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Marked increase of β-amyloid(1–42) and amyloid precursor protein in ventricular cerebrospinal fluid after severe traumatic brain injury

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Abstract.

Severe traumatic brain injury (TBI) may result in widespread damage to axons, termed diffuse axonal injury. Alzheimer’s disease (AD) is characterised by synaptic and axonal degeneration together with senile plaques (SP). SP are mainly composed of aggregated β-amyloid (Aβ), which are peptides derived from the amyloid precursor protein (APP). Apart from TBI in itself being considered a risk factor for AD, severe head injury seems to initiate a cascade of molecular events that are also associated with AD. We have therefore analysed the 42 amino acid forms of Aβ (Aβ(1–42)) and two soluble forms of APP (α-sAPP and ßsAPP) in ventricular cerebrospinal fluid (VCSF) and Aβ(1–42) in plasma from 28 patients in a serial samples 0–11 days after TBI. The levels of α-sAPP, ß-sAPP and Aβ(1–42) were determined using ELISA assays. After TBI, there was a significant stepwise increase in VCSF-Aβ(1–42) up to 1173 % from day 0–1 to day 5–6 and in VCSF-β-sAPP up to 2033 % increase from day 0–1 to day 7–11. There was also a slight but significant increase of VCSF-β-sAPP from day 0–1 to day 5–6 and day 7–11. By contrast, the plasma- Aβ(1–42) level is unchanged after injury. The marked increase in VCSFAβ( 1–42) implies that increased Aβ expression may occur as a secondary phenomenon after TBI with axonal damage. The unchanged level of plasma-Aβ(1–42) in contrast to the marked increase in VCSF-Aβ(1–42) after severe TBI, supports the suggestion that plasma Aβ(1–42) does not reflect Aβ metabolism in the central nervous system (CNS).

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Abbreviations

Aβ:

β-amyloid

AD:

Alzheimer’s disease

APLP:

amyloid precursor-like proteins

APP:

amyloid precursor protein

BBB:

blood brain barrier

CT:

computed tomography

CNS:

central nervous system

GAD:

gracile axonal dystrophy

GCS:

Glasgow Coma Scale

ICP:

intracranial pressure

MRI:

magnetic resonance imaging

VCSF:

ventricular cerebrospinal fluid

sAPP:

soluble amyloid precursor protein

TBI:

traumatic brain injury

References

  1. Blennow K, Ricksten A, Prince JA, Brookes AJ, Emahazion T, Wasslavik C, Bogdanovic N, Andreasen N, Båtsman S, Marcusson J, Nägga K, Wallin A, Regland B, Olofsson H, Hesse C, Davidsson P, Minthon L, Jansson A, Palmqvist L, Rymo L (2000) No association between the alpha2-macroglobulin (A2M) deletion and Alzheimer’s disease, and no change in A2M mRNA, protein, or protein expression. J Neural Transm 107:1065–1079

    Article  CAS  PubMed  Google Scholar 

  2. De Strooper B, Annaert W (2000) Proteolytic processing and cell biological functions of the amyloid precursor protein. J Cell Sci 113:1857–1870

    CAS  PubMed  Google Scholar 

  3. Emmerling MR, Morganti-Kossmann MC, Kossmann T, Stahel PF, Watson MD, Evans LM, Mehta PD, Spiegel K, Kuo YM, Roher AE, Raby CA (2000) Traumatic brain injury elevates the Alzheimer’s amyloid peptide A beta 42 in human CSF. A possible role for nerve cell injury. Ann N Y Acad Sci 903:118–122

    CAS  PubMed  Google Scholar 

  4. Furukawa K, Sopher BL, Rydel RE, Begley JG, Pham DG, Martin GM, Fox M,Mattson MP (1996) Increased activity-regulating and neuroprotective efficacy of alpha-secretase-derived secreted amyloid precursor protein conferred by a C-terminal heparinbinding domain. J Neurochem 67:1882–1896

    CAS  PubMed  Google Scholar 

  5. Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F, Guido T, Hagopian S, Johnson-Wood K, Khan K, Lee M, Leibowitz P, Lieberburg I, Little S, Masliah E, Mc-Conlogue L, Montoya-Zavala M, Mucke L, Paganini L, Penniman E, Power M, Schenk D, Seubert P, Snyder B, Soriano F, Tan H, Vitale J, Wadsworth S, Wolozin B, Zhao J (1995) Alzheimertype neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373:523–527

    Article  CAS  PubMed  Google Scholar 

  6. Gentleman SM, Nash MJ, Sweeting CJ, Graham DI, Roberts GW (1993) Betaamyloid precursor protein (beta APP) as a marker for axonal injury after head injury. Neurosci Lett 160:139–144

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  8. Graham DI, Gentleman SM, Nicoll JA, Royston MC, McKenzie JE, Roberts GW, Griffin WS (1996) Altered beta-APP metabolism after head injury and its relationship to the aetiology of Alzheimer’s disease. Acta Neurochir Suppl (Wien) 66:96–102

    CAS  Google Scholar 

  9. Grande PO, Asgeirsson B, Nordstrom CH (2002) Volume-targeted therapy of increased intracranial pressure: the Lund concept unifies surgical and non-surgical treatments. Acta Anaesthesiol Scand 46:929–941

    Article  PubMed  Google Scholar 

  10. Hamberger A, Huang YL, Zhu H, Bao F, Ding M, Blennow K, Olsson A, Hansson HA, Viano D, Haglid KG (2003) Redistribution of neurofilaments and accumulation of beta-amyloid protein after brain injury by rotational acceleration of the head. J Neurotrauma 20:169–178

    Article  PubMed  Google Scholar 

  11. Hesse C, Rosengren L,Vanmechelen E, Vanderstichele H, Jensen C, Davidsson P, Blennow K (2000) Cerebrospinal Fluid Markers for Alzheimer’s Disease Evaluated after Acute Ischemic Stroke. J Alzheimers Dis 2:199–206

    CAS  PubMed  Google Scholar 

  12. Horsburgh K, Cole GM, Yang F, Savage MJ, Greenberg BD, Gentleman SM, Graham DI,Nicoll JA (2000) Beta-amyloid (Abeta)42(43), abeta42, abeta40 and apoE immunostaining of plaques in fatal head injury. Neuropathol Appl Neurobiol 26:124–132

    Article  CAS  PubMed  Google Scholar 

  13. Ichihara N, Wu J, Chui DH, Yamazaki K, Wakabayashi T, Kikuchi T (1995) Axonal degeneration promotes abnormal accumulation of amyloid betaprotein in ascending gracile tract of gracile axonal dystrophy (GAD) mouse. Brain Res 695:173–178

    Article  CAS  PubMed  Google Scholar 

  14. Iwatsubo T,Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y (1994) Visualization of A beta 42(43) and Abeta40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is Abeta 42(43). Neuron 13:45–53

    Article  CAS  PubMed  Google Scholar 

  15. Kawarabayashi T, Shoji M, Harigaya Y, Yamaguchi H, Hirai S (1991) Expression of APP in the early stage of brain damage. Brain Res 563:334–338

    Article  CAS  PubMed  Google Scholar 

  16. Koo EH, Sisodia SS, Archer DR, Martin LJ, Weidemann A, Beyreuther K, Fischer P,Masters CL, Price DL (1990) Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport. Proc Natl Acad Sci U S A 87:1561–1565

    CAS  PubMed  Google Scholar 

  17. LeBlanc AC, Xue R, Gambetti P (1996) Amyloid precursor protein metabolism in primary cell cultures of neurons, astrocytes, and microglia. J Neurochem 66:2300–2310

    CAS  PubMed  Google Scholar 

  18. Marshall LF, Marshall SB, Klauber MR, Van Berkum Clark M, Eisenberg HM, Jane JA, Luerssen TG, Marmarou A, Foulkes MA (1991) A new classification of head injury based on computerized tomography. J Neurosurg 75:S14–S20

    Google Scholar 

  19. Matsubara E, Ghiso J, Frangione B, Amari M, Tomidokoro Y, Ikeda Y, Harigaya Y, Okamoto K, Shoji M (1999) Lipoprotein-free amyloidogenic peptides in plasma are elevated in patients with sporadic Alzheimer’s disease and Down’s syndrome. Ann Neurol 45 537–541

    Article  CAS  PubMed  Google Scholar 

  20. Maxwell WL, Povlishock JT, Graham DL (1997) A mechanistic analysis of nondisruptive axonal injury: a review. J Neurotrauma 14:419–440

    CAS  PubMed  Google Scholar 

  21. Mayeux R, Tang MX, Jacobs DM, Manly J, Bell K, Merchant C, Small SA, Stern Y, Wisniewski HM, Mehta PD (1999) Plasma amyloid beta-peptide 1–42 and incipient Alzheimer’s disease. Ann Neurol 46:412–416

    Article  CAS  PubMed  Google Scholar 

  22. McKenzie JE, Gentleman SM, Roberts GW, Graham DI, Royston MC (1994) Increased numbers of beta APP-immunoreactive neurones in the entorhinal cortex after head injury. Neuroreport 6:161–164

    CAS  PubMed  Google Scholar 

  23. Mehta PD, Pirttila T, Mehta SP, Sersen EA, Aisen PS,W isniewski HM (2000) Plasma and cerebrospinal fluid levels of amyloid beta proteins 1–40 and 1–42 in Alzheimer disease. Arch Neurol 57:100–105

    Article  CAS  PubMed  Google Scholar 

  24. Ohgami T, Kitamoto T, Tateishi J (1992) Alzheimer’s amyloid precursor protein accumulates within axonal swellings in human brain lesions. Neurosci Lett 136:75–78

    Article  CAS  PubMed  Google Scholar 

  25. Olsson A, Hoglund K, Sjogren M, Andreasen N, Minthon L, Lannfelt L, Buerger K, Moller HJ, Hampel H, Davidsson P, Blennow K (2003) Measurement of alpha- and beta-secretase cleaved amyloid precursor protein in cerebrospinal fluid from Alzheimer patients. Exp Neurol 183:74–80

    Article  CAS  PubMed  Google Scholar 

  26. Oltersdorf T, Ward PJ, Henriksson T, Beattie EC, Neve R, Lieberburg I, Fritz LC (1990) The Alzheimer amyloid precursor protein. Identification of a stable intermediate in the biosynthetic/degradative pathway. J Biol Chem 265:4492–4497

    CAS  PubMed  Google Scholar 

  27. 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

    Article  CAS  PubMed  Google Scholar 

  28. Povlishock JT (1992) Traumatically induced axonal injury: pathogenesis and pathobiological implications. Brain Pathol 2:1–12

    CAS  PubMed  Google Scholar 

  29. Raby CA, Morganti-Kossmann MC, Kossmann T, Stahel PF, Watson MD, Evans LM, Mehta PD, Spiegel K, Kuo YM, Roher AE, Emmerling MR (1998) Traumatic brain injury increases betaamyloid peptide 1–42 in cerebrospinal fluid. J Neurochem 71:2505–2509

    CAS  PubMed  Google Scholar 

  30. Roberts GW, Allsop D, Bruton C (1990) The occult aftermath of boxing. J Neurol Neurosurg Psychiatry 53:373–378

    CAS  PubMed  Google Scholar 

  31. Roberts GW, Gentleman SM, Lynch A, Murray L, Landon M, Graham DI (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

    CAS  PubMed  Google Scholar 

  32. Seubert P, Oltersdorf T, Lee MG, Barbour R, Blomquist C, Davis DL, Bryant K, Fritz LC, Galasko D, Thal LJ, Lieberburg I, Schenk D (1993) Secretion of beta-amyloid precursor protein cleaved at the amino terminus of the beta-amyloid peptide. Nature 361:260–263

    Article  CAS  PubMed  Google Scholar 

  33. Seubert P, Vigo-Pelfrey C, Esch F, Lee M, Dovey H, Davis D, Sinha S, Schlossmacher M, Whaley J, Swindlehurst C, McCormack R,Wolfert R, Selkoe D, Lieberburg I, Schenk D (1992) Isolation and quantification of soluble Alzheimer’s beta-peptide from biological fluids. Nature 359:325–327

    Article  CAS  PubMed  Google Scholar 

  34. Siman R, Card JP, Nelson RB, Davis LG (1989) Expression of beta-amyloid precursor protein in reactive astrocytes following neuronal damage. Neuron 3:275–285

    Article  CAS  PubMed  Google Scholar 

  35. Smith DH, Chen XH, Iwata A, Graham DI (2003) Amyloid beta accumulation in axons after traumatic brain injury in humans. J Neurosurg 98:1072–1077

    CAS  PubMed  Google Scholar 

  36. Smith DH, Nakamura M, McIntosh TK, Wang J, Rodriguez A, Chen XH, Raghupathi R, Saatman KE, Clemens J, Schmidt ML, Lee VM, Trojanowski JQ (1998) Brain trauma induces massive hippocampal neuron death linked to a surge in beta-amyloid levels in mice overexpressing mutant amyloid precursor protein. Am J Pathol 153:1005–1010

    CAS  PubMed  Google Scholar 

  37. Tamaoka A, Fukushima T, Sawamura N, Ishikawa K, Oguni E, Komatsuzaki Y, Shoji S (1996) Amyloid beta protein in plasma from patients with sporadic Alzheimer’s disease. J Neurol Sci 151:65–68

    Article  Google Scholar 

  38. Tamaoka A, Kondo T, Odaka A, Sahara N, Sawamura N, Ozawa K, Suzuki N, Shoji S,Mori H (1994) Biochemical evidence for the long-tail form (A beta 1-42/43) of amyloid beta protein as a seed molecule in cerebral deposits of Alzheimer’s disease. Biochem Biophys Res Commun 205:834–842

    Article  CAS  PubMed  Google Scholar 

  39. Teller JK, Russo C, DeBusk LM, Angelini G, Zaccheo D, Dagna-Bricarelli F, Scartezzini P, Bertolini S, Mann DM, Tabaton M, Gambetti P (1996) Presence of soluble amyloid beta-peptide precedes amyloid plaque formation in Down’s syndrome. Nat Med 2:93–95

    CAS  PubMed  Google Scholar 

  40. Tokuda T, Ikeda S, Yanagisawa N, Ihara Y, Glenner GG (1991) Re-examination of ex-boxers’ brains using immunohistochemistry with antibodies to amyloid beta-protein and tau protein. Acta Neuropathol (Berl) 82:280–285

    CAS  Google Scholar 

  41. Uryu K, Laurer H, McIntosh T, Pratico D, Martinez D, Leight S, Lee VM, Trojanowski JQ (2002) Repetitive mild brain trauma accelerates Abeta deposition, lipid peroxidation, and cognitive impairment in a transgenic mouse model of Alzheimer amyloidosis. J Neurosci 22:446–454

    CAS  PubMed  Google Scholar 

  42. van Duijn CM, Tanja TA, Haaxma R, Schulte W, Saan RJ, Lameris AJ, Antonides-Hendriks G, Hofman A (1992) Head trauma and the risk of Alzheimer’s disease. Am J Epidemiol 135:775–782

    CAS  PubMed  Google Scholar 

  43. Vanderstichele H, Van Kerschaver E, Hesse C, Davidsson P, Buyse MA, Andreasen N, Minthon L, Wallin A, Blennow K,Vanmechelen E (2000) Standardization of measurement of beta-amyloid(1–42) in cerebrospinal fluid and plasma. Amyloid 7:245–258

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Institute of Clinical Neuroscience Section, Sahlgrenska University Hospital/Mölndal, SE-43180, Mölndal, Sweden

    Annika Olsson, Kina Höglund & Kaj Blennow

  2. Department of Anaesthesia and Intensive Care Medicine, Sahlgrenska University Hospital, SE-41345, Göteborg, Sweden

    Ludvig Csajbok, Martin Öst & Bengt Nellgård

  3. Institute of Clinical Neuroscience, Sahlgrenska University Hospital, SE-41345, Göteborg, Sweden

    Karin Nylén & Lars Rosengren

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  1. Annika Olsson
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Correspondence to Annika Olsson.

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Olsson, A., Csajbok, L., Öst, M. et al. Marked increase of β-amyloid(1–42) and amyloid precursor protein in ventricular cerebrospinal fluid after severe traumatic brain injury. J Neurol 251, 870–876 (2004). https://doi.org/10.1007/s00415-004-0451-y

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  • DOI: https://doi.org/10.1007/s00415-004-0451-y

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