Skip to main content
SpringerLink
Log in

Is There a Genetic Basis for the Deposition of β-Amyloid After Fatal Head Injury?

  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

1. Alzheimer's disease is a heterogeneous disorder that may be caused by genetic or environmental factors or by a combination of both. Abnormalities in chromosomes 1, 14, and 21 have all been implicated in the pathogenesis of the early-onset form of the disease, while the ε4 allele of the apolipoprotein E gene (on chromosome 19) is now recognized as a risk factor for early- and late-onset sporadic and familial Alzheimer's disease.

2. The best-established environmental trigger for the disease is a head injury, based on epidemiological and neuropathological evidence. Approximately 30% of patients who die after a single episode of severe head injury show intracerebral deposition of β-amyloid protein (Aβ), a protein that is thought to be central to the pathogenesis of Alzheimer's disease.

3. Recent studies have revealed an over-representation of the apoE ε4 allele in those head-injured patients displaying Aβ pathology, thus providing the first evidence for a link between a genetic susceptibility (apoE ε4) and an environmental trigger (head injury) in the development of Alzheimer-type pathology.

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

  • Abe, K., Tanzi, R. E., and Kogure, K. (1991). Selective induction of Kunitz-type protein: Inhibitor domain containing amyloid precursor protein mRNA after persistent focal ischaemia in rat cerebral cortex. Neuro. Sci. Lett. 125:172–174.

    Google Scholar 

  • Adams, J. H. (1992). Head injury. In Adams, J. H., and Duchen, L. W. (eds.), Greenfield's Neuropathology, 5th ed., Edward Arnold, London, pp. 106–152.

    Google Scholar 

  • Baggott, P. J., Sheng, J. G., Cork, L., Del Bigio, M. R., Brumback, R. A., Roberts, G. W., Mrak, R. E., and Griffin, W. S. T. (1993). Expression of Alzheimer's disease (AD)-related proteins during development in Down's syndrome (DS). Soc. Neurosci. Abstr. 19 (Part 1):182.

    Google Scholar 

  • Braak, H., and Braak, E. (1991). Neuropathological staging of Alzheimer-related changes. Acta. Neuropathol. 82:239–259.

    Google Scholar 

  • Buxbaum, J. D., Oishi, M, Chen, H. I., Pinkas-Kramarski, R., Jaffe, E. A., Gandy, S. E., and Greengard, P. (1992). Cholinergic agonists and interleukin 1 regulate processing and secretion of Alzheimer β/A4 amyloid protein precursor. Proc. Natl. Acad. Sci. USA 8:10075–10078.

    Google Scholar 

  • Cacabelos, R., Alvarez, X. A., Fernandez-Novoa, L., Franco, A., Mangues, R., Pellicer, A., and Nishimura, T. (1994). Brain interleukin-a beta in Alzheimer's disease and vascular dementia. Met. Find. Exp. Clin. Pharm. 16:141–151.

    Google Scholar 

  • Chartier-Harlin, M.-C., Parfitt, M., Legrain, S., Perez-Tur, J., Brousseau, T., Evans, A., et al. (1994). Apolipoprotein E, ε4 allele as a major risk factor for sporadic early and late onset forms of Alzheimer's disease: Analysis of the 19q13.2 chromosomal region. Hum. Mol. Genet. 3:569–574.

    Google Scholar 

  • Clinton, J., Ambler, M. W., and Roberts, G. W. (1991). Post-traumatic Alzheimer's disease: Preponderance of a single plaque type. Neuropathol. Appl. Neurobiol. 17:69–74.

    Google Scholar 

  • Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., and Pericak-Vance, M. A.(1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261:921–923.

    Google Scholar 

  • Corsellis, J. A. N., Bruton, C. J., and Freeman-Browne, D. (1973). The aftermath of boxing. Psychol. Med. 3:270–273.

    Google Scholar 

  • Das, S., and Potter, H. (1995). Expression of the Alzheimer amyloid-promoting factors a-antichymotrypsin and apolipoprotein E is induced in astrocytes by IL-1. Neuron 14:447–456.

    Google Scholar 

  • Forloni, G., Demicheli, F., Giorgi, S., Bendotti, D., and Angeretti, N. (1992). Expression of amyloid precursor protein mRNAs in endothelial, neuronal and glial cells: Modulation by interleukin-1. Brain Res. Mol. Brain Res. 16:128–134.

    Google Scholar 

  • Gentleman, S. M., Graham, D. I., and Roberts, G. W. (1993). Molecular pathology of head injury: Altered β-APP metabolism and the aetiology of Alzheimer's disease. Prog. Brain Res. 96:237–246.

    Google Scholar 

  • Giulian, D., Woodward, J., Young, D. G., Krebs, J. F., and Lachman, L. B. (1988). Interleukin-1 injected into mammalian brain stimulates astrogliosis and neovascularization. J. Neurosci. 8:2485–2490.

    Google Scholar 

  • Goate, A., Chartier-Harlin, M.-C., and Mullan, M. (1991). Segregation of a missense mutation in the amyloid precurser protein gene with familial Alzheimer's disease. Nature 349:704–706.

    Google Scholar 

  • Goldgaber, D., Lerman, M. I., McBride, O. W., Saffiotti, U., and Gajdusek, D. C. (1987). Characterization and chromosonal localization of a DNA including brain amyloid of Alzheimer's disease. Science 235:877–880.

    Google Scholar 

  • Goldgaber, D., Harris, H. W., Hla, T., Maciag, T., Donnelly, R. G., Jacobsen, J. S., Vitek, M. P., and Gajdusek, D. C. (1989a). Interleukin 1 regulates synthesis of amyloid β protein precursor mRNA in human endothelial cells. Proc. Natl. Acad. Sci. USA. 86:7606–7610.

    Google Scholar 

  • Goldgaber, D., Harris, H. W., Hla, T., Maciag, T., Donnelly, R. G., Jacobson, J. S., Vitek, M. P., and Gajdusek, D. C. (1989b). Interleukin 1 regulates synthesis of amyloid β-protein precursor mRNA in human endothelial cells. Proc. Natl. Acad. Sci. USA. 86:7611–7615.

    Google Scholar 

  • Graham, D. I., Adams, J. H., and Gennarelli, T. A. (1992). Pathology of brain damage in head injury. In Cooper, P. R. (ed.), Head Injury, Williams and Wilkins, Baltimore, pp. 91–113.

    Google Scholar 

  • Graham, D. I., Gentleman, S. M., Lynch, A., and Roberts, G. W. (1995). Distribution of β amyloid protein in the brain following severe head injury. Neuropathol. Appl. Neurobiol. 21:27–34.

    Google Scholar 

  • Griffin, W. S. T., Stanley, L. C., Ling, C., White, C. L., III, Perrot, L. J., and Aroaz, C. (1989). Brain interleukin-1 and S100 immunoreactivity elevated in Down's syndrome and Alzheimer's disease. Proc. Natl. Acad. Sci. USA 86:7611–7615.

    Google Scholar 

  • Griffin, W. S. T., Sheng, J. G., Gentleman, S. M., Graham, D. I., Mrak, R. E., and Roberts, G. W. (1994). Microglial interleukin-1a expression in human head injury: correlations with neuronal and neuritic β-amyloid precursor protein expression. Neurosci. Lett. 176:133–136.

    Google Scholar 

  • Griffin, W. S. T., Sheng, J. G., Roberts, G. W., and Mrak, R. E. (1995). Interleukin-1 expression in different plaques in Alzheimer's disease: Signficance in plaque evolution. J. Neuropathol. Exp. Neurol. 54:276–281.

    Google Scholar 

  • Horsburgh, K., and Nicoll, J. A. R. (1996). Selective cellular alterations in amyloid precursor protein and apolipoprotein E following transient cerebral ischaemia in the rat. Alzheimer's Res. 2:37–42.

    Google Scholar 

  • Huber, A., Gabbert, K., Kelemen, J., and Cervos-Navarro, J. (1993). Density of amyloid plaques in brain after head trauma. J. Neurotrauma 10(Suppl 1):S18O.

    Google Scholar 

  • Iwatsubo, T., Mann, D. M. A., Odaka, A., Suzuki, N., and Ihara, Y. (1995). Amyloid β protein (Aβ) deposition: Aβ42 (43) precedes Aβ40 in Down syndrome. Ann. Neurol. 37:294–299.

    Google Scholar 

  • Kang, J., Lemaire, H. G., Unterbeck, A., Salbaum, J. M., Masters, C. L., Grzeschik, K. H., Multhaup, G., Beyreuther, K., and Muller-Hill, B. (1987). The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 325:733–736.

    Google Scholar 

  • Kida, E., Pluta, R., Lossinsky, A. S., Golabek, A. A., Choi-Muira, N.-H., Wisniewski, H. M., and Mossakowski, M. J. (1995). Complete cerebral ischaemia with short-term survival in rat induced by cardiac arrest. II. Extracellular and intracellular accumulation of apolipoproteins E and J in the brain. Brain Res. 674:341–146.

    Google Scholar 

  • LaDu, M. J., Falduto, M. T., Manelli, A. M., Reardon, C. A., Getz, G. S., and Frail, D. E. (1994). Isoform-specific binding of apolipoprotein E to β-amyloid. J. Biol. Chem. 269:23403–23406.

    Google Scholar 

  • Ladu, M. J., Pederson, T. M., Frail, D. E., Reardon, C. A., Getz, G. S., and Falduto, M. T. (1995). Purification of apolipoprotein E attenuates isoform-specific binding to β-amyloid. J. Biol. Chem. 270:9039–9042.

    Google Scholar 

  • Levy-Lahad, E., Wasco, W., Poorkaj, P., Romano, D. M., Oshima, J., Pettingell, W. H., Yu, C. E., Jondro, P. D., Schmidt, S. D., Wane, K., et al. (1995). Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269:973–977.

    Google Scholar 

  • Ma, J., Yee, A., Brewer, H. B., Jr., Das, S., and Potter, H. (1994). Amyloid-associated proteins Alpha 1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer beta-protein into filaments. Nature 372:45–46.

    Google Scholar 

  • Marshak, D. R., Pesce, S. A., Stanley, L. C., and Griffin, W. S. T. (1991). Increased S100β-Neurotrophic activity in Alzheimer's disease temporal lobe. Neurobiol. Aging 13:1–7.

    Google Scholar 

  • Mayeux, R., Ottman, R., Tang, M.-X., Noboabauza, L., Marder, K., Gurland, B., and Stern, Y. (1993). Genetic susceptibility and head injury as risk factors for Alzheimer's disease amongst community-dwelling elderly persons and their first-degree relatives. Ann. Neurol. 33:494–501.

    Google Scholar 

  • Mayeux, R., Ottman, R., Maestre, G., Ngae, B. S., Tang, M.-X., Ginsburg, H., Chun, M., Tycko, B., and Shelanski, M. (1995). Synergistic effects of traumatic head injury and apolipoprotein-E in patients with Alzheimer's disease. Neurology 45:555–557.

    Google Scholar 

  • McGeer, P. L., and Rogers, J. (1992). Anti-inflammatory agents as a therapeutic approach to Alzheimer's disease. Neurology. 42:447–448.

    Google Scholar 

  • McKenzie, J. E., Gentleman, S. M., Roberts, G. W., Graham, D. I., and Royston, M. C. (1994). Increased numbers of β-APP-immunoactive neurons in the entorhinal cortex after head injury. Neuroreport 6:161–164.

    Google Scholar 

  • McKenzie, J. E., Gentleman, S. M., Roberts, G. W., Graham, D. I., and Royston, M. C. (1995). Quantification of β-APP immunoreactive pre-a cells in the entorhinal cortex using image analysis. Neurodegeneration 4:299–306.

    Google Scholar 

  • Mortimer, J. A., Van Duijn, C. M., and Chandra, V. (1991). Head trauma as a risk factor for Alzheimer's disease: A collaborative re-analysis of case-control studies. Int. J. Epidemiol. 20(Suppl 2):S28-S35.

    Google Scholar 

  • Mrak, R. E., Sheng, J. G., and Griffin, W. S. T. (1996). Corelation of astrocytic S100 expression with dystrophic neurites in amyloid plaques of Alzheimer's disease. J. Neuropathol. Exp. Neurol. 55:273–79.

    Google Scholar 

  • Nicoll, J. A. R. (1995). Apolipoprotein E and head injury. Neuropathol. Appl. Neurobiol. 21(Suppl. 1):10.

    Google Scholar 

  • Nicoll, J. A. R., and Graham, D. I. (1995). The load of Aβ protein deposition in fatal head injury is related to the apolipoprotein E gene dose. J. Neurotrauma 12:434.

    Google Scholar 

  • Nicoll, J. A. R., Roberts, G. W., and Graham, D. I. (1995). Apolipoprotein E ε4 allele is associated with deposition of amyloid β-protein following head injury. Nature Med. 1:135–137.

    Google Scholar 

  • Peacock, M. L., and Fink, J. K. (1994). ApoE apolipoprotein ε4 allelic association with Alzheimer's disease: Independent confirmation using denaturing gradient gel electrophoresis. Neurology 44:339–341.

    Google Scholar 

  • Pluta, R., Kida, E., Lossinsky, A. S., Golabak, A. A., Mossakowski, M. J., and Wisniewski, H. M. (1994). Complete cerebral ischaemia with short-term survival in rats induced by cardiac arrest. Extracellular accumulation of Alzheimer's β-amyloid protein prescursor in the brain. Brain Res. 649:323–328.

    Google Scholar 

  • Poirier, J. (1994). Apolipoprotein E in animal models of CNS injury and in Alzheimer's disease. TINS 17:525–530.

    Google Scholar 

  • Poirier, J., Davignon, J., Bouthillier, D., Kogan, S., Bertrand, P., and Gauthier, S. (1993). Apolipoprotein E polymorphism and Alzheimer's disease. Lancet 342:697–699.

    Google Scholar 

  • Roberts, G. W., Allsop, D., and Bruton, C. J. (1990a). The occult aftermath of boxing. J. Neurol. Neurosurg. Psychiat. 53:373–378.

    Google Scholar 

  • Roberts, G. W., Whitwell, H. L., Acland, P. R., and Bruton, C. J. (1990b). Dementia in a punch-drunk wife. Lancet 335:918–919.

    Google Scholar 

  • Roberts, G. W., Gentleman, S. M., Lynch, A., and Graham, D. I. (1991). β A4 amyloid protein deposition in brain after head trauma. Lancet 338:1422–1423.

    Google Scholar 

  • Roberts, G. W., Gentleman, S. M., Lynch, A., Murray, L., Landon, M., and Graham, D. I. (1994). βA4 amyloid protein deposition in brain after severe head injury: Implications for the pathogenesis of Alzheimer's disease. J. Neurol. Neurosurg. Psychiat. 57:419–425.

    Google Scholar 

  • Rogers, J., Cooper, N. R., Webster, S., Schultz, J., McGeer, P. L., Styren, S. D., Civin, W. H., Brachova, L., Bradt, B., and Ward, P. (1992). Complement activation by β-amyloid in Alzheimer's disease. Proc. Natl. Acad. Sci. USA 89:10016–10020.

    Google Scholar 

  • Royston, M. C., Rothwell, N. J., and Roberts, G. W. (1992). Alzheimer's disease: Aetiology: Pathology to potential treatments. Trends Pharmacol. Sci. 13:131–133.

    Google Scholar 

  • Saunders, A. M., Strittmatter, W. J., Schmechel, D., St. George-Hyslop, P. H., Pericak-Vance, M. A., Joo, S. H., Rosi, B. A., Gusclla, J. F., Crapper-MacLachlan, D. R., Alberts, M. J., Hulette, C., Crain, B., Goldgaber, D., and Roses, A. D. (1993a). Association of apolipoprotein E allele ε4 with late-onset familial and sporadic Alzheimer's disease. Neurology 43:1467–1472.

    Google Scholar 

  • Saunders, A. M., Schmader, K., Breitner, J. C. S., Benson, M. D., Brown, W. T., Godfarb, L., Goldgaber, D., Manwaring, M. G., Szymarkski, M. H., McCown, N., Dole, D. C., Schmechel, D. E., Strittmatter, W. J., Pericak-Vance, M. A., and Roses, A. D. (1993b) Apolipoprotein E ε4 allele distributions in late-onset Alzheimer's disease and in other amyloid-forming diseases. Lancet 342:710–711.

    Google Scholar 

  • Schellenberg, G. D., Bird, T. D., Wijsman, E. M., Orr, H. T., Anderson, L., Nemens, E., White, J. A., Bonny-Castle, L., Weber, J. L., Alonso, M. E., Potter, H., Heston, L. L., and Martin, G. M. (1992). Genetic linkage evidence for a familial Alzheimer's disease/locus on chromosome 14. Science 258:668–671.

    Google Scholar 

  • Sheng, J. E., Boup, F. A., Mrak, R. E., and Griffin, W. S. T. (1994a). Increased neuronal beta-amyloid amyloid precursor protein expression in human temporal lobe epilepsy: Association with interleukin-1 alpha immunoreactivity. J. Neurochem. 63:1872–1879.

    Google Scholar 

  • Sheng, J. G., Mrak, R. E., and Griffin, W. S. T. (1994b). S100 protein expression in Alzheimer's disease: Potential role in the pathogenesis of neuritic plaques. J. Neurosci. Res. 39:398–404.

    Google Scholar 

  • Sherrington, R., Rogaev, E. I., Liang, Y., Rogaeva, E. A., Levesque, G., Ikeda, M., Chi, H., Lin, C., Li, G., Holman, K., et al. (1995). Cloning of a gene bearing a missense mutations in early-onset familial Alzheimer's disease. Nature 375:754–760.

    Google Scholar 

  • Scott, J. N., Parhad, I. M., and Clark, A. W. (1991). β-amyloid precursor protein gene is differentially expressed in axonotomized sensory and motor systems. Mol. Brain Res. 10:315–325.

    Google Scholar 

  • Stanley, L. C., Mrak, R. E., Woody, R. C., Perrot, L. J., Zhang, S. X., Marshak, D. R., Nelson, S. J., and Griffin, W. S. T. (1993). Glial cytokines as neuropathogenic factors in HIV infection: Pathogenic similarities to Alzheimer's disease. J. Neuropathol. Exp. Neurol. 53:231–238.

    Google Scholar 

  • Strittmatter, W. J., Weisgraber, K. H., Huang, D. Y., Dong, L. M., Salvesen, G. S., PericakVance, M., Schmechel, D., Saunders, A. M., Goldgaber, D., and Roses, A. D. (1993a). Binding of human apolipoprotein E to synthetic amyloid beta peptide: Isoform-specific effects and implications for late-onset Alzheimer disease. Proc. Natl. Acad. Sci. USA. 90:8098–8102.

    Google Scholar 

  • Strittmatter, W. J., Saunders, A. M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G. S., and Roses, A. D. (1993b). Apolipoprotein E: High-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer's disease. Proc. Natl. Acad. Sci. USA. 90:1977–1981.

    Google Scholar 

  • Tomlinson, B. E. (1992). Aging and the dementias. In Adams, J. H., Duncan, L. W. (eds.), Greenfields Neuropathology, 5th ed., Edward Arnold, London, pp. 1284–1410.

    Google Scholar 

  • Tsai, M.-S., Tangalos, E. G., Peterson, R. C., Smith, G. E., Schaid, D. J., Kokmen, E., Ivnik, R. J., and Thibodeau, S. N. (1994). Apolipoprotein E: Risk factor for Alzheimer's disease. Am. J. Hum. Genet. 6:643–649.

    Google Scholar 

  • Van Broeckhoven, C. L. (1995). Molecular genetics of Alzheimer disease: Identification of genes and gene mutations. Eur. Neurol. 35:8–19.

    Google Scholar 

  • Van Denabelle, P., and Fiers, W. (1991). Is amyloidogenesis during Alzheimer's disease due to an 1L-1/1L-6-mediated “acute phase response” in the brain? Immunol. Today 12:217–219.

    Google Scholar 

  • Van Duijn, C. M., de Kinijff, P., Cruts, M., Wehnert, A., Havekes, L. M., Hofman, A., and Van Broeckhoven, C. (1994). Apolipoprotein ε4 allele in a population-based study of early-onset Alzheimer's disease. Nature Genet 7:74–78.

    Google Scholar 

  • Wisniewski, T., and Frangione, B. (1992). Apolipoprotein E: A pathological chaperone protein in patients with cerebral and systemic amyloid. Neurosci. Lett. 135:235–238.

    Google Scholar 

  • Wisniewski, K. E., Wisniewski, H. M., and Wen, G. Y. (1985). Occurrence of neuropathological changes and dementia of Alzheimer's disease in Down's syndrome. Ann. Neurol. 17:278–282.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neuropathology, University of Glasgow, Glasgow, Scotland, U.K.

    D. I. Graham & J. A. R. Nicoll

  2. Department of Anatomy, Charing Cross and Westminster Medical School, London, U.K.

    S. M. Gentleman

  3. Department of Psychiatry, Charing Cross and Westminster Medical School, London, U.K.

    M. C. Royston & J. E. McKenzie

  4. Department of Molecular Neuropathology, SmithKline Beecham, Harlow, U.K.

    G. W. Roberts

  5. Department of Neuropathology, and Paediatrics and Anatomy, Arkansas Children's Hospital Research Institute, Little Rock, Arkansas, USA

    R. E. Mrak & W. S. T. Griffin

Authors
  1. D. I. Graham
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. M. Gentleman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. A. R. Nicoll
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. C. Royston
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. E. McKenzie
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G. W. Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R. E. Mrak
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. W. S. T. Griffin
    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

Graham, D.I., Gentleman, S.M., Nicoll, J.A.R. et al. Is There a Genetic Basis for the Deposition of β-Amyloid After Fatal Head Injury?. Cell Mol Neurobiol 19, 19–30 (1999). https://doi.org/10.1023/A:1006956306099

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1006956306099

Search

Navigation