Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E

Abstract

A role for β-amyloid precursor protein (β-APP) in the development of Alzheimer's disease has been indicated by genetics1, and many conditions in which β-APP is raised have been associated with an increased risk of Alzheimer's disease or an Alzheimer's-like pathology2,3,4. Inflammatory events may also contribute to Alzheimer's disease5. Here we investigate whether a secreted derivative of β-APP (sAPP-α) can induce inflammatory reactions in microglia, which are brain cells of monocytic lineage. We found that treatment with sAPP-α increased markers of activation in microglia and enhanced their production of neurotoxins. The ability of sAPP-α to activate microglia was blocked by prior incubation of the protein with apolipoprotein E3 but not apolipoprotein E4, a variant associated with an increased risk for Alzheimer's6. A product of amyloidogenic β-APP processing (sAPP-β) also activated microglia. Because sAPP-β is deficient in the neuroprotective activity shown by sAPP-α, our results indicate that increased amyloidogenic processing could adversely affect the balance of sAPP activities that determine neuronal viability.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Activation of NF-κB in N9 microglial cells by sAPPN9 cultures were treated for 90 min with control buffer or 5 nM sAPP (sAPP), and nuclear extracts were assayed by EMSA with a κB DNA probe.
Figure 2: Increase in IL-1β and iNOS in microglial cells by sAPP.
Figure 3: Structural requirements for sAPP stimulation of microglia.
Figure 4: Interaction between ApoE and sAPP.

Similar content being viewed by others

References

  1. Hardy, J. New insights into the genetics of Alzheimer's disease. Ann. Med. 28, 255–258 (1996).

    Google Scholar 

  2. Rumble, B.et al. N. Engl. J. Med. 320, 1446–1452 (1989).

    Google Scholar 

  3. Griffin, W. S.et al. Microglial interleukin-1α expression in human head injury: correlations with neuronal and neuritic β-amyloid precursor protein expression. Neurosci. Lett. 176, 133–136 (1994).

    Google Scholar 

  4. Moran, P. M., Higgins, L. S., Cordell, B. & Moser, P. C. Age-related learning deficits in transgenic mice expressing the 751-amino acid isoform of human β-amyloid precursor protein. Proc. Natl Acad. Sci. USA 92, 5341–5345 (1995).

    Google Scholar 

  5. Mrak, R. E., Sheng, J. G. & Griffin, W. S. Glial cytokines in Alzheimer's disease: review and pathogenic implications. Hum. Pathol. 26, 816–823 (1995).

    Google Scholar 

  6. Roses, A. D. Apolipoprotein E alleles as risk factors in Alzheimer's disease. Annu. Rev. Med. 47, 387–400 (1996).

    Google Scholar 

  7. . Corradin, S. B., Mauel, J., Donini, S. D., Quattrocchi, E. & Ricciardi-Caastagnoli, P. Inducible nitric oxide synthase activity of cloned murine microglial cells. Glia 7, 255–262 (1993).

    Google Scholar 

  8. . Barger, S. W. & Mattson, M. P. Induction of neuroprotective κB-dependent transcription by secreted form of the Alzheimer's β-amyloid precursor. Mol. Brain Res. 40, 116–126 (1996).

    Google Scholar 

  9. Furukawa, K.et al. Increased activity-regulating and neuroprotective efficacy of α-secretase-derived secreted amyloid precursor protein conferred by a c-terminal heparin-binding domain. J. Neurochem. 67, 1882–1896 (1996).

    Google Scholar 

  10. Barger, S. W. & Mattson, M. P. Isoform-specific modulation by apolipoprotein E of the activities of secreted β-amyloid precursor protein. J. Neurochem. 69, 60–67 (1997).

    Google Scholar 

  11. Breitner, J. C.et al. Delayed onset of Alzheimer's disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs. Neurobiol. Aging 16, 523–530 (1995).

    Google Scholar 

  12. Rogers, J.et al. Clinical trial of indomethacin in Alzheimer's disease. Neurology 43, 1609–1611 (1993).

    Google Scholar 

  13. Griffin, W. S., Sheng, J. G., Roberts, G. W. & Mrak, R. E. Interleukin-1 expression in different plaque types in Alzheimer's disease: significance in plaque evolution. J. Neuropathol. Exp. Neurol. 54, 276–281 (1995).

    Google Scholar 

  14. Mayeux, R.et al. Synergistic effects of traumatic head injury and apolipoprotein-ε4 in patients with Alzheimer's disease. Neurology 45, 555–557 (1995).

    Google Scholar 

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

    Google Scholar 

  16. Sheng, J. G., Boop, F. A., Mrak, R. E. & Griffin, W. S. Increased neuronal β-amyloid precursor protein expression in human temporal lobe epilepsy: association with interleukin-1α immunoreactivity. J. Neurochem. 63, 1872–1879 (1994).

    Google Scholar 

  17. Nordstedt, C.et al. Alzheimer β/A4 amyloid precursor protein in human brain: aging-associated increases in holoprotein and in a proteolytic fragment. Proc. Natl Acad. Sci. USA 88, 8910–8914 (1991).

    Google Scholar 

  18. Martin, L. J., Pardo, C. A., Cork, L. C. & Price, D. L. Synaptic pathology and glial responses to neuronal injury precede the formation of senile plaques and amyloid deposits in the aging cerebral cortex. Am. J. Pathol. 145, 1358–1381 (1994).

    Google Scholar 

  19. Loffler, K. U., Edward, D. P. & Tso, M. O. Immunoreactivity against tau, amyloid precursor protein, and β-amyloid in the human retina. Invest. Aphthal. Vis. Sci. 36, 24–31 (1995).

    Google Scholar 

  20. Corder, E. H.et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921–923 (1993).

    Google Scholar 

  21. Clay, M. A. Anantharamaiah, G. M., Mistry, M. J., Balasubramaniam, A. & Harmony, J. A. Localization of a domain in apolipoprotein E with both cytostatic and cytotoxic activity. Biochemistry 34, 11142–11151 (1995).

    Google Scholar 

  22. Meda, L.et al. Activation of microglial cells by β-amyloid protein and interferon-γ. Nature 374, 647–650 (1995).

    Article  ADS  CAS  Google Scholar 

  23. Yan, S. D.et al. RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease. Nature 382, 685–691 (1996).

    Article  ADS  CAS  Google Scholar 

  24. Rossi, F. & Bianchini, E. Synergistic induction of nitric oxide by β-amyloid and cytokines in astrocytes. Biochem. Biophys. Res. Commun. 225, 474–478 (1996).

    Google Scholar 

  25. Palmert, M. R.et al. Soluble derivatives of the β amyloid protein precursor in cerebrospinal fluid: alterations in normal aging and in Alzheimer's disease. Neurology 40, 1028–1034 (1990).

    Google Scholar 

  26. Van Nostrand, W. E.et al. Decreased levels of soluble amyloid β-protein precursor in cerebrospinal fluid of live Alzheimer disease patients. Proc. Natl Acad. Sci. USA 89, 2551–2555 (1992).

    Google Scholar 

  27. Giulian, D.et al. Senile plaques stimulate microglia to release a neurotoxin found in Alzheimer brain. Neurochem. Int. 27, 119–137 (1995).

    Google Scholar 

  28. Oltersdorf, T.et al. The secreted form of the Alzheimer's amyloid precursor protein with the Kunitz domain is protease nexin-II. Nature 341, 144–147 (1989).

    Article  ADS  CAS  Google Scholar 

  29. Ostrowski, J.et al. Aserine/threonine kinase activity is closely associated with a 65-kDa phosphoprotein specifically recognized by the κB enhancer element. J. Biol. Chem. 266, 12722–12733 (1991).

    Google Scholar 

Download references

Acknowledgements

We are indebted to Paola Ricciardi-Castagnoli for the N9 cell line, to D. Davies for advice on microglial culture techniques, to M. Lucas for technical assistance, and to S. Griffin and M. J. LaDu for helpful comments. This work was supported by funds granted to S.W.B. by the Inglewood Foundation, NIH (NINDS), Alzheimer's Association, and a UAMS pilot project award.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Steven W. Barger.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Barger, S., Harmon, A. Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E. Nature 388, 878–881 (1997). https://doi.org/10.1038/42257

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/42257

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing