Molecular and Cellular Biochemistry

, Volume 324, Issue 1–2, pp 191–199 | Cite as

Improvement of cerebral function by anti-amyloid precursor protein antibody infusion after traumatic brain injury in rats

  • Tatsuki Itoh
  • Takao Satou
  • Shozo Nishida
  • Masahiro Tsubaki
  • Shigeo Hashimoto
  • Hiroyuki Ito


We previously demonstrated the increased amyloid precursor protein (APP) immunoreactivity around the site of damage after traumatic brain injury (TBI). However, the function of APP after TBI has not been evaluated. In this study, we investigated the effects of direct infusion of an anti-APP antibody into the damaged brain region on cerebral function and morphological changes following TBI in rats. Three days after TBI, there were many TUNEL-positive neurons and astrocytes around the damaged region and a significantly greater number of TUNEL-positive cells in the PBS group compared with the anti-APP group found. Seven days after TBI, there were significantly a greater number of large glial fibrillary acidic protein-positive cells, long elongated projections, and microtubule-associated protein-2-positive cells around the damaged region in the anti-APP group compared with the PBS group found. Seven days after TBI, the region of brain damage was significantly smaller and the time to arrival at a platform was significantly shorter in the anti-APP group compared with the PBS group. Furthermore, after TBI in the anti-APP group, the time to arrival at the platform recovered to that observed in uninjured sham operation group rats. These data suggest that the overproduction of APP after TBI inhibits astrocyte activity and reduces neural cell survival around the damaged brain region, which speculatively may be related to the induction of Alzheimer disease-type dementia after TBI.


Amyloid precursor protein Anti-APP antibody Brain function Traumatic brain injury Water maze 


  1. 1.
    Goldgaber D, Lerman MI, McBride OW et al (1987) Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer’s disease. Science 235:877–880. doi:10.1126/science.3810169 PubMedCrossRefGoogle Scholar
  2. 2.
    Robakis NK, Ramakrishna N, Wolfe G et al (1987) Molecular cloning and characterization of a cDNA encoding the cerebrovascular and the neuritic plaque amyloid peptides. Proc Natl Acad Sci U S A 84:4190–4194. doi:10.1073/pnas.84.12.4190 PubMedCrossRefGoogle Scholar
  3. 3.
    Masters CL, Multhaup G, Simms G et al (1985) Neuronal origin of a cerebral amyloid: neurofibrillary tangles of Alzheimer’s disease contain the same protein as the amyloid of plaque cores and blood vessels. EMBO J 4:2757–2763PubMedGoogle Scholar
  4. 4.
    Selkoe DJ, Abraham CR, Podlisny MB et al (1986) Isolation of low-molecular-weight proteins from amyloid plaque fibers in Alzheimer’s disease. J Neurochem 46:1820–1834PubMedGoogle Scholar
  5. 5.
    Golde TE, Estus S, Younkin LH et al (1992) Processing of the amyloid protein precursor to potentially amyloidogenic derivatives. Science 255:728–730. doi:10.1126/science.1738847 PubMedCrossRefGoogle Scholar
  6. 6.
    Murakami N, Yamaki T, Iwamoto Y et al (1998) Experimental brain injury induces expression of amyloid precursor protein, which may be related to neuronal loss in the hippocampus. J Neurotrauma 15:993–1003PubMedCrossRefGoogle Scholar
  7. 7.
    Stephenson DT, Rash K, Clemens JA (1992) Amyloid precursor protein accumulates in regions of neurodegeneration following focal cerebral ischemia in the rat. Brain Res 593:128–135. doi:10.1016/0006-8993(92)91274-I PubMedCrossRefGoogle Scholar
  8. 8.
    Otsuka N, Tomonaga M, Ikeda K (1991) Rapid appearance of beta-amyloid precursor protein immunoreactivity in damaged axons and reactive glial cells in rat brain following needle stab injury. Brain Res 568:335–338. doi:10.1016/0006-8993(91)91422-W PubMedCrossRefGoogle Scholar
  9. 9.
    Itoh T, Satou T, Nishida S et al (2009) Expression of amyloid precursor protein after rat traumatic brain injury. Neurol Res (in press)Google Scholar
  10. 10.
    Roberts GW, Allsop D, Bruton C (1990) The occult aftermath of boxing. J Neurol Neurosurg Psychiatry 53:373–378. doi:10.1136/jnnp.53.5.373 PubMedCrossRefGoogle Scholar
  11. 11.
    Schofield PW, Tang M, Marder K et al (1997) Alzheimer’s disease after remote head injury: an incidence study. J Neurol Neurosurg Psychiatry 62:119–124. doi:10.1136/jnnp.62.2.119 PubMedCrossRefGoogle Scholar
  12. 12.
    Nicoll JA, Roberts GW, Graham DI (1995) Apolipoprotein E epsilon 4 allele is associated with deposition of amyloid beta-protein following head injury. Nat Med 1:135–137. doi:10.1038/nm0295-135 PubMedCrossRefGoogle Scholar
  13. 13.
    Xiong Y, Mahmood A, Lu D et al (2008) Histological and functional outcomes after traumatic brain injury in mice null for the erythropoietin receptor in the central nervous system. Brain Res 1230:247–257. doi:10.1016/j.brainres.2008.06.127 PubMedCrossRefGoogle Scholar
  14. 14.
    Itoh T, Satou T, Hashimoto S et al (2005) Isolation of neural stem cells from damaged rat cerebral cortex after TBI. Neuroreport 16:1687–1691. doi:10.1097/01.wnr.0000183330.44112.ab PubMedCrossRefGoogle Scholar
  15. 15.
    Itoh T, Satou T, Nishida S et al (2007) Immature and mature neurons coexist among glial scars after rat traumatic brain injury. Neurol Res 29:734–742. doi:10.1179/016164107X208086 PubMedCrossRefGoogle Scholar
  16. 16.
    Green-Sadan T, Kinor N, Roth-Deri I et al (2003) Transplantation of glial cell line-derived neurotrophic factor-expressing cells into the striatum and nucleus accumbens attenuates acquisition of cocaine self-administration in rats. Eur J Neurosci 18:2093–2098. doi:10.1046/j.1460-9568.2003.02943.x PubMedCrossRefGoogle Scholar
  17. 17.
    Elvander E, Schott PA, Sandin J et al (2004) Intraseptal muscarinic ligands and galanin: influence on hippocampal acetylcholine and cognition. Neuroscience 126:541–557. doi:10.1016/j.neuroscience.2004.03.058 PubMedCrossRefGoogle Scholar
  18. 18.
    Roberts GW (1988) Immunocytochemistry of neurofibrillary tangles in dementia pugilistica and Alzheimer’s disease: evidence for common genesis. Lancet 2:1456–1458. doi:10.1016/S0140-6736(88)90934-8 PubMedCrossRefGoogle Scholar
  19. 19.
    Roberts GW, Gentleman SM, Lynch A et al (1994) Beta amyloid protein deposition in the brain after severe head injury: implications for the pathogenesis of Alzheimer’s disease. J Neurol Neurosurg Psychiatry 57:419–425. doi:10.1136/jnnp.57.4.419 PubMedCrossRefGoogle Scholar
  20. 20.
    Rumble B, Retallack R, Hilbich C et al (1989) Amyloid A4 protein and its precursor in Down’s syndrome and Alzheimer’s disease. N Engl J Med 320:1446–1452PubMedGoogle Scholar
  21. 21.
    Sun KH, Sun GH, Su Y et al (2004) Acidic-rich region of amyloid precursor protein induces glial cell apoptosis. Apoptosis 9:833–841. doi:10.1023/B:APPT.0000045793.44842.e7 PubMedCrossRefGoogle Scholar
  22. 22.
    Bouron A, Mbebi C, Loeffler JP et al (2004) The beta-amyloid precursor protein controls a store-operated Ca2+ entry in cortical neurons. Eur J Neurosci 20:2071–2078. doi:10.1111/j.1460-9568.2004.03680.x PubMedCrossRefGoogle Scholar
  23. 23.
    Feng Z, Chang Y, Cheng Y et al (2004) Melatonin alleviates behavioral deficits associated with apoptosis and cholinergic system dysfunction in the APP 695 transgenic mouse model of Alzheimer’s disease. J Pineal Res 37:129–136. doi:10.1111/j.1600-079X.2004.00144.x PubMedCrossRefGoogle Scholar
  24. 24.
    Gentleman SM, Nash MJ, Sweeting CJ et al (1993) Beta-amyloid precursor protein (beta APP) as a marker for axonal injury after head injury. Neurosci Lett 160:139–144. doi:10.1016/0304-3940(93)90398-5 PubMedCrossRefGoogle Scholar
  25. 25.
    Blumbergs PC, Scott G, Manavis J et al (1995) Topography of axonal injury as defined by amyloid precursor protein and the sector scoring method in mild and severe closed head injury. J Neurotrauma 12:565–572PubMedCrossRefGoogle Scholar
  26. 26.
    Pierce JE, Trojanowski JQ, Graham DI et al (1996) Immunohistochemical characterization of alterations in the distribution of amyloid precursor proteins and beta-amyloid peptide after experimental brain injury in the rat. J Neurosci 16:1083–1090PubMedGoogle Scholar
  27. 27.
    Van den Heuvel C, Blumbergs PC, Finnie JW et al (1999) Upregulation of amyloid precursor protein messenger RNA in response to traumatic brain injury: an ovine head impact model. Exp Neurol 159:441–450. doi:10.1006/exnr.1999.7150 PubMedCrossRefGoogle Scholar
  28. 28.
    Chen XH, Siman R, Iwata A et al (2004) Long-term accumulation of amyloid-beta, beta-secretase, presenilin-1, and caspase-3 in damaged axons following brain trauma. Am J Pathol 165:357–371PubMedGoogle Scholar
  29. 29.
    Smith DH, Uryu K, Saatman KE et al (2003) Protein accumulation in traumatic brain injury. Neuromolecular Med 4:59–72. doi:10.1385/NMM:4:1-2:59 PubMedCrossRefGoogle Scholar
  30. 30.
    Ikonomovic MD, Uryu K, Abrahamson EE et al (2004) Alzheimer’s pathology in human temporal cortex surgically excised after severe brain injury. Exp Neurol 190:192–203. doi:10.1016/j.expneurol.2004.06.011 PubMedCrossRefGoogle Scholar
  31. 31.
    Blasko I, Beer R, Bigl M et al (2004) Experimental traumatic brain injury in rats stimulates the expression, production and activity of Alzheimer’s disease beta-secretase (BACE-1). J Neural Transm 111:523–536. doi:10.1007/s00702-003-0095-6 PubMedCrossRefGoogle Scholar
  32. 32.
    Stone JR, Okonkwo DO, Singleton RH et al (2002) Caspase-3-mediated cleavage of amyloid precursor protein and formation of amyloid Beta peptide in traumatic axonal injury. J Neurotrauma 19:601–614. doi:10.1089/089771502753754073 PubMedCrossRefGoogle Scholar
  33. 33.
    Van Den Heuvel C, Donkin JJ, Finnie JW et al (2004) Downregulation of amyloid precursor protein (APP) expression following post-traumatic cyclosporin-A administration. J Neurotrauma 21:1562–1572. doi:10.1089/0897715042441783 CrossRefGoogle Scholar
  34. 34.
    Hardy J (1997) Amyloid, the presenilins and Alzheimer’s disease. Trends Neurosci 20:154–159. doi:10.1016/S0166-2236(96)01030-2 PubMedCrossRefGoogle Scholar
  35. 35.
    Mattson MP, Cheng B, Culwell AR et al (1993) Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the beta-amyloid precursor protein. Neuron 10:243–254. doi:10.1016/0896-6273(93)90315-I PubMedCrossRefGoogle Scholar
  36. 36.
    Thornton E, Vink R, Blumbergs PC et al (2006) Soluble amyloid precursor protein alpha reduces neuronal injury and improves functional outcome following diffuse traumatic brain injury in rats. Brain Res 1094:38–46. doi:10.1016/j.brainres.2006.03.107 PubMedCrossRefGoogle Scholar
  37. 37.
    Suh YH, Checler F (2002) Amyloid precursor protein, presenilins, and alpha-synuclein: molecular pathogenesis and pharmacological applications in Alzheimer’s disease. Pharmacol Rev 54:469–525. doi:10.1124/pr.54.3.469 PubMedCrossRefGoogle Scholar
  38. 38.
    Sola Vigo F, Kedikian G, Heredia L et al (2008) Amyloid-beta precursor protein mediates neuronal toxicity of amyloid beta through Go protein activation. Neurobiol Aging. doi:10.1016/j.neurobiolaging.2007.11.017
  39. 39.
    Matrone C, Di Luzio A, Meli G et al (2008) Activation of the amyloidogenic route by NGF deprivation induces apoptotic death in PC12 cells. J Alzheimers Dis 13:81–96PubMedGoogle Scholar
  40. 40.
    Mills J, Reiner PB (1999) Regulation of amyloid precursor protein cleavage. J Neurochem 72:443–460. doi:10.1046/j.1471-4159.1999.0720443.x PubMedCrossRefGoogle Scholar
  41. 41.
    Nakagawa K, Kitazume S, Oka R et al (2006) Sialylation enhances the secretion of neurotoxic amyloid-beta peptides. J Neurochem 96:924–933. doi:10.1111/j.1471-4159.2005.03595.x PubMedCrossRefGoogle Scholar
  42. 42.
    Jurynec MJ, Riley CP, Gupta DK et al (2003) TIGR is upregulated in the chronic glial scar in response to central nervous system injury and inhibits neurite outgrowth. Mol Cell Neurosci 23:69–80. doi:10.1016/S1044-7431(03)00019-8 PubMedCrossRefGoogle Scholar
  43. 43.
    Davies SJ, Goucher DR, Doller C et al (1999) Robust regeneration of adult sensory axons in degenerating white matter of the adult rat spinal cord. J Neurosci 19:5810–5822PubMedGoogle Scholar
  44. 44.
    Rudge JS, Silver J (1990) Inhibition of neurite outgrowth on astroglial scars in vitro. J Neurosci 10:3594–3603PubMedGoogle Scholar
  45. 45.
    Pekny M, Nilsson M (2005) Astrocyte activation and reactive gliosis. Glia 50:427–434. doi:10.1002/glia.20207 PubMedCrossRefGoogle Scholar
  46. 46.
    Bechmann I, Nitsch R (2000) Involvement of non-neuronal cells in entorhinal-hippocampal reorganization following lesions. Ann N Y Acad Sci 911:192–206PubMedGoogle Scholar
  47. 47.
    Deller T, Haas CA, Frotscher M (2000) Reorganization of the rat fascia dentata after a unilateral entorhinal cortex lesion. Role of the extracellular matrix. Ann N Y Acad Sci 911:207–220PubMedCrossRefGoogle Scholar
  48. 48.
    Gallo V, Chittajallu R (2001) Neuroscience. Unwrapping glial cells from the synapse: what lies inside? Science 292:872–873. doi:10.1126/science.1060854 PubMedCrossRefGoogle Scholar
  49. 49.
    Silver IA, Deas J, Erecinska M (1997) Ion homeostasis in brain cells: differences in intracellular ion responses to energy limitation between cultured neurons and glial cells. Neuroscience 78:589–601. doi:10.1016/S0306-4522(96)00600-8 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Tatsuki Itoh
    • 1
  • Takao Satou
    • 1
    • 2
    • 3
  • Shozo Nishida
    • 4
  • Masahiro Tsubaki
    • 4
  • Shigeo Hashimoto
    • 5
  • Hiroyuki Ito
    • 1
  1. 1.Department of PathologyKinki University School of MedicineOsakaJapan
  2. 2.Division of Hospital PathologyHospital of Kinki University School of MedicineOsakaJapan
  3. 3.Division of Sports Medicine, Institute of Life ScienceKinki UniversityOsakaJapan
  4. 4.Kinki University School of Pharmaceutical SciencesOsakaJapan
  5. 5.Department of PathologyPL HospitalOsakaJapan

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