Skip to main content
SpringerLink
Log in

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

  • Original Research
  • Published:
NeuroMolecular Medicine Aims and scope Submit manuscript

Abstract

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.

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

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Birmingham, K. and Frantz, S. (2002) Set back to Alzheimer vaccine studies. Nat. Med. 8, 199–200.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • Chao, C. C., Hu, S., and Peterson, P. K. (1996) Glia: the not so innocent by standers. J. Neurovirol. 2, 234–239.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Hardy, J. (1997) Amyloid, the presenilins and Alzheimer’s disease. Trends Neurosci. 20, 154–159.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Mattson, M. P. (1997) Cellular actions of β-amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiol. Rev. 77, 1081–1132.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • McGeer, E. G. and McGeer, P. L. (1999) Brain inflammation in Alzheimer disease and the therapeutic implications. Curr. Pharm. Des. 5, 821–836.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, 5600 Nathan Shock Drive-4F 02, 21224, Baltimore, MD

    Jaewon Lee, Sic L. Chan & Mark P. Mattson

  2. Department of Neuroscience, Johns Hopkins University School of Medicine, 21205, Baltimore, MD

    Mark P. Mattson

Authors
  1. Jaewon Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sic L. Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mark P. Mattson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mark P. Mattson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, J., Chan, S.L. & Mattson, M.P. Adverse effect of a presenilin-1 mutation in microglia results in enhanced nitric oxide and inflammatory cytokine responses to immune challenge in the brain. Neuromol Med 2, 29–45 (2002). https://doi.org/10.1385/NMM:2:1:29

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1385/NMM:2:1:29

Index Entries

Search

Navigation