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.

  • Article
  • Published:

Role of CD40 ligand in amyloidosis in transgenic Alzheimer's mice

Nature Neuroscience volume 5, pages 1288–1293 (2002)Cite this article

Abstract

We have shown that interaction of CD40 with CD40L enables microglial activation in response to amyloid-β peptide (Aβ), which is associated with Alzheimer's disease (AD)-like neuronal tau hyperphosphorylation in vivo. Here we report that transgenic mice overproducing Aβ, but deficient in CD40L, showed decreased astrocytosis and microgliosis associated with diminished Aβ levels and β-amyloid plaque load. Furthermore, in the PSAPP transgenic mouse model of AD, a depleting antibody against CD40L caused marked attenuation of Aβ/β-amyloid pathology, which was associated with decreased amyloidogenic processing of amyloid precursor protein (APP) and increased circulating levels of Aβ. Conversely, in neuroblastoma cells overexpressing wild-type human APP, the CD40–CD40L interaction resulted in amyloidogenic APP processing. These findings suggest several possible mechanisms underlying mitigation of AD pathology in response to CD40L depletion, and validate the CD40–CD40L interaction as a target for therapeutic intervention in AD.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Quantitative analysis of β-amyloid plaques in Tg APPsw/CD40L def. mice versus Tg APPsw mice at 16 months of age.
Figure 2: Microgliosis and astrocytosis are reduced in Tg APPsw/CD40L def. mice.
Figure 3: β-amyloid deposits are markedly reduced in 8-month-old PSAPP mice treated with anti-CD40L antibody.
Figure 4: CD40L modulates APP processing in vivo and in vitro.

Similar content being viewed by others

References

  1. Selkoe, D.J. Alzheimer's disease: genes, proteins and therapy. Physiol. Rev. 81, 741–766 (2001).

    Article  CAS  Google Scholar 

  2. McGeer, E.G. & McGeer, P.L. The importance of inflammatory mechanisms in Alzheimer disease. Exp. Gerontol. 33, 371–378 (1998).

    Article  CAS  Google Scholar 

  3. Rogers, J. et al. Inflammation and Alzheimer's disease pathogenesis. Neurobiol. Aging 17, 681–686 (1996).

    Article  CAS  Google Scholar 

  4. Itagaki, S., McGeer, P.L., Akiyama, H., Zhu, S. & Selkoe, D. Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease. J. Neuroimmunol. 24, 173–182 (1989).

    Article  CAS  Google Scholar 

  5. Giulian, D. Microglia and the immune pathology of Alzheimer disease. Am. J. Hum. Genet. 65, 13–18 (1999).

    Article  CAS  Google Scholar 

  6. Barger, S.W. & Harmon, A.D. Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E. Nature 388, 878–881 (1997).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Grewal, I.S. & Flavell, R.A. CD40 and CD154 in cell-mediated immunity. Annu. Rev. Immunol. 16, 111–135 (1998).

    Article  CAS  Google Scholar 

  9. Nguyen, V.T, Walker, W.S. & Benveniste, E.N. Post-transcriptional inhibition of CD40 gene expression in microglia by transforming growth factor-beta. Eur. J. Immunol. 28, 2537–2548 (1998).

    Article  CAS  Google Scholar 

  10. Tan, J. et al. Microglial activation resulting from CD40–CD40L interaction after beta-amyloid stimulation. Science 286, 2352–2355 (1999).

    Article  CAS  Google Scholar 

  11. Calingasan, N.Y., Erdely, H.A. & Altar, C.A. Identification of CD40 ligand in Alzheimer's disease and in animal models of Alzheimer's disease and brain injury. Neurobiol. Aging 23, 31–39 (2002).

    Article  CAS  Google Scholar 

  12. Togo, T. et al. Expression of CD40 in the brain of Alzheimer's disease and other neurological diseases. Brain Res. 885, 117–121 (2000).

    Article  CAS  Google Scholar 

  13. Hsiao, K. et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274, 99–102 (1996).

    Article  CAS  Google Scholar 

  14. Irizarry, M.C., McNamara, M., Fedorchak, K., Hsiao, K. & Hyman, B.T. APPSw transgenic mice develop age-related A beta deposits and neuropil abnormalities, but noneuronal loss in CA1. Neuropathol. Exp. Neurol. 56, 965–973 (1997).

    Article  CAS  Google Scholar 

  15. Holcomb, L. et al. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat. Med. 4, 97–100 (1998).

    Article  CAS  Google Scholar 

  16. Schonbeck, U., Sukhova, G.K., Shimizu, K., Mach, F. & Libby, P. Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice. Proc. Natl. Acad. Sci. U S A 97, 7458–7463 (2000).

    Article  CAS  Google Scholar 

  17. Schmidt, M.L., Lee, V.M. & Trojanowski, J.Q. Relative abundance of tau and neurofilament epitopes in hippocampal neurofibrillary tangles. Am. J. Pathol. 136, 1069–1075 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Ball, M.J. et al. A new definition of Alzheimer's disease: a hippocampal dementia. Lancet 1, 14–16 (1985).

    Article  CAS  Google Scholar 

  19. Luo, Y. et al. Mice deficient in BACE1, the Alzheimer's beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nat. Neurosci. 4, 231–232 (2001).

    Article  CAS  Google Scholar 

  20. Tan, J. et al. CD40 is expressed and functional on neuronal cells. EMBO J. 21, 643–652 (2002).

    Article  CAS  Google Scholar 

  21. Thinakaran, G., Teplow, D.B., Siman, R., Greenberg, B. & Sisodia, S.S. Metabolism of the “Swedish” amyloid precursor protein variant in neuro2a (N2a) cells. Evidence that cleavage at the “beta-secretase” site occurs in the golgi apparatus. J. Biol. Chem. 271, 9390–9397 (1996).

    Article  CAS  Google Scholar 

  22. Schonbeck, U. et al. Ligation of CD40 activates interleukin-1beta-converting enzyme (caspase-1) activity in vascular smooth muscle and endothelial cells and promotes elaboration of active interleukin 1beta. J. Biol. Chem. 272, 19569–19574 (1997).

    Article  CAS  Google Scholar 

  23. Mach, F. et al. Functional CD40 ligand is expressed on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for CD40–CD40 ligand signaling in atherosclerosis. Proc. Natl. Acad. Sci. U S A 94, 1931–1936 (1997).

    Article  CAS  Google Scholar 

  24. Piguet, P.F. et al. Role of CD40–CD40L in mouse severe malaria. Am. J. Pathol. 159, 733–742 (2001).

    Article  CAS  Google Scholar 

  25. DeMattos, R.B. et al. Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. U S A 98, 8850–8855 (2001).

    Article  CAS  Google Scholar 

  26. DeMattos, R.B., Bales, K.R., Cummins, D.J., Paul, S.M. & Holtzman, D.M. Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer's disease. Science 295, 2264–2267 (2002).

    Article  CAS  Google Scholar 

  27. Schenk D. et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400, 173–177 (1999).

    Article  CAS  Google Scholar 

  28. Wilcock, D.M. et al. Number of Abeta inoculations in APP+PS1 transgenic mice influences antibody titers, microglial activation, and congophilic plaque levels. DNA Cell Biol. 20, 731–736 (2001).

    Article  CAS  Google Scholar 

  29. DiCarlo G. et al. Intrahippocampal LPS injections reduce Abeta load in APP+PS1 transgenic mice. Neurobiol. Aging 22, 1007–1012 (2001).

    Article  CAS  Google Scholar 

  30. Qiao, X., Cummins, D.J. & Paul, S.M. Neuroinflammation-induced acceleration of amyloid deposition in the APPV717F transgenic mouse. Eur. J. Neurosci. 14, 474–482 (2001).

    Article  CAS  Google Scholar 

  31. Lim, G.P. et al. Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease. J. Neurosci. 20, 5709–5714 (2000).

    Article  CAS  Google Scholar 

  32. Lim, G.P. et al. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J. Neurosci. 21, 8370–8377 (2001).

    Article  CAS  Google Scholar 

  33. Jantzen, P.T. et al. Microglial activation and beta-amyloid deposit reduction caused by a nitric oxide-releasing nonsteroidal anti-inflammatory drug in amyloid precursor protein plus presenilin-1 transgenic mice. J. Neurosci. 22, 2246–2256 (2002).

    Article  CAS  Google Scholar 

  34. Xu, J. et al. Mice deficient for the CD40 ligand. Immunity 1, 423–431 (1994).

    Article  CAS  Google Scholar 

  35. Johnson-Wood, K. et al. Amyloid precursor protein processing and A beta42 deposition in a transgenic mouse model of Alzheimer disease. Proc. Natl. Acad. Sci. USA 94, 1550–1555 (1997).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to D. Roskamp and R. Roskamp for support, which made this work possible. This work was supported in part by the Alzheimer's Association. We thank Y. Wu and J. Zeng for assistance in preparating mouse brain homogenates and for western analysis. We also thank S. Gandy (New York University, Nathan S. Kline Institute for Psychiatric Research) and H. Steiner (Adolf Butenandt-Institute, Ludwig-Maximilians-University) for providing antibodies against the C-terminus of APP and G. Thinakaran (University of Chicago, Committee on Neurobiology) and S. Gandy for providing the N2a cell line that stably overexpresses wild-type human APP-695.

Author information

Author notes

  1. Jun Tan and Terrence Town: The first two authors contributed equally to this work

Authors and Affiliations

  1. Department of Psychiatry, The Roskamp Institute, University of South Florida, 3515 East Fletcher Avenue, Tampa, 33613, Florida, USA

    Jun Tan, Terrence Town, Fiona Crawford, Takashi Mori, Anthony DelleDonne, Robert Crescentini, Demian Obregon & Michael J. Mullan

  2. Howard Hughes Medical Institute, Yale University School of Medicine, 310 Cedar Street, New Haven, 06520, Connecticut, USA

    Richard A. Flavell

Authors
  1. Jun Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Terrence Town
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fiona Crawford
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takashi Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anthony DelleDonne
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Robert Crescentini
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Demian Obregon
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Richard A. Flavell
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Michael J. Mullan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael J. Mullan.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tan, J., Town, T., Crawford, F. et al. Role of CD40 ligand in amyloidosis in transgenic Alzheimer's mice. Nat Neurosci 5, 1288–1293 (2002). https://doi.org/10.1038/nn968

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn968

This article is cited by

Search

Advanced 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