NeuroMolecular Medicine

, Volume 2, Issue 1, pp 29–45 | Cite as

Adverse effect of a presenilin-1 mutation in microglia results in enhanced nitric oxide and inflammatory cytokine responses to immune challenge in the brain

  • Jaewon Lee
  • Sic L. Chan
  • Mark P. Mattson
Original Research


Inflammatory processes involving glial cell activation are associated with amyloid plaques and neurofibrillary tangles, the cardinal neuropathological lesions in the brains of Alzheimer’s disease (AD) patients, However, it is unclear whether these inflammatory processes occur as a response to neuronal degeneration or might represent more seminal events in the disease process. Some cases of AD are caused by mutations in presenilin-1 (PS1), and it has been shown that PS1 mutations perturb neuronal calcium homeostasis, promote increased production of amyloid β-peptide (Aβ), and render neurons vulnerable to synaptic dysfunction, excitotoxicity, and apoptosis. Although glial cells express PS1, it is not known if PS1 mutations alter glial cell functions. We now report on studies of glial cells in PS1 mutant knockin mice that demonstrate an adverse effect PS1 mutations in microglial cells. Specifically, PS1 mutant mice exhibit an enhanced inflammatory cytokine response to immune challenge with bacterial lipopolysaccharide (LPS). LPS-induced levels of mRNAs encoding tumor necrosis fctor-α (TNFα), interleukin (IL)-1α, IL-1β, IL-1 receptor antagonist, and IL-6 are significantly greater in the hippocampus and cerebral cortex of PS1 mutant mice as compared to wild-type mice. In contrast, the cytokine responses to LPS in the spleen is unaffected by the PS1 mutation. Studies of cultured microglia from PS1 mutant and wild-type mice reveal that PS1 is expressed in microglia and that the PS1 mutation confers a heightened sensitivity to LPS, as indicated by superinduction of inducible nitric oxide synthase (NOS) and activation of mitogen-activated protein kinase (MAPK). These findings demonstrate an adverse effect of PS1 mutations on microglial cells that results in their hyper-activation under pro-inflammatory conditions, which may, together with direct effects of mutant PS1 in neurons, contribute to the neurodegenerative process in AD. These findings also have important implications for development of a “vaccine” for the prevention or treatment of AD.

Index Entries

Alzheimer’s disease amyloid astrocytes calcium hippocampus inflammation interleukin-1 tumor necrosis factor vaccine 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Albensi, B. C. and Mattson, M. P. (2000) Evidence for the involvement of TNF and NF-kappaB in hippocampal synaptic plasticity. Synapse 35, 151–159.PubMedCrossRefGoogle Scholar
  2. Anthony, J. C., Breitner, J. C., Zandi, P. P., Meyer, M. R., Jurasova, I., Norton, M. C., and Stone, S. V. (2000) Reduced prevalence of AD in users of NSAIDs and H2 receptor antagonists: the Cache County study. Neurology 54, 2066–2071.PubMedGoogle Scholar
  3. Barger, S. W., Horster, D., Furukawa, K., Goodman, Y., Krieglstein, J., and Mattson, M. P. (1995) Tumor necrosis factors alpha and beta protect neurons against amyloid beta-peptide toxicity: evidence for involvement of a kappa B-binding factor and attenuation of peroxide and Ca2+ accumulation. Proc. Natl. Acad. Sci. USA 92, 9328–9332.PubMedCrossRefGoogle Scholar
  4. Birmingham, K. and Frantz, S. (2002) Set back to Alzheimer vaccine studies. Nat. Med. 8, 199–200.PubMedCrossRefGoogle Scholar
  5. Bornemann, K. D., Wiederhold, K. H., Pauli, C., Ermini, F., Stalder, M., Schnell, L., et al. (2001) Abeta-induced inflammatory processes in microglia cells of APP23 transgenic mice. Am. J. Pathol. 158, 63–73.PubMedGoogle Scholar
  6. Bruce, A. J., Boling, W., Kindy, M. S., Peschon, J., Kraemer, P. J., Carpenter, M. K., et al. (1996) Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nat. Med. 2, 788–794.PubMedCrossRefGoogle Scholar
  7. Bruce-Keller, A. J., Keeling, J. L., Keller, J. N., Huang, F. F., Camondola, S., and Mattson, M. P. (2000) Anti-inflammatory effects of estrogen on microglial activation. Endocrinology 141, 3646–3656.PubMedCrossRefGoogle Scholar
  8. Chan, S. L., Mayne, M., Holden, C. P., Geiger, J. D., and Mattson, M. P. (2000) Presenilin-1 mutations increase levels of ryanodine receptors and calcium release in PC12 cells and cortical neurons. J. Biol. Chem. 275, 18,195–18,200.Google Scholar
  9. Chao, C. C., Hu, S., and Peterson, P. K. (1996) Glia: the not so innocent by standers. J. Neurovirol. 2, 234–239.PubMedGoogle Scholar
  10. Citron, M., Westaway, D., Xia, W., Carlson, G., Diehl, T., Levesque, G., et al. (1997) Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nat. Med. 3, 67–72.PubMedCrossRefGoogle Scholar
  11. Combs, C. K., Karlo, J. C., Kao, S. C., and Landreth, G. E. (2001) beta-Amyloid stimulation of microglia and monocytes results in TNFalpha-dependent expression of inducible nitric oxide synthase and neuronal apoptosis. J. Neurosci. 21, 1179–1188.PubMedGoogle Scholar
  12. Cribbs, D. H., Chen, L. S., Bende, S. M., and LaFerla, F. M. (1996) Widespread neuronal expression of the presenilin-1 early-onset Alzheimer’s disease gene in the murine brain. Am. J. Pathol. 148, 1797–1806.PubMedGoogle Scholar
  13. Cunningham, A. J., Murray, C. A., O’Neill, L. A., Lynch, M. A., and O’Connor, J. J. (1996) Interleukin-1 beta (IL-1 beta) and tumour necrosis factor (TNF) inhibit long-term potentiation in the rat dentate gyrus in vitro. Neurosci. Lett. 203, 17–20.PubMedCrossRefGoogle Scholar
  14. Galasko, D., Hansen, L. A., Katzman, R., Wiederholt, W., Masliah, E., Terry, R., et al. (1994) Clinical-neuropathological correlations in Alzheimer’s disease and related dementias. Arch. Neurol. 51, 888–895.PubMedGoogle Scholar
  15. Gatti, S. and Bartfai, T. (1993) Induction of tumor necrosis factor-alpha mRNA in the brain after peripheral endotoxin treatment: comparison with interleukin-1 family and interleukin-6. Brain Res. 624, 291–294.PubMedCrossRefGoogle Scholar
  16. Guo, Q., Furukawa, K., Sopher, B. L., Pham, D. G., Robinson, N., Martin, G. M., and Mattson, M. P. (1996) Alzheimer’s PS-1 mutation perturbs calcium homeostasis and sensitizes PC12 cells to death induced by amyloid β-peptide. Neuro Report 8, 379–383.Google Scholar
  17. Guo, Q., Sopher, B. L., Pham, D. G., Furukawa, K., Robinson, N., Martin, G. M., and Mattson, M. P. (1997) Alzheimer’s presenilin mutation sensitizes neural cells to apoptosis induced by trophic factor withdrawal and amyloid β-peptide. J. Neurosci. 17, 4212–4222.PubMedGoogle Scholar
  18. Guo, Q., Sebastian, L., Sopher, B. L., Miller, M. W., Glazner, G. W., Ware, C. B., et al. (1999a) Neurotrophic factors [activity-dependent neurotrophic factor (ADNF) and basic fibroblast growth factor (bFGF)] interrupt excitotoxic neurodegenerative cascades promoted by a PS1 mutation. Proc. Natl. Acad. Sci. USA 96, 4125–4130.PubMedCrossRefGoogle Scholar
  19. Guo, Q., Fu, W., Sopher, B. L., Miller, M. W., Ware, C. B., Martin, G. M., and Mattson, M. P. (1999b) Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knockin mice. Nature Med. 5, 101–107.PubMedCrossRefGoogle Scholar
  20. Guo, Q., Fu, W., Holtsberg, F. W., Steiner, S. M., and Mattson, M. P. (1999) Superoxide mediates the cell-death-enhancing action of presenilin-1 mutations. J. Neurosci. Res. 56, 457–470.PubMedCrossRefGoogle Scholar
  21. Hardy, J. (1997) Amyloid, the presenilins and Alzheimer’s disease. Trends Neurosci. 20, 154–159.PubMedCrossRefGoogle Scholar
  22. Hartlage-Rubsamen, M., Lemke, R., and Schliebs, R. (1999) Interleukin-1beta, inducible nitric oxide synthase, and nuclear factor-kappaB are induced in morphologically distinct microglia after rat hippocampal lipopolysaccharide/interferon-gamma injection. J. Neurosci. Res. 57, 388–398.PubMedCrossRefGoogle Scholar
  23. Ishii, K., Muelhauser, F., Liebl, U., Picard, M., Kuhl, S., Penke, B., et al. (2000) Subacute NO generation induced by Alzheimer’s beta-amyloid in the living brain: reversal by inhibition of the inducible NO synthase. FASEB J. 14, 1485–1489.PubMedCrossRefGoogle Scholar
  24. Klegeris, A., Walker, D. G., and McGeer, P. L. (1994) Activation of macrophages by Alzheimer beta amyloid peptide. Biochem. Biophys. Res. Commun. 199, 984–991.PubMedCrossRefGoogle Scholar
  25. Law, A., Gauthier, S., and Quirion, R. (2001) Neuroprotective and neurorescuing effects of isoform-specific nitric oxide synthase inhibitors, nitric oxide scavenger, and antioxidant against beta-amyloid toxicity. Br. J. Pharmacol. 133, 1114–1124.PubMedCrossRefGoogle Scholar
  26. Laye, S., Parnet, P., Goujon, E., and Dantzer, R. (1994) Peripheral administration of lipopolysaccharide induces the expression of cytokine transcripts in the brain and pituitary of mice. Mol. Brain Res. 27, 157–162.PubMedCrossRefGoogle Scholar
  27. Lee, S. C., Liu, W., Dickson, D. W., Brosnan, C. F., and Berman, J. W. (1993) Cytokine production by human fetal microglia and astrocytes. Differential induction by lipopolysaccharide and IL-1 beta. J. Immunol. 150, 2659–2667.PubMedGoogle Scholar
  28. Lee, M. K., Slunt, H. H., Martin, L. J., Thinakaran, G., Kim, G., Gandy, S. E., et al. (1996) Expression of presenilin 1 and 2 (PS1 and PS2) in human and murine tissues. J. Neurosci. 16, 7513–7525.PubMedGoogle Scholar
  29. Lee, J., Duan, W., Long, J. M., Ingram, D. K., and Mattson, M. P. (2000) Dietary restriction increases the number of newly generated neural cells, and induces BDNF expression, in the dentate gyrus of rats. J. Mol. Neurosci. 15, 99–108.PubMedCrossRefGoogle Scholar
  30. Leissring, M. A., Akbari, Y., Fanger, C. M., Cahalan, M. D., Mattson, M. P., and LaFerla, F. M. (2000) Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice. J. Cell Biol. 149, 793–798.PubMedCrossRefGoogle Scholar
  31. Lim, G. P., Yang, F., Chu, T., Chen, P., Beech, W., Teter, B., et al. (2000) Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer’s disease. J. Neurosci. 20, 5709–5714.PubMedGoogle Scholar
  32. Long, J. M., Kalehua, A. N., Muth, N. J., Hengemihle, J. M., Jucker, M., Calhoun, M. E., et al. (1998) Stereological estimation of total microglia number in mouse hippocampus. J. Neurosci. Methods 84, 101–108.PubMedCrossRefGoogle Scholar
  33. Major, D. E., Kesslak, J. P., Cotman, C. W., Finch, C. E., and Day, J. R. (1997) Life-long dietary restriction attenuates age-related increases in hippocampal glial fibrillary acidic protein mRNA. Neurobiol. Aging 18, 523–526.PubMedCrossRefGoogle Scholar
  34. Mattson, M. P. (1997) Cellular actions of β-amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiol. Rev. 77, 1081–1132.PubMedGoogle Scholar
  35. Mattson, M. P., Goodman, Y., Luo, H., Fu, W., and Furukawa, K. (1997) Activation of NF-kappaB protects hippocampal neurons against oxidative stress-induced apoptosis: evidence for induction of manganese superoxide dismutase and suppression of peroxynitrite production and protein tyrosine nitration. J. Neurosci. Res. 49, 681–697.PubMedCrossRefGoogle Scholar
  36. Mattson, M. P., Duan, W., Lee, J., and Guo, Z. (2001) Suppression of brain aging and neurodegenerative disorders by dietary restriction and environmental enrichment: molecular mechanisms. Mech. Ageing Dev. 122, 757–778.PubMedCrossRefGoogle Scholar
  37. McGeer, E. G. and McGeer, P. L. (1999) Brain inflammation in Alzheimer disease and the therapeutic implications. Curr. Pharm. Des. 5, 821–836.PubMedGoogle Scholar
  38. Meda, L., Baron, P., and Scarlato, G. (2001) Glial activation in Alzheimer’s disease: the role of Abeta and its associated proteins. Neurobiol. Aging 22, 885–893.PubMedCrossRefGoogle Scholar
  39. Moller, T., Nolte, C., Burger, R., Verkhratsky, A., and Kettenmann, H. (1997) Mechanisms of C5a and C3a complement fragment-induced [Ca2+]i signaling in mouse microglia. J. Neurosci. 17, 615–624.PubMedGoogle Scholar
  40. Mrak, R. E., Sheng, J. G., and Griffin, W. S. (1995) Glial cytokines in Alzheimer’s disease: review and pathogenic implications. Hum. Pathol. 26, 816–823.PubMedCrossRefGoogle Scholar
  41. Palin, K., Pousset, F., Verrier, D., Dantzer, R., Kelley, K., Parnet, P., and Lestage, J. (2001) Characterization of interleukin-1 receptor antagonist isoform expression in the brain of lipopolysaccharide-treated rats. Neuroscience 103, 161–169.PubMedCrossRefGoogle Scholar
  42. Penkowa, M., Moos, T., Carrasco, J., Hadberg, H., Molinero, A., Bluethmann, H., and Hidalgo, J. (1999) Strongly compromised inflammatory response to brain injury in interleukin-6-deficient mice. Glia 25, 343–357.PubMedCrossRefGoogle Scholar
  43. Perlmutter, L. S., Scott, S. A., Barron, E., and Chui, H. C. (1992) MHC class II-positive microglia in human brain: association with Alzheimer lesions. J. Neurosci. Res. 33, 549–558.PubMedCrossRefGoogle Scholar
  44. Possel, H., Noack, H., Putzke, J., Wolf, G., and Sies, H. (2000) Selective upregulation of inducible nitric oxide synthase (iNOS) by lipopolysaccharide (LPS) and cytokines in microglia: in vitro and in vivo studies. Glia 32, 51–59.PubMedCrossRefGoogle Scholar
  45. Scheuner, D., Eckman, C., Jensen, M., Song, X., Citron, M., Suzuki, N., et al. (1996) Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat. Med. 2, 864–870.PubMedCrossRefGoogle Scholar
  46. Sheng, J. G., Jones, R. A., Zhou, X. Q., McGinness, J. M., Van Eldik, L. J., Mrak, R. E., and Griffin, W. S. (2001) Interleukin-1 promotion of MAPK-p38 overexpression in experimental animals and in Alzheimer’s disease: potential significance for tau protein phosphorylation. Neurochem. Int. 39, 341–348.PubMedCrossRefGoogle Scholar
  47. Smith, M. A., Richey Harris, P. L., Sayre, L. M., Beckman, J. S., and Perry, G. (1997) Widespread peroxynitrite-mediated damage in Alzheimer’s disease. J. Neurosci. 17, 2653–2657.PubMedGoogle Scholar
  48. Stalder, M., Phinney, A., Probst, A., Sommer, B., Staufenbiel, M., and Jucker, M. (1999) Association of microglia with amyloid plaques in brains of APP23 transgenic mice. Am. J. Pathol. 154, 1673–1684.PubMedGoogle Scholar
  49. Tan, J., Town, T., Paris, D., Mori, T., Suo, Z., Crawford, F., et al. (1999) Microglial activation resulting from CD40-CD40L interaction after beta-amyloid stimulation. Science 286, 2352–2355.PubMedCrossRefGoogle Scholar
  50. Tehranian, R., Hasanvan, H., Iverfeldt, K., Post, C., and Schultzberg, M. (2001) Early induction of interleukin-6 mRNA in the hippocampus and cortex of APPsw transgenic mice Tg2576. Neurosci. Lett. 301, 54–58.PubMedCrossRefGoogle Scholar
  51. Veld, B. A., Ruitenberg, A., Hofman, A., Launer, L. J., van Duijn, C. M., Stijnen, T., et al. (2001) Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N. Engl. J. Med. 345, 1515–1521.CrossRefGoogle Scholar
  52. Wang, H., Zhan, Y., Xu, L., Feuerstein, G. Z., and Wang, X. (2001) Use of suppression subtractive hybridization for differential gene expression in stroke: discovery of CD44 gene expression and localization in permanent focal stroke in rats. Stroke 32, 1020–1027.PubMedGoogle Scholar
  53. Weggen, S., Diehlmann, A., Buslei, R., Beyreuther, K., and Bayer, T. A. (1998) Prominent expression of presenilin-1 in senile plaques and reactive astrocytes in Alzheimer’s disease brain. Neuroreport 9, 3279–3283.PubMedGoogle Scholar
  54. Wu, Q., Combs, C., Cannady, S. B., Geldmacher, D. S., and Herrup, K. (2000) Beta-amyloid activated microglia induce cell cycling and cell death in cultured cortical neurons. Neurobiol. Aging 21, 797–806.PubMedCrossRefGoogle Scholar
  55. Xia, M. Q., Berezovska, O., Kim, T. W., Xia, W. M., Liao, A., Tanzi, R. E., et al. (1998) Lack of specific association of presenilin 1 (PS-1) protein with plaques and tangles in Alzheimer’s disease. J. Neurol. Sci. 158, 15–23.PubMedCrossRefGoogle Scholar
  56. Yu, Z. F., Nikolova-Karakashian, M., Zhou, D., Cheng, G., Schuchman, E. H., and Mattson, M. P (2000) Pivotal role for acidic sphingomyelinase in cerebral ischemia-induced ceramide and cytokine production, and neuronal apoptosis. J. Mol. Neurosci. 15, 85–97.PubMedCrossRefGoogle Scholar
  57. Zhu, H., Guo, Q., and Mattson, M. P. (1999) Dietary restriction protects hippocampal neurons against the death-promoting action of a presenilin-1 mutation. Brain Res. 842, 224–229.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2002

Authors and Affiliations

  1. 1.Laboratory of NeurosciencesNational Institute on Aging Gerontology Research CenterBaltimore
  2. 2.Department of NeuroscienceJohns Hopkins University School of MedicineBaltimore

Personalised recommendations