouse models of Huntington’s disease, a relatively rare fatal disease that is currently untreatable. This report describes a modest improvement in the motor function of the mice and moderate extension of life, a first step in the effort to find effect therapies for this severely debilitating disease.

    Article  PubMed  CAS  Google Scholar 

  64. Parge HD, Hallewell RA, Tainer JA: Atomic structures of wild-type and thermostable mutant recombinant human Cu,Zn superoxide dismutase. Proc Natl Acad Sci U S A 1992, 89:6109–6113.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Pathology and Neuroscience, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Building Room 558, 21205, Baltimore, MD, USA

    Joanna L. Jankowsky PhD, Alena Savonenko MD, PhD, Gabriele Schilling PhD, Jiou Wang PhD, Guilian Xu PhD & David R. Borchelt PhD

Authors
  1. Joanna L. Jankowsky PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alena Savonenko MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gabriele Schilling PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jiou Wang PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guilian Xu PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David R. Borchelt PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jankowsky, J.L., Savonenko, A., Schilling, G. et al. Transgenic mouse models of neurodegenerative disease: Opportunities for therapeutic development. Curr Neurol Neurosci Rep 2, 457–464 (2002). https://doi.org/10.1007/s11910-002-0073-7

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11910-002-0073-7

Keywords

Search

Navigation