Molecular Neurobiology

, Volume 47, Issue 3, pp 868–882 | Cite as

Making the Brain Glow: In Vivo Bioluminescence Imaging to Study Neurodegeneration

  • Katja Hochgräfe
  • Eva-Maria Mandelkow


Bioluminescence imaging (BLI) takes advantage of the light-emitting properties of luciferase enzymes, which produce light upon oxidizing a substrate (i.e., d-luciferin) in the presence of molecular oxygen and energy. Photons emitted from living tissues can be detected and quantified by a highly sensitive charge-coupled device camera, enabling the investigator to noninvasively analyze the dynamics of biomolecular reactions in a variety of living model organisms such as transgenic mice. BLI has been used extensively in cancer research, cell transplantation, and for monitoring of infectious diseases, but only recently experimental models have been designed to study processes and pathways in neurological disorders such as Alzheimer disease, Parkinson disease, or amyotrophic lateral sclerosis. In this review, we highlight recent applications of BLI in neuroscience, including transgene expression in the brain, longitudinal studies of neuroinflammatory responses to neurodegeneration and injury, and in vivo imaging studies of neurogenesis and mitochondrial toxicity. Finally, we highlight some new developments of BLI compounds and luciferase substrates with promising potential for in vivo studies of neurological dysfunctions.


Bioluminescence imaging Luciferase Neurodegeneration Mouse model 



Alzheimer disease


Amyotrophic lateral sclerosis

Amyloid beta






Blood–brain barrier


Bioluminescence imaging


Bioluminescence resonance energy transfer


Calcium/calmodulin-dependent protein kinase II alpha


Charged-coupled device camera


Central nervous system


C-terminal half of luc


Computed tomography








Experimental autoimmune encephalomyelitis


Epidermal growth factor receptor


Fluorescence resonance energy transfer


Frontotemporal lobar degeneration


Growth-associated protein 43


Glyceraldehyde 3-phosphate dehydrogenase


Green fluorescent protein


Glial fibrillary acidic protein


Hypoxia-inducible transcriptional factor 1

hTau40 (2N4R)

The longest human Tau isoform


Pro-aggregant variant of human Tau


Anti-aggregant variant of human Tau


Kainic acid






Middle cerebral artery occlusion


Mitochondrial DNA


Magnetic resonance imaging


Mutated mitochondrial DNA repair enzyme


Neurofibrillary tangles


N-methyl-d-aspartic acid


Neuronal stem cells


N-terminal half of luc


Nuclear factor kappa B


Olfactory bulb


Parkinson disease


Positron emission tomography


Photons per second


Quantum dots


Renilla luciferase


Reactive oxygen species


Smad binding elements


Single-photon emission computed tomography


Subventricular zone


Repeat domain of human Tau


Transactive response DNA-binding protein 43


Transforming growth factor beta


Toll-like receptor II






Wild type



We thank Eckhard Mandelkow for stimulating discussions throughout this project and Astrid Sydow and Dorthe Matenia for helpful suggestions regarding this review. The work of the laboratory described here was supported by grants from MPG, DZNE, WellcomeTrust/MRC, and Tau Consortium.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Massoud TF, Gambhir SS (2003) Molecular imaging in living subjects: seeing fundamental biological processes in a new light. Genes Dev 17(5):545–580. doi: 10.1101/gad.1047403 PubMedGoogle Scholar
  2. 2.
    Ewers M, Frisoni GB, Teipel SJ, Grinberg LT, Amaro E Jr, Heinsen H, Thompson PM, Hampel H (2011) Staging Alzheimer’s disease progression with multimodality neuroimaging. Prog Neurobiol 95(4):535–546. doi: 10.1016/j.pneurobio.2011.06.004 PubMedGoogle Scholar
  3. 3.
    Herholz K, Ebmeier K (2011) Clinical amyloid imaging in Alzheimer’s disease. Lancet Neurol 10(7):667–670. doi: 10.1016/S1474-4422(11)70123-5 PubMedGoogle Scholar
  4. 4.
    Ono M, Saji H (2012) Molecular approaches to the treatment, prophylaxis, and diagnosis of Alzheimer’s disease: novel PET/SPECT imaging probes for diagnosis of Alzheimer’s disease. J Pharmacol Sci 118(3):338–344PubMedGoogle Scholar
  5. 5.
    Troy T, Jekic-McMullen D, Sambucetti L, Rice B (2004) Quantitative comparison of the sensitivity of detection of fluorescent and bioluminescent reporters in animal models. Mol Imaging 3(1):9–23. doi: 10.1162/153535004773861688 PubMedGoogle Scholar
  6. 6.
    Contag CH (2007) In vivo pathology: seeing with molecular specificity and cellular resolution in the living body. Annu Rev Pathol 2:277–305. doi: 10.1146/annurev.pathol.2.010506.091930 PubMedGoogle Scholar
  7. 7.
    Keyaerts M, Remory I, Caveliers V, Breckpot K, Bos TJ, Poelaert J, Bossuyt A, Lahoutte T (2012) Inhibition of firefly luciferase by general anesthetics: effect on in vitro and in vivo bioluminescence imaging. PLoS One 7(1):e30061. doi: 10.1371/journal.pone.0030061 PubMedGoogle Scholar
  8. 8.
    Luker KE, Luker GD (2008) Applications of bioluminescence imaging to antiviral research and therapy: multiple luciferase enzymes and quantitation. Antivir Res 78(3):179–187. doi: 10.1016/j.antiviral.2008.01.158 PubMedGoogle Scholar
  9. 9.
    Prescher JA, Contag CH (2010) Guided by the light: visualizing biomolecular processes in living animals with bioluminescence. Curr Opin Chem Biol 14(1):80–89. doi: 10.1016/j.cbpa.2009.11.001 PubMedGoogle Scholar
  10. 10.
    Virostko J, Jansen ED (2009) Validation of bioluminescent imaging techniques. Methods Mol Biol 574:15–23. doi: 10.1007/978-1-60327-321-3_2 PubMedGoogle Scholar
  11. 11.
    Day JC, Tisi LC, Bailey MJ (2004) Evolution of beetle bioluminescence: the origin of beetle luciferin. Luminescence 19(1):8–20. doi: 10.1002/bio.749 PubMedGoogle Scholar
  12. 12.
    Widder EA (2010) Bioluminescence in the ocean: origins of biological, chemical, and ecological diversity. Science 328(5979):704–708. doi: 10.1126/science.1174269 PubMedGoogle Scholar
  13. 13.
    Contag CH, Spilman SD, Contag PR, Oshiro M, Eames B, Dennery P, Stevenson DK, Benaron DA (1997) Visualizing gene expression in living mammals using a bioluminescent reporter. Photochem Photobiol 66(4):523–531PubMedGoogle Scholar
  14. 14.
    Marques SM, Esteves da Silva JC (2009) Firefly bioluminescence: a mechanistic approach of luciferase catalyzed reactions. IUBMB Life 61(1):6–17. doi: 10.1002/iub.134 PubMedGoogle Scholar
  15. 15.
    Tromberg BJ, Shah N, Lanning R, Cerussi A, Espinoza J, Pham T, Svaasand L, Butler J (2000) Non-invasive in vivo characterization of breast tumors using photon migration spectroscopy. Neoplasia 2(1–2):26–40PubMedGoogle Scholar
  16. 16.
    Zhao H, Doyle TC, Coquoz O, Kalish F, Rice BW, Contag CH (2005) Emission spectra of bioluminescent reporters and interaction with mammalian tissue determine the sensitivity of detection in vivo. J Biomed Opt 10(4):41210. doi: 10.1117/1.2032388 PubMedGoogle Scholar
  17. 17.
    Lalancette-Hebert M, Phaneuf D, Soucy G, Weng YC, Kriz J (2009) Live imaging of Toll-like receptor 2 response in cerebral ischaemia reveals a role of olfactory bulb microglia as modulators of inflammation. Brain: J Neurol 132(Pt 4):940–954. doi: 10.1093/brain/awn345 Google Scholar
  18. 18.
    Virostko J, Chen Z, Fowler M, Poffenberger G, Powers AC, Jansen ED (2004) Factors influencing quantification of in vivo bioluminescence imaging: application to assessment of pancreatic islet transplants. Mol Imaging 3(4):333–342. doi: 10.1162/1535350042973508 PubMedGoogle Scholar
  19. 19.
    Allard M, Cote D, Davidson L, Dazai J, Henkelman RM (2007) Combined magnetic resonance and bioluminescence imaging of live mice. J Biomed Opt 12(3):034018. doi: 10.1117/1.2745298 PubMedGoogle Scholar
  20. 20.
    Klose AD, Beattie BJ, Dehghani H, Vider L, Le C, Ponomarev V, Blasberg R (2010) In vivo bioluminescence tomography with a blocking-off finite-difference SP3 method and MRI/CT coregistration. Med Phys 37(1):329–338PubMedGoogle Scholar
  21. 21.
    Razansky D, Deliolanis NC, Vinegoni C, Ntziachristos V (2012) Deep tissue optical and optoacoustic molecular imaging technologies for pre-clinical research and drug discovery. Curr Pharm Biotechnol 13(4):504–522PubMedGoogle Scholar
  22. 22.
    Kuo C, Coquoz O, Troy TL, Xu H, Rice BW (2007) Three-dimensional reconstruction of in vivo bioluminescent sources based on multispectral imaging. J Biomed Opt 12(2):024007. doi: 10.1117/1.2717898 PubMedGoogle Scholar
  23. 23.
    Sydow A, Van der Jeugd A, Zheng F, Ahmed T, Balschun D, Petrova O, Drexler D, Zhou L, Rune G, Mandelkow E, D'Hooge R, Alzheimer C, Mandelkow EM (2011) Tau-induced defects in synaptic plasticity, learning, and memory are reversible in transgenic mice after switching off the toxic Tau mutant. J Neurosci 31(7):2511–2525. doi: 10.1523/JNEUROSCI.5245-10.2011 PubMedGoogle Scholar
  24. 24.
    Berger F, Paulmurugan R, Bhaumik S, Gambhir SS (2008) Uptake kinetics and biodistribution of 14C-D-luciferin—a radiolabeled substrate for the firefly luciferase catalyzed bioluminescence reaction: impact on bioluminescence based reporter gene imaging. Eur J Nucl Med Mol Imaging 35(12):2275–2285. doi: 10.1007/s00259-008-0870-6 PubMedGoogle Scholar
  25. 25.
    Lee KH, Byun SS, Paik JY, Lee SY, Song SH, Choe YS, Kim BT (2003) Cell uptake and tissue distribution of radioiodine labelled D-luciferin: implications for luciferase based gene imaging. Nucl Med Commun 24(9):1003–1009. doi: 10.1097/01.mnm.0000090431.24184.49 PubMedGoogle Scholar
  26. 26.
    Paroo Z, Bollinger RA, Braasch DA, Richer E, Corey DR, Antich PP, Mason RP (2004) Validating bioluminescence imaging as a high-throughput, quantitative modality for assessing tumor burden. Mol Imaging 3(2):117–124. doi: 10.1162/1535350041464865 PubMedGoogle Scholar
  27. 27.
    Selkoe DJ (1991) The molecular pathology of Alzheimer’s disease. Neuron 6(4):487–498PubMedGoogle Scholar
  28. 28.
    Denk F, Wade-Martins R (2009) Knock-out and transgenic mouse models of tauopathies. Neurobiol Aging 30(1):1–13. doi: 10.1016/j.neurobiolaging.2007.05.010 PubMedGoogle Scholar
  29. 29.
    Lee VM, Kenyon TK, Trojanowski JQ (2005) Transgenic animal models of tauopathies. Biochim Biophys Acta 1739(2–3):251–259. doi: 10.1016/j.bbadis.2004.06.014 PubMedGoogle Scholar
  30. 30.
    Eckermann K, Mocanu MM, Khlistunova I, Biernat J, Nissen A, Hofmann A, Schonig K, Bujard H, Haemisch A, Mandelkow E, Zhou L, Rune G, Mandelkow EM (2007) The beta-propensity of Tau determines aggregation and synaptic loss in inducible mouse models of tauopathy. J Biol Chem 282(43):31755–31765. doi: 10.1074/jbc.M705282200 PubMedGoogle Scholar
  31. 31.
    Mocanu MM, Nissen A, Eckermann K, Khlistunova I, Biernat J, Drexler D, Petrova O, Schonig K, Bujard H, Mandelkow E, Zhou L, Rune G, Mandelkow EM (2008) The potential for beta-structure in the repeat domain of tau protein determines aggregation, synaptic decay, neuronal loss, and coassembly with endogenous Tau in inducible mouse models of tauopathy. J Neurosci 28(3):737–748. doi: 10.1523/JNEUROSCI.2824-07.2008 PubMedGoogle Scholar
  32. 32.
    Van der Jeugd A, Hochgrafe K, Ahmed T, Decker JM, Sydow A, Hofmann A, Wu D, Messing L, Balschun D, D'Hooge R, Mandelkow EM (2012) Cognitive defects are reversible in inducible mice expressing pro-aggregant full-length human Tau. Acta neuropathol 123(6):787–805. doi: 10.1007/s00401-012-0987-3 PubMedGoogle Scholar
  33. 33.
    Baron U, Freundlieb S, Gossen M, Bujard H (1995) Co-regulation of two gene activities by tetracycline via a bidirectional promoter. Nucleic Acids Res 23(17):3605–3606PubMedGoogle Scholar
  34. 34.
    Krestel HE, Mayford M, Seeburg PH, Sprengel R (2001) A GFP-equipped bidirectional expression module well suited for monitoring tetracycline-regulated gene expression in mouse. Nucleic Acids Res 29(7):E39PubMedGoogle Scholar
  35. 35.
    Mayford M, Bach ME, Huang YY, Wang L, Hawkins RD, Kandel ER (1996) Control of memory formation through regulated expression of a CaMKII transgene. Science 274(5293):1678–1683PubMedGoogle Scholar
  36. 36.
    Gossen M, Bujard H (2002) Studying gene function in eukaryotes by conditional gene inactivation. Annu Rev Genet 36:153–173. doi: 10.1146/annurev.genet.36.041002.120114 PubMedGoogle Scholar
  37. 37.
    Luker KE, Luker GD (2010) Bioluminescence imaging of reporter mice for studies of infection and inflammation. Antivir Res 86(1):93–100. doi: 10.1016/j.antiviral.2010.02.002 PubMedGoogle Scholar
  38. 38.
    Luo J, Ho P, Steinman L, Wyss-Coray T (2008) Bioluminescence in vivo imaging of autoimmune encephalomyelitis predicts disease. Journal of Neuroinflammation 5:6. doi: 10.1186/1742-2094-5-6 PubMedGoogle Scholar
  39. 39.
    Burgin KE, Waxham MN, Rickling S, Westgate SA, Mobley WC, Kelly PT (1990) In situ hybridization histochemistry of Ca2+/calmodulin-dependent protein kinase in developing rat brain. J Neurosci: Off J Soc Neurosci 10(6):1788–1798Google Scholar
  40. 40.
    Crain B, Cotman C, Taylor D, Lynch G (1973) A quantitative electron microscopic study of synaptogenesis in the dentate gyrus of the rat. Brain Res 63:195–204PubMedGoogle Scholar
  41. 41.
    Yamauchi T (2005) Neuronal Ca2+/calmodulin-dependent protein kinase II—discovery, progress in a quarter of a century, and perspective: implication for learning and memory. Biol Pharm Bull 28(8):1342–1354PubMedGoogle Scholar
  42. 42.
    Wang Y, Mandelkow E (2012) Degradation of tau protein by autophagy and proteasomal pathways. Biochem Soc Trans 40(4):644–652. doi: 10.1042/BST20120071 PubMedGoogle Scholar
  43. 43.
    Gould SJ, Subramani S (1988) Firefly luciferase as a tool in molecular and cell biology. Anal Biochem 175(1):5–13PubMedGoogle Scholar
  44. 44.
    Keller GA, Gould S, Deluca M, Subramani S (1987) Firefly luciferase is targeted to peroxisomes in mammalian cells. Proc Natl Acad Sci U S A 84(10):3264–3268PubMedGoogle Scholar
  45. 45.
    Ignowski JM, Schaffer DV (2004) Kinetic analysis and modeling of firefly luciferase as a quantitative reporter gene in live mammalian cells. Biotechnol Bioeng 86(7):827–834. doi: 10.1002/bit.20059 PubMedGoogle Scholar
  46. 46.
    Thompson JF, Hayes LS, Lloyd DB (1991) Modulation of firefly luciferase stability and impact on studies of gene regulation. Gene 103(2):171–177PubMedGoogle Scholar
  47. 47.
    Price JC, Guan S, Burlingame A, Prusiner SB, Ghaemmaghami S (2010) Analysis of proteome dynamics in the mouse brain. Proc Natl Acad Sci U S A 107(32):14508–14513. doi: 10.1073/pnas.1006551107 PubMedGoogle Scholar
  48. 48.
    Riond JL, Riviere JE (1988) Pharmacology and toxicology of doxycycline. Vet Hum Toxicol 30(5):431–443PubMedGoogle Scholar
  49. 49.
    Middeldorp J, Hol EM (2011) GFAP in health and disease. Prog Neurobiol 93(3):421–443. doi: 10.1016/j.pneurobio.2011.01.005 PubMedGoogle Scholar
  50. 50.
    Zhu L, Ramboz S, Hewitt D, Boring L, Grass DS, Purchio AF (2004) Non-invasive imaging of GFAP expression after neuronal damage in mice. Neurosci Lett 367(2):210–212. doi: 10.1016/j.neulet.2004.06.020 PubMedGoogle Scholar
  51. 51.
    Cho W, Hagemann TL, Johnson DA, Johnson JA, Messing A (2009) Dual transgenic reporter mice as a tool for monitoring expression of glial fibrillary acidic protein. J Neurochem 110(1):343–351. doi: 10.1111/j.1471-4159.2009.06146.x PubMedGoogle Scholar
  52. 52.
    Cordeau P Jr, Lalancette-Hebert M, Weng YC, Kriz J (2008) Live imaging of neuroinflammation reveals sex and estrogen effects on astrocyte response to ischemic injury. Stroke 39(3):935–942. doi: 10.1161/STROKEAHA.107.501460 PubMedGoogle Scholar
  53. 53.
    Maysinger D, Behrendt M, Lalancette-Hebert M, Kriz J (2007) Real-time imaging of astrocyte response to quantum dots: in vivo screening model system for biocompatibility of nanoparticles. Nano Lett 7(8):2513–2520. doi: 10.1021/nl071611t PubMedGoogle Scholar
  54. 54.
    Di Giorgio FP, Carrasco MA, Siao MC, Maniatis T, Eggan K (2007) Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nat Neurosci 10(5):608–614. doi: 10.1038/nn1885 PubMedGoogle Scholar
  55. 55.
    Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H, Przedborski S (2007) Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci 10(5):615–622. doi: 10.1038/nn1876 PubMedGoogle Scholar
  56. 56.
    Cheng C, Zochodne DW (2002) In vivo proliferation, migration and phenotypic changes of Schwann cells in the presence of myelinated fibers. Neuroscience 115(1):321–329PubMedGoogle Scholar
  57. 57.
    Keller AF, Gravel M, Kriz J (2009) Live imaging of amyotrophic lateral sclerosis pathogenesis: disease onset is characterized by marked induction of GFAP in Schwann cells. Glia 57(10):1130–1142. doi: 10.1002/glia.20836 PubMedGoogle Scholar
  58. 58.
    Swarup V, Phaneuf D, Bareil C, Robertson J, Rouleau GA, Kriz J, Julien JP (2011) Pathological hallmarks of amyotrophic lateral sclerosis/frontotemporal lobar degeneration in transgenic mice produced with TDP-43 genomic fragments. Brain: J Neurol 134(Pt 9):2610–2626. doi: 10.1093/brain/awr159 Google Scholar
  59. 59.
    Verkhratsky A, Olabarria M, Noristani HN, Yeh CY, Rodriguez JJ (2010) Astrocytes in Alzheimer’s disease. Neurotherapeutics 7(4):399–412. doi: 10.1016/j.nurt.2010.05.017 PubMedGoogle Scholar
  60. 60.
    Balducci C, Forloni G (2011) APP transgenic mice: their use and limitations. Neuromol Med 13(2):117–137. doi: 10.1007/s12017-010-8141-7 Google Scholar
  61. 61.
    Watts JC, Giles K, Grillo SK, Lemus A, DeArmond SJ, Prusiner SB (2011) Bioluminescence imaging of Abeta deposition in bigenic mouse models of Alzheimer’s disease. Proc Natl Acad Sci U S A 108(6):2528–2533. doi: 10.1073/pnas.1019034108 PubMedGoogle Scholar
  62. 62.
    Meyer-Luehmann M, Coomaraswamy J, Bolmont T, Kaeser S, Schaefer C, Kilger E, Neuenschwander A, Abramowski D, Frey P, Jaton AL, Vigouret JM, Paganetti P, Walsh DM, Mathews PM, Ghiso J, Staufenbiel M, Walker LC, Jucker M (2006) Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 313(5794):1781–1784. doi: 10.1126/science.1131864 PubMedGoogle Scholar
  63. 63.
    Stohr J, Watts JC, Mensinger ZL, Oehler A, Grillo SK, Dearmond SJ, Prusiner SB, Giles K (2012) Purified and synthetic Alzheimer’s amyloid beta (Abeta) prions. Proc Natl Acad Sci U S A 109(27):11025–11030. doi: 10.1073/pnas.1206555109 PubMedGoogle Scholar
  64. 64.
    Kovacs GG, Budka H (2008) Prion diseases: from protein to cell pathology. Am J Pathol 172(3):555–565. doi: 10.2353/ajpath.2008.070442 PubMedGoogle Scholar
  65. 65.
    Tamguney G, Francis KP, Giles K, Lemus A, DeArmond SJ, Prusiner SB (2009) Measuring prions by bioluminescence imaging. Proc Natl Acad Sci U S A 106(35):15002–15006. doi: 10.1073/pnas.0907339106 PubMedGoogle Scholar
  66. 66.
    Beynon SB, Walker FR (2012) Microglial activation in the injured and healthy brain: what are we really talking about? Practical and theoretical issues associated with the measurement of changes in microglial morphology. Neuroscience. doi: 10.1016/j.neuroscience.2012.07.029
  67. 67.
    Olson JK, Miller SD (2004) Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol 173(6):3916–3924PubMedGoogle Scholar
  68. 68.
    Lalancette-Hebert M, Moquin A, Choi AO, Kriz J, Maysinger D (2010) Lipopolysaccharide-QD micelles induce marked induction of TLR2 and lipid droplet accumulation in olfactory bulb microglia. Mol Pharm 7(4):1183–1194. doi: 10.1021/mp1000372 PubMedGoogle Scholar
  69. 69.
    Malek R, Borowicz KK, Jargiello M, Czuczwar SJ (2007) Role of nuclear factor kappaB in the central nervous system. Pharmacol Rep 59(1):25–33PubMedGoogle Scholar
  70. 70.
    Memet S (2006) NF-kappaB functions in the nervous system: from development to disease. Biochem Pharmacol 72(9):1180–1195. doi: 10.1016/j.bcp.2006.09.003 PubMedGoogle Scholar
  71. 71.
    Blackwell TS, Yull FE, Chen CL, Venkatakrishnan A, Blackwell TR, Hicks DJ, Lancaster LH, Christman JW, Kerr LD (2000) Multiorgan nuclear factor kappa B activation in a transgenic mouse model of systemic inflammation. Am J Respir Crit Care Med 162(3 Pt 1):1095–1101PubMedGoogle Scholar
  72. 72.
    Carlsen H, Moskaug JO, Fromm SH, Blomhoff R (2002) In vivo imaging of NF-kappa B activity. J Immunol 168(3):1441–1446PubMedGoogle Scholar
  73. 73.
    Hubbard AK, Timblin CR, Shukla A, Rincon M, Mossman BT (2002) Activation of NF-kappaB-dependent gene expression by silica in lungs of luciferase reporter mice. Am J Physiol Lung Cell Mol Physiol 282(5):L968–L975. doi: 10.1152/ajplung.00327.2001 PubMedGoogle Scholar
  74. 74.
    Zangani M, Carlsen H, Kielland A, Os A, Hauglin H, Blomhoff R, Munthe LA, Bogen B (2009) Tracking early autoimmune disease by bioluminescent imaging of NF-kappaB activation reveals pathology in multiple organ systems. Am J Pathol 174(4):1358–1367. doi: 10.2353/ajpath.2009.080700 PubMedGoogle Scholar
  75. 75.
    Sadikot RT, Blackwell TS (2005) Bioluminescence imaging. Proc Am Thorac Soc 2(6):537–540. doi: 10.1513/pats.200507-067DS, 511–532PubMedGoogle Scholar
  76. 76.
    Dohlen G, Carlsen H, Blomhoff R, Thaulow E, Saugstad OD (2005) Reoxygenation of hypoxic mice with 100 % oxygen induces brain nuclear factor-kappa B. Pediatr Res 58(5):941–945. doi: 10.1203/01.PDR.0000182595.62545.EE PubMedGoogle Scholar
  77. 77.
    Dohlen G, Odland HH, Carlsen H, Blomhoff R, Thaulow E, Saugstad OD (2008) Antioxidant activity in the newborn brain: a luciferase mouse model. Neonatology 93(2):125–131. doi: 10.1159/000107777 PubMedGoogle Scholar
  78. 78.
    Gutierrez H, Davies AM (2011) Regulation of neural process growth, elaboration and structural plasticity by NF-kappaB. Trends Neurosci 34(6):316–325. doi: 10.1016/j.tins.2011.03.001 PubMedGoogle Scholar
  79. 79.
    Tesseur I, Wyss-Coray T (2006) A role for TGF-beta signaling in neurodegeneration: evidence from genetically engineered models. Current Alzheimer Res 3(5):505–513Google Scholar
  80. 80.
    Lin AH, Luo J, Mondshein LH, ten Dijke P, Vivien D, Contag CH, Wyss-Coray T (2005) Global analysis of Smad2/3-dependent TGF-beta signaling in living mice reveals prominent tissue-specific responses to injury. J Immunol 175(1):547–554PubMedGoogle Scholar
  81. 81.
    Luo J, Wyss-Coray T (2009) Bioluminescence analysis of Smad-dependent TGF-beta signaling in live mice. Methods Mol Biol 574:193–202. doi: 10.1007/978-1-60327-321-3_16 PubMedGoogle Scholar
  82. 82.
    de Heredia LL, Gengatharan A, Foster J, Mather S, Magoulas C (2011) Bioluminescence imaging of the brain response to acute inflammation in living C/EBP reporter mice. Neurosci Lett 497(2):134–138. doi: 10.1016/j.neulet.2011.04.046 Google Scholar
  83. 83.
    Li L, Fei Z, Ren J, Sun R, Liu Z, Sheng Z, Wang L, Sun X, Yu J, Wang Z, Fei J (2008) Functional imaging of interleukin 1 beta expression in inflammatory process using bioluminescence imaging in transgenic mice. BMC Immunol 9:49. doi: 10.1186/1471-2172-9-49 PubMedGoogle Scholar
  84. 84.
    Zhao C, Deng W, Gage FH (2008) Mechanisms and functional implications of adult neurogenesis. Cell 132(4):645–660. doi: 10.1016/j.cell.2008.01.033 PubMedGoogle Scholar
  85. 85.
    Couillard-Despres S, Finkl R, Winner B, Ploetz S, Wiedermann D, Aigner R, Bogdahn U, Winkler J, Hoehn M, Aigner L (2008) In vivo optical imaging of neurogenesis: watching new neurons in the intact brain. Mol Imaging 7(1):28–34PubMedGoogle Scholar
  86. 86.
    Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, Fainberg N, Ding Z, Eggel A, Lucin KM, Czirr E, Park JS, Couillard-Despres S, Aigner L, Li G, Peskind ER, Kaye JA, Quinn JF, Galasko DR, Xie XS, Rando TA, Wyss-Coray T (2011) The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477(7362):90–94. doi: 10.1038/nature10357 PubMedGoogle Scholar
  87. 87.
    Reumers V, Deroose CM, Krylyshkina O, Nuyts J, Geraerts M, Mortelmans L, Gijsbers R, Van den Haute C, Debyser Z, Baekelandt V (2008) Noninvasive and quantitative monitoring of adult neuronal stem cell migration in mouse brain using bioluminescence imaging. Stem Cells 26(9):2382–2390. doi: 10.1634/stemcells.2007-1062 PubMedGoogle Scholar
  88. 88.
    Reekmans KP, Praet J, De Vocht N, Tambuyzer BR, Bergwerf I, Daans J, Baekelandt V, Vanhoutte G, Goossens H, Jorens PG, Ysebaert DK, Chatterjee S, Pauwels P, Van Marck E, Berneman ZN, Van der Linden A, Ponsaerts P (2011) Clinical potential of intravenous neural stem cell delivery for treatment of neuroinflammatory disease in mice? Cell Transplant 20(6):851–869. doi: 10.3727/096368910X543411 PubMedGoogle Scholar
  89. 89.
    Gravel M, Weng YC, Kriz J (2011) Model system for live imaging of neuronal responses to injury and repair. Mol Imaging 10(6):434–445PubMedGoogle Scholar
  90. 90.
    Denny JB (2006) Molecular mechanisms, biological actions, and neuropharmacology of the growth-associated protein GAP-43. Curr Neuropharmacol 4(4):293–304PubMedGoogle Scholar
  91. 91.
    Lezi E, Swerdlow RH (2012) Mitochondria in neurodegeneration. Adv Exp Med Biol 942:269–286. doi: 10.1007/978-94-007-2869-1_12 PubMedGoogle Scholar
  92. 92.
    Lauritzen KH, Moldestad O, Eide L, Carlsen H, Nesse G, Storm JF, Mansuy IM, Bergersen LH, Klungland A (2010) Mitochondrial DNA toxicity in forebrain neurons causes apoptosis, neurodegeneration, and impaired behavior. Mol Cell Biol 30(6):1357–1367. doi: 10.1128/MCB.01149-09 PubMedGoogle Scholar
  93. 93.
    Lauritzen KH, Cheng C, Wiksen H, Bergersen LH, Klungland A (2011) Mitochondrial DNA toxicity compromises mitochondrial dynamics and induces hippocampal antioxidant defenses. DNA Repair (Amst) 10(6):639–653. doi: 10.1016/j.dnarep.2011.04.011 Google Scholar
  94. 94.
    Close DM, Xu T, Sayler GS, Ripp S (2011) In vivo bioluminescent imaging (BLI): noninvasive visualization and interrogation of biological processes in living animals. Sensors (Basel) 11(1):180–206. doi: 10.3390/s110100180 Google Scholar
  95. 95.
    Massoud TF, Paulmurugan R, De A, Ray P, Gambhir SS (2007) Reporter gene imaging of protein–protein interactions in living subjects. Curr Opin Biotechnol 18(1):31–37. doi: 10.1016/j.copbio.2007.01.007 PubMedGoogle Scholar
  96. 96.
    Villalobos V, Naik S, Piwnica-Worms D (2007) Current state of imaging protein–protein interactions in vivo with genetically encoded reporters. Annu Rev Biomed Eng 9:321–349. doi: 10.1146/annurev.bioeng.9.060906.152044 PubMedGoogle Scholar
  97. 97.
    Naik S, Piwnica-Worms D (2007) Real-time imaging of beta-catenin dynamics in cells and living mice. Proc Natl Acad Sci U S A 104(44):17465–17470. doi: 10.1073/pnas.0704465104 PubMedGoogle Scholar
  98. 98.
    Kesarwala AH, Samrakandi MM, Piwnica-Worms D (2009) Proteasome inhibition blocks ligand-induced dynamic processing and internalization of epidermal growth factor receptor via altered receptor ubiquitination and phosphorylation. Cancer Res 69(3):976–983. doi: 10.1158/0008-5472.CAN-08-2938 PubMedGoogle Scholar
  99. 99.
    Moroz E, Carlin S, Dyomina K, Burke S, Thaler HT, Blasberg R, Serganova I (2009) Real-time imaging of HIF-1alpha stabilization and degradation. PLoS One 4(4):e5077. doi: 10.1371/journal.pone.0005077 PubMedGoogle Scholar
  100. 100.
    Ray P, Pimenta H, Paulmurugan R, Berger F, Phelps ME, Iyer M, Gambhir SS (2002) Noninvasive quantitative imaging of protein–protein interactions in living subjects. Proc Natl Acad Sci U S A 99(5):3105–3110. doi: 10.1073/pnas.052710999 PubMedGoogle Scholar
  101. 101.
    Paulmurugan R, Umezawa Y, Gambhir SS (2002) Noninvasive imaging of protein–protein interactions in living subjects by using reporter protein complementation and reconstitution strategies. Proc Natl Acad Sci U S A 99(24):15608–15613. doi: 10.1073/pnas.242594299 PubMedGoogle Scholar
  102. 102.
    Zhang L, Lee KC, Bhojani MS, Khan AP, Shilman A, Holland EC, Ross BD, Rehemtulla A (2007) Molecular imaging of Akt kinase activity. Nat Med 13(9):1114–1119. doi: 10.1038/nm1608 PubMedGoogle Scholar
  103. 103.
    Coppola JM, Ross BD, Rehemtulla A (2008) Noninvasive imaging of apoptosis and its application in cancer therapeutics. Clin Cancer Res 14(8):2492–2501. doi: 10.1158/1078-0432.CCR-07-0782 PubMedGoogle Scholar
  104. 104.
    Hickson J, Ackler S, Klaubert D, Bouska J, Ellis P, Foster K, Oleksijew A, Rodriguez L, Schlessinger S, Wang B, Frost D (2010) Noninvasive molecular imaging of apoptosis in vivo using a modified firefly luciferase substrate, Z-DEVD-aminoluciferin. Cell Death Differ 17(6):1003–1010. doi: 10.1038/cdd.2009.205 PubMedGoogle Scholar
  105. 105.
    Shah K, Tung CH, Breakefield XO, Weissleder R (2005) In vivo imaging of S-TRAIL-mediated tumor regression and apoptosis. Mol Ther 11(6):926–931. doi: 10.1016/j.ymthe.2005.01.017 PubMedGoogle Scholar
  106. 106.
    Pfleger KD, Eidne KA (2006) Illuminating insights into protein-protein interactions using bioluminescence resonance energy transfer (BRET). Nat Methods 3(3):165–174. doi: 10.1038/nmeth841 PubMedGoogle Scholar
  107. 107.
    Xia Z, Rao J (2009) Biosensing and imaging based on bioluminescence resonance energy transfer. Curr Opin Biotechnol 20(1):37–44. doi: 10.1016/j.copbio.2009.01.001 PubMedGoogle Scholar
  108. 108.
    Dragulescu-Andrasi A, Chan CT, De A, Massoud TF, Gambhir SS (2011) Bioluminescence resonance energy transfer (BRET) imaging of protein-protein interactions within deep tissues of living subjects. Proc Natl Acad Sci U S A 108(29):12060–12065. doi: 10.1073/pnas.1100923108 PubMedGoogle Scholar
  109. 109.
    Loening AM, Wu AM, Gambhir SS (2007) Red-shifted Renilla reniformis luciferase variants for imaging in living subjects. Nat Methods 4(8):641–643. doi: 10.1038/nmeth1070 PubMedGoogle Scholar
  110. 110.
    Walls ZF, Gambhir SS (2008) BRET-based method for detection of specific RNA species. Bioconjug Chem 19(1):178–184. doi: 10.1021/bc700278n PubMedGoogle Scholar
  111. 111.
    Gammon ST, Villalobos VM, Roshal M, Samrakandi M, Piwnica-Worms D (2009) Rational design of novel red-shifted BRET pairs: platforms for real-time single-chain protease biosensors. Biotechnol Prog 25(2):559–569. doi: 10.1002/btpr.144 PubMedGoogle Scholar
  112. 112.
    Gross S, Gammon ST, Moss BL, Rauch D, Harding J, Heinecke JW, Ratner L, Piwnica-Worms D (2009) Bioluminescence imaging of myeloperoxidase activity in vivo. Nat Med 15(4):455–461. doi: 10.1038/nm.1886 PubMedGoogle Scholar
  113. 113.
    Lee D, Khaja S, Velasquez-Castano JC, Dasari M, Sun C, Petros J, Taylor WR, Murthy N (2007) In vivo imaging of hydrogen peroxide with chemiluminescent nanoparticles. Nat Mater 6(10):765–769. doi: 10.1038/nmat1983 PubMedGoogle Scholar
  114. 114.
    Stafford P, Abdelwahab MG, Kim do Y, Preul MC, Rho JM, Scheck AC (2010) The ketogenic diet reverses gene expression patterns and reduces reactive oxygen species levels when used as an adjuvant therapy for glioma. Nutr Metab (Lond) 7(74). doi: 10.1186/1743-7075-7-74
  115. 115.
    Hall DJ, Han SH, Chepetan A, Inui EG, Rogers M, Dugan LL (2012) Dynamic optical imaging of metabolic and NADPH oxidase-derived superoxide in live mouse brain using fluorescence lifetime unmixing. J Cereb Blood Flow Metab 32(1):23–32. doi: 10.1038/jcbfm.2011.119 PubMedGoogle Scholar
  116. 116.
    Kundu K, Knight SF, Lee S, Taylor WR, Murthy N (2010) A significant improvement of the efficacy of radical oxidant probes by the kinetic isotope effect. Angew Chem 49(35):6134–6138. doi: 10.1002/anie.201002228 Google Scholar
  117. 117.
    Liu H, Ren G, Miao Z, Zhang X, Tang X, Han P, Gambhir SS, Cheng Z (2010) Molecular optical imaging with radioactive probes. PLoS One 5(3):e9470. doi: 10.1371/journal.pone.0009470 PubMedGoogle Scholar
  118. 118.
    Robertson R, Germanos MS, Li C, Mitchell GS, Cherry SR, Silva MD (2009) Optical imaging of Cerenkov light generation from positron-emitting radiotracers. Phys Med Biol 54(16):N355–N365. doi: 10.1088/0031-9155/54/16/N01 PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.DZNE (German Center for Neurodegenerative Diseases)BonnGermany
  2. 2.CAESAR Research CenterBonnGermany
  3. 3.Max-Planck-Institute for Neurological Research, Hamburg Outstation, c/o DESYHamburgGermany

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