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.

Systemic infections and inflammation affect chronic neurodegeneration

Abstract

It is well known that systemic infections cause flare-ups of disease in individuals with asthma and rheumatoid arthritis, and that relapses in multiple sclerosis can often be associated with upper respiratory-tract infections. Here we review evidence to support our hypothesis that in chronic neurodegenerative diseases such as Alzheimer's disease, with an ongoing innate immune response in the brain, systemic infections and inflammation can cause acute exacerbations of symptoms and drive the progression of neurodegeneration.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Models of activation of microglia.
Figure 2: Microglial priming and phenotypic switching without morphological change.
Figure 3: Fluctuating symptoms in Alzheimer's disease.

References

  1. Combrinck, M. I., Perry, V. H. & Cunningham, C. Peripheral infection evokes exaggerated sickness behaviour in pre-clinical murine prion disease. Neuroscience 112, 7–11 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Cunningham, C., Wilcockson, D. C., Campion, S., Lunnon, K. & Perry, V. H. Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J. Neurosci. 25, 9275–9284 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Dantzer, R. Cytokine-induced sickness behaviour: a neuroimmune response to activation of innate immunity. Eur. J. Pharmacol. 500, 399–411 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Tracey, K. J. The inflammatory reflex. Nature 420, 853–859 (2002).

    Article  CAS  PubMed  Google Scholar 

  5. Laflamme, N. & Rivest, S. Effects of systemic immunogenic insults and circulating proinflammatory cytokines on the transcription of the inhibitory factor κBα within specific cellular populations of the rat brain. J. Neurochem. 73, 309–321 (1999).

    Article  CAS  PubMed  Google Scholar 

  6. Chakravarty, S. & Herkenham, M. Toll-like receptor 4 on nonhematopoietic cells sustains CNS inflammation during endotoxemia, independent of systemic cytokines. J. Neurosci. 25, 1788–1796 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ek, M. et al. Inflammatory response: pathway across the blood–brain barrier. Nature 410, 430–431 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Perry, V. H. & Gordon, S. Macrophages and microglia in the nervous system. Trends Neurosci. 11, 273–277 (1988).

    Article  CAS  PubMed  Google Scholar 

  9. Nimmerjahn, A., Kirchhoff, F. & Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Hoek, R. M. et al. Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 290, 1768–1771 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Mott, R. T. et al. Neuronal expression of CD22: novel mechanism for inhibiting microglial proinflammatory cytokine production. Glia 46, 369–379 (2004).

    Article  PubMed  Google Scholar 

  12. Daws, M. R. et al. Pattern recognition by TREM-2: binding of anionic ligands. J. Immunol. 171, 594–599 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Schmid, C. D. et al. Heterogeneous expression of the triggering receptor expressed on myeloid cells-2 on adult murine microglia. J. Neurochem. 83, 1309–1320 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kreutzberg, G. W. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 19, 312–318 (1996).

    Article  CAS  PubMed  Google Scholar 

  15. Raivich, G. et al. Neuroglial activation repertoire in the injured brain: graded response, molecular mechanisms and cues to physiological function. Brain Res. Brain Res. Rev. 30, 77–105 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Gordon, S. Alternative activation of macrophages. Nature Rev. Immunol. 3, 23–35 (2003).

    Article  CAS  Google Scholar 

  17. Stout, R. D. et al. Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences. J. Immunol. 175, 342–349 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Etminan, M., Gill, S. & Samii, A. Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer's disease: systematic review and meta-analysis of observational studies. BMJ 327, 128 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chen, H. et al. Nonsteroidal antiinflammatory drug use and the risk for Parkinson's disease. Ann. Neurol. 58, 963–967 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Akiyama, H. et al. Inflammation and Alzheimer's disease. Neurobiol. Aging 21, 383–421 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. McGeer, P. L., Itagaki, S., Tago, H. & McGeer, E. G. Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci. Lett. 79, 195–200 (1987).

    Article  CAS  PubMed  Google Scholar 

  22. Simard, A. R., Soulet, D., Gowing, G., Julien, J. P. & Rivest, S. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease. Neuron 49, 489–502 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. D'Andrea, M. R., Cole, G. M. & Ard, M. D. The microglial phagocytic role with specific plaque types in the Alzheimer disease brain. Neurobiol. Aging 25, 675–683 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Combs, C. K., Karlo, J. C., Kao, S. C. & Landreth, G. E. β-Amyloid stimulation of microglia and monocytes results in TNFα-dependent expression of inducible nitric oxide synthase and neuronal apoptosis. J. Neurosci. 21, 1179–1188 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Brown, D. R., Schmidt, B. & Kretzschmar, H. A. Role of microglia and host prion protein in neurotoxicity of a prion protein fragment. Nature 380, 345–347 (1996).

    Article  CAS  PubMed  Google Scholar 

  26. Bamberger, M. E., Harris, M. E., McDonald, D. R., Husemann, J. & Landreth, G. E. A cell surface receptor complex for fibrillar β-amyloid mediates microglial activation. J. Neurosci. 23, 2665–2674 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Koenigsknecht, J. & Landreth, G. Microglial phagocytosis of fibrillar β-amyloid through a β1 integrin-dependent mechanism. J. Neurosci. 24, 9838–9846 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ajmone-Cat, M. A., Nicolini, A. & Minghetti, L. Prolonged exposure of microglia to lipopolysaccharide modifies the intracellular signaling pathways and selectively promotes prostaglandin E2 synthesis. J. Neurochem. 87, 1193–1203 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Griffin, W. S. & Mrak, R. E. Interleukin-1 in the genesis and progression of and risk for development of neuronal degeneration in Alzheimer's disease. J. Leukoc. Biol. 72, 233–238 (2002).

    CAS  PubMed  Google Scholar 

  30. 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  PubMed  PubMed Central  Google Scholar 

  31. Lim, G. P. et al. Ibuprofen effects on Alzheimer pathology and open field activity in APPsw transgenic mice. Neurobiol. Aging 22, 983–991 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Quinn, J. et al. Inflammation and cerebral amyloidosis are disconnected in an animal model of Alzheimer's disease. J. Neuroimmunol. 137, 32–41 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Sly, L. M. et al. Endogenous brain cytokine mRNA and inflammatory responses to lipopolysaccharide are elevated in the Tg2576 transgenic mouse model of Alzheimer's disease. Brain Res. Bull. 56, 581–588 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Wyss-Coray, T. et al. Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice. Proc. Natl Acad. Sci. USA 99, 10837–10842 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hensley, K. et al. Temporal patterns of cytokine and apoptosis-related gene expression in spinal cords of the G93A-SOD1 mouse model of amyotrophic lateral sclerosis. J. Neurochem. 82, 365–374 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Hensley, K. et al. Message and protein-level elevation of tumor necrosis factor α (TNFα) and TNFα-modulating cytokines in spinal cords of the G93A-SOD1 mouse model for amyotrophic lateral sclerosis. Neurobiol. Dis. 14, 74–80 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Nguyen, M. D., Julien, J. P. & Rivest, S. Induction of proinflammatory molecules in mice with amyotrophic lateral sclerosis: no requirement for proapoptotic interleukin-1β in neurodegeneration. Ann. Neurol. 50, 630–639 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Depino, A. M. et al. Microglial activation with atypical proinflammatory cytokine expression in a rat model of Parkinson's disease. Eur. J. Neurosci. 18, 2731–2742 (2003).

    Article  PubMed  Google Scholar 

  39. Sriram, K. et al. Mice deficient in TNF receptors are protected against dopaminergic neurotoxicity: implications for Parkinson's disease. FASEB J. 16, 1474–1476 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Rousselet, E. et al. Role of TNF-α receptors in mice intoxicated with the parkinsonian toxin MPTP. Exp. Neurol. 177, 183–192 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Leng, A., Mura, A., Feldon, J. & Ferger, B. Tumor necrosis factor-α receptor ablation in a chronic MPTP mouse model of Parkinson's disease. Neurosci. Lett. 375, 107–111 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Brown, A. R. et al. Inducible cytokine gene expression in the brain in the ME7/CV mouse model of scrapie is highly restricted, is at a strikingly low level relative to the degree of gliosis and occurs only late in disease. J. Gen. Virol. 84, 2605–2611 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. Cunningham, C., Wilcockson, D. C., Boche, D. & Perry, V. H. Comparison of inflammatory and acute-phase responses in the brain and peripheral organs of the ME7 model of prion disease. J. Virol. 79, 5174–5184 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Cunningham, C., Boche, D. & Perry, V. H. Transforming growth factor β1, the dominant cytokine in murine prion disease: influence on inflammatory cytokine synthesis and alteration of vascular extracellular matrix. Neuropathol. Appl. Neurobiol. 28, 107–119 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. Felton, L. M. et al. MCP-1 and murine prion disease: Separation of early behavioural dysfunction from overt clinical disease. Neurobiol. Dis. 20, 283–295 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Mabbott, N. A. et al. Tumor necrosis factor α-deficient, but not interleukin-6-deficient, mice resist peripheral infection with scrapie. J. Virol. 74, 3338–3344 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Schultz, J. et al. Role of interleukin-1 in prion disease-associated astrocyte activation. Am. J. Pathol. 165, 671–678 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bogdan, C., Paik, J., Vodovotz, Y. & Nathan, C. Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-β and interleukin-10. J. Biol. Chem. 267, 23301–23308 (1992).

    CAS  PubMed  Google Scholar 

  49. McDonald, P. P., Fadok, V. A., Bratton, D. & Henson, P. M. Transcriptional and translational regulation of inflammatory mediator production by endogenous TGF-β in macrophages that have ingested apoptotic cells. J. Immunol. 163, 6164–6172 (1999).

    CAS  PubMed  Google Scholar 

  50. Schook, L. B., Albrecht, H., Gallay, P. & Jongeneel, C. V. Cytokine regulation of TNF-α mRNA and protein production by unprimed macrophages from C57Bl/6 and NZW mice. J. Leukoc. Biol. 56, 514–520 (1994).

    Article  CAS  PubMed  Google Scholar 

  51. Chantry, D., Turner, M., Abney, E. & Feldmann, M. Modulation of cytokine production by transforming growth factor-β. J. Immunol. 142, 4295–4300 (1989).

    CAS  PubMed  Google Scholar 

  52. Ye, S. M. & Johnson, R. W. An age-related decline in interleukin-10 may contribute to the increased expression of interleukin-6 in brain of aged mice. Neuroimmunomodulation 9, 183–192 (2001).

    Article  CAS  PubMed  Google Scholar 

  53. De Simone, R., Ajmone-Cat, M. A., Carnevale, D. & Minghetti, L. Activation of α7 nicotinic acetylcholine receptor by nicotine selectively up-regulates cyclooxygenase-2 and prostaglandin E2 in rat microglial cultures. J. Neuroinflammation 2, 4 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Cunningham, C. et al. Synaptic changes characterize early behavioural changes in the ME7 model of murine prion disease. Eur. J. Neurosci. 17, 2147–2155 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Boche, D., Cunningham, C., Docagne, F., Scott, H. & Perry, V. H. TGFβ1 regulates the inflammatory response during chronic neurodegeneration. Neurobiol. Dis. 22, 638–650 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Thackray, A. M., McKenzie, A. N., Klein, M. A., Lauder, A. & Bujdoso, R. Accelerated prion disease in the absence of interleukin-10. J. Virol. 78, 13697–13707 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. DiCarlo, G., Wilcock, D., Henderson, D., Gordon, M. & Morgan, D. Intrahippocampal LPS injections reduce Aβ load in APP+PS1 transgenic mice. Neurobiol. Aging 22, 1007–1012 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. Herber, D. L. et al. Time-dependent reduction in Aβ levels after intracranial LPS administration in APP transgenic mice. Exp. Neurol. 190, 245–253 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Wilcock, D. M. et al. Microglial activation facilitates Aβ plaque removal following intracranial anti-Aβ antibody administration. Neurobiol. Dis. 15, 11–20 (2004).

    Article  CAS  PubMed  Google Scholar 

  60. Bard, F. et al. Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nature Med. 6, 916–919 (2000).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  62. Perry, V. H., Newman, T. A. & Cunningham, C. The impact of systemic infection on the progression of neurodegenerative disease. Nature Rev. Neurosci. 4, 103–112 (2003).

    Article  CAS  Google Scholar 

  63. Godbout, J. P. et al. Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. FASEB J. 19, 1329–1331 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. Perry, V. H., Matyszak, M. K. & Fearn, S. Altered antigen expression of microglia in the aged rodent CNS. Glia 7, 60–67 (1993).

    Article  CAS  PubMed  Google Scholar 

  65. Godbout, J. P. & Johnson, R. W. Interleukin-6 in the aging brain. J. Neuroimmunol. 147, 141–144 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Kyrkanides, S., O'Banion, M. K., Whiteley, P. E., Daeschner, J. C. & Olschowka, J. A. Enhanced glial activation and expression of specific CNS inflammation-related molecules in aged versus young rats following cortical stab injury. J. Neuroimmunol. 119, 269–277 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Barrientos, R. M. et al. Peripheral infection and aging interact to impair hippocampal memory consolidation. Neurobiol. Aging 27, 723–732 (2006).

    Article  PubMed  Google Scholar 

  68. 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. Neuromolecular Med. 2, 29–45 (2002).

    Article  CAS  PubMed  Google Scholar 

  69. Kitazawa, M., Oddo, S., Yamasaki, T. R., Green, K. N. & LaFerla, F. M. Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer's disease. J. Neurosci. 25, 8843–8853 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Nguyen, M. D., D'Aigle, T., Gowing, G., Julien, J. P. & Rivest, S. Exacerbation of motor neuron disease by chronic stimulation of innate immunity in a mouse model of amyotrophic lateral sclerosis. J. Neurosci. 24, 1340–1349 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. McCusker, J., Cole, M., Dendukuri, N., Belzile, E. & Primeau, F. Delirium in older medical inpatients and subsequent cognitive and functional status: a prospective study. Can. Med. Assoc. J. 165, 575–583 (2001).

    CAS  Google Scholar 

  72. Rahkonen, T., Luukkainen-Markkula, R., Paanila, S., Sivenius, J. & Sulkava, R. Delirium episode as a sign of undetected dementia among community dwelling elderly subjects: a 2 year follow up study. J. Neurol. Neurosurg. Psychiatry 69, 519–521 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Fick, D. M., Agostini, J. V. & Inouye, S. K. Delirium superimposed on dementia: a systematic review. J. Am. Geriatr. Soc. 50, 1723–1732 (2002).

    Article  PubMed  Google Scholar 

  74. Dunn, N., Mullee, M., Perry, V. H. & Holmes, C. Association between dementia and infectious disease: evidence from a case–control study. Alzheimer Dis. Assoc. Disord. 19, 91–94 (2005).

    Article  PubMed  Google Scholar 

  75. Engelhart, M. J. et al. Inflammatory proteins in plasma and the risk of dementia: The Rotterdam Study. Arch. Neurol. 61, 668–672 (2004).

    Article  PubMed  Google Scholar 

  76. Tilvis, R. S. et al. Predictors of cognitive decline and mortality of aged people over a 10-year period. J. Gerontol. A 59, 268–274 (2004).

    Article  Google Scholar 

  77. Ott, A. et al. Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 53, 1937–1942 (1999).

    Article  CAS  PubMed  Google Scholar 

  78. Andersen, K., Lolk, A., Kragh-Sorensen, P., Petersen, N. E. & Green, A. Depression and the risk of Alzheimer disease. Epidemiology 16, 233–238 (2005).

    Article  PubMed  Google Scholar 

  79. Fleminger, S., Oliver, D. L., Lovestone, S., Rabe-Hesketh, S. & Giora, A. Head injury as a risk factor for Alzheimer's disease: the evidence 10 years on; a partial replication. J. Neurol. Neurosurg. Psychiatry 74, 857–862 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Craig, D., Mirakhur, A., Hart, D. J., McIlroy, S. P. & Passmore, A. P. A cross-sectional study of neuropsychiatric symptoms in 435 patients with Alzheimer's disease. Am. J. Geriatr. Psychiatry 13, 460–468 (2005).

    Article  PubMed  Google Scholar 

  81. Starkstein, S. E., Jorge, R., Mizrahi, R. & Robinson, R. G. A prospective longitudinal study of apathy in Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 77, 8–11 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Hope, T., Keene, J., Fairburn, C. G., Jacoby, R. & McShane, R. Natural history of behavioural changes and psychiatric symptoms in Alzheimer's disease. A longitudinal study. Br. J. Psychiatry 174, 39–44 (1999).

    Article  CAS  PubMed  Google Scholar 

  83. Yip, A. G., Brayne, C. & Matthews, F. E. Risk factors for incident dementia in England and Wales: The Medical Research Council Cognitive Function and Ageing Study. A population-based nested case-control study. Age Ageing 35, 154–160 (2006).

    Article  PubMed  Google Scholar 

  84. Robert, P. H. et al. Apathy in patients with mild cognitive impairment and the risk of developing dementia of Alzheimer's disease. A one-year follow-up study. Clin. Neurol. Neurosurg. 108, 733–736 (2006).

    Article  PubMed  Google Scholar 

  85. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) 4th edn (American Psychiatric Association, Washington DC, 1994).

  86. Clark, C. M. et al. Variability in annual Mini-Mental State Examination score in patients with probable Alzheimer disease: a clinical perspective of data from the Consortium to Establish a Registry for Alzheimer's Disease. Arch. Neurol. 56, 857–862 (1999).

    Article  CAS  PubMed  Google Scholar 

  87. Holmes, C. & Lovestone, S. Long-term cognitive and functional decline in late onset Alzheimer's disease: therapeutic implications. Age Ageing 32, 200–204 (2003).

    Article  PubMed  Google Scholar 

  88. Holmes, C. et al. Systemic infection, interleukin 1β, and cognitive decline in Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 74, 788–789. (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Hart, B. L. Biological basis of the behavior of sick animals. Neurosci. Biobehav. Rev. 12, 123–137 (1988).

    Article  CAS  PubMed  Google Scholar 

  90. Blond, D., Campbell, S. J., Butchart, A. G., Perry, V. H. & Anthony, D. C. Differential induction of interleukin-1β and tumour necrosis factor-α may account for specific patterns of leukocyte recruitment in the brain. Brain Res. 958, 89–99 (2002).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Work in the authors' laboratories was supported by the Alzheimer's Research Trust, the UK Medical Research Council, and the Wellcome Trust.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to V. Hugh Perry.

Related links

Related links

DATABASES

Entrez Gene

TNF

OMIM

Alzheimer’s disease

Amyotrophic lateral sclerosis

Parkinson’s disease

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Perry, V., Cunningham, C. & Holmes, C. Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol 7, 161–167 (2007). https://doi.org/10.1038/nri2015

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2015

Further reading

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