Skip to main content

Advertisement

SpringerLink
Log in

Outdoor Ambient Air Pollution and Neurodegenerative Diseases: the Neuroinflammation Hypothesis

  • Mechanisms of Toxicity (JR Richardson, Section Editor)
  • Published:
Current Environmental Health Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Accumulating research indicates that ambient outdoor air pollution impacts the brain and may affect neurodegenerative diseases, yet the potential underlying mechanisms are poorly understood.

Recent Findings

The neuroinflammation hypothesis holds that elevation of cytokines and reactive oxygen species in the brain mediates the deleterious effects of urban air pollution on the central nervous system (CNS). Studies in human and animal research document that neuroinflammation occurs in response to several inhaled pollutants. Microglia are a prominent source of cytokines and reactive oxygen species in the brain, implicated in the progressive neuron damage in diverse neurodegenerative diseases, and activated by inhaled components of urban air pollution through both direct and indirect pathways. The MAC1-NOX2 pathway has been identified as a mechanism through which microglia respond to different forms of air pollution, suggesting a potential common deleterious pathway.

Summary

Multiple direct and indirect pathways in response to air pollution exposure likely interact in concert to exert CNS effects.

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

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Calderon-Garciduenas L, Maronpot RR, Torres-Jardon R, Henriquez-Roldan C, Schoonhoven R, Acuna-Ayala H, et al. DNA damage in nasal and brain tissues of canines exposed to air pollutants is associated with evidence of chronic brain inflammation and neurodegeneration. Toxicol Pathol. 2003;31(5):524–38.

    Article  CAS  PubMed  Google Scholar 

  2. Calderon-Garciduenas L, Azzarelli B, Acuna H, Garcia R, Gambling TM, Osnaya N, et al. Air pollution and brain damage. Toxicol Pathol. 2002;30(3):373–89.

    Article  CAS  PubMed  Google Scholar 

  3. • Calderon-Garciduenas L, Reed W, Maronpot RR, Henriquez-Roldan C, Delgado-Chavez R, Calderon-Garciduenas A, et al. Brain inflammation and Alzheimer’s-like pathology in individuals exposed to severe air pollution. Toxicol Pathol. 2004;32(6):650–8. This is a hallmark paper from a small case study that was the first to suggest air pollution exposure may be linked to human Alzhiemer’s disease-like neuropathology and central nervous system damage. Since this time, many animal model experimental research and epidemiology studies have further investigated this premise, work which now comprises an entire field.

  4. Calderon-Garciduenas L, Leray E, Heydarpour P, Torres-Jardon R, Reis J. Air pollution, a rising environmental risk factor for cognition, neuroinflammation and neurodegeneration: the clinical impact on children and beyond. Rev Neurol (Paris). 2016;172(1):69–80.

    Article  CAS  Google Scholar 

  5. Block ML, Calderon-Garciduenas L. Air pollution: mechanisms of neuroinflammation and CNS disease. Trends Neurosci. 2009;32(9):506–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kurt OK, Zhang J, Pinkerton KE. Pulmonary health effects of air pollution. Curr Opin Pulm Med. 2016;22(2):138–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Akimoto H. Global air quality and pollution. Science. 2003;302(5651):1716–9.

    Article  CAS  PubMed  Google Scholar 

  8. Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2224–60.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Stanek LW, Brown JS, Stanek J, Gift J, Costa DL. Air pollution toxicology—a brief review of the role of the science in shaping the current understanding of air pollution health risks. Toxicol Sci. 2011;120(Suppl 1):S8–27.

    Article  CAS  PubMed  Google Scholar 

  10. Cui P, Huang YB, Han JL, Song FJ, Chen KX. Ambient particulate matter and lung cancer incidence and mortality: a meta-analysis of prospective studies. Eur J Pub Health. 2015;25(2):324–9.

    Article  Google Scholar 

  11. Kaufman JD, Adar SD, Barr RG, Budoff M, Burke GL, Curl CL, et al. Association between air pollution and coronary artery calcification within six metropolitan areas in the USA (the Multi-Ethnic Study of Atherosclerosis and Air Pollution): a longitudinal cohort study. Lancet. 2016;388(10045):696–704.

    Article  CAS  PubMed  Google Scholar 

  12. Bravo MA, Anthopolos R, Bell ML, Miranda ML. Racial isolation and exposure to airborne particulate matter and ozone in understudied US populations: environmental justice applications of downscaled numerical model output. Environ Int. 2016;92-93:247–55.

    Article  CAS  PubMed  Google Scholar 

  13. Wang CC, Tu YF, Yu ZL, Lu RZ. PM2.5 and cardiovascular diseases in the elderly: an overview. Int J Environ Res Public Health. 2015;12(7):8187–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Giannadaki D, Lelieveld J, Pozzer A. Implementing the US air quality standard for PM2.5 worldwide can prevent millions of premature deaths per year. Environmental Health. 2016;15.

  15. Craig L, Brook JR, Chiotti Q, Croes B, Gower S, Hedley A, et al. Air pollution and public health: a guidance document for risk managers. J Toxicol Environ Health A. 2008;71(9–10):588–698.

    Article  CAS  PubMed  Google Scholar 

  16. Muhlfeld C, Rothen-Rutishauser B, Blank F, Vanhecke D, Ochs M, Gehr P. Interactions of nanoparticles with pulmonary structures and cellular responses. Am J Physiol Lung Cell Mol Physiol. 2008;294(5):L817–29.

    Article  CAS  PubMed  Google Scholar 

  17. Valavanidis A, Fiotakis K, Vlachogianni T. Airborne particulate matter and human health: toxicological assessment and importance of size and composition of particles for oxidative damage and carcinogenic mechanisms. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2008;26(4):339–62.

    Article  CAS  PubMed  Google Scholar 

  18. Rothen-Rutishauser B, Mueller L, Blank F, Brandenberger C, Muehlfeld C, Gehr P. A newly developed in vitro model of the human epithelial airway barrier to study the toxic potential of nanoparticles. ALTEX. 2008;25(3):191–6.

    Article  PubMed  Google Scholar 

  19. Kioumourtzoglou MA, Schwartz JD, Weisskopf MG, Melly SJ, Wang Y, Dominici F, et al. Long-term PM2.5 exposure and neurological hospital admissions in the northeastern United States. Environ Health Perspect. 2016;124(1):23–9.

    PubMed  Google Scholar 

  20. Jung CR, Lin YT, Hwang BF. Ozone, particulate matter, and newly diagnosed Alzheimer’s disease: a population-based cohort study in taiwan. J Alzheimers Dis. 2015;44(2):573–84.

    CAS  PubMed  Google Scholar 

  21. Ailshire JA, Clarke P. Fine particulate matter air pollution and cognitive function among US older adults. J Gerontol B-Psychol. 2015;70(2):322–8.

    Article  Google Scholar 

  22. Ailshire JA, Crimmins EM. Fine particulate matter air pollution and cognitive function among older US adults. Am J Epidemiol. 2014;180(4):359–66.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Gatto NM, Henderson VW, Hodis HN, St John JA, Lurmann F, Chen JC, et al. Components of air pollution and cognitive function in middle-aged and older adults in Los Angeles. Neurotoxicology. 2014;40:1–7.

    Article  CAS  PubMed  Google Scholar 

  24. Schikowski T, Vossoughi M, Vierkotter A, Schulte T, Teichert T, Sugiri D, et al. Association of air pollution with cognitive functions and its modification by APOE gene variants in elderly women. Environ Res. 2015;142:10–6.

    Article  CAS  PubMed  Google Scholar 

  25. Tonne C, Elbaz A, Beevers S, Singh-Manoux A. Traffic-related air pollution in relation to cognitive function in older adults. Epidemiology. 2014;25(5):674–81.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Weuve J, Puett RC, Schwartz J, Yanosky JD, Laden F, Grodstein F. Exposure to particulate air pollution and cognitive decline in older women. Arch Intern Med. 2012;172(3):219–27.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Loop MS, Kent ST, Al-Hamdan MZ, Crosson WL, Estes SM, Estes Jr MG, et al. Fine particulate matter and incident cognitive impairment in the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. PLoS One. 2013;8(9):e75001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Chen JC, Wang X, Wellenius GA, Serre ML, Driscoll I, Casanova R, et al. Ambient air pollution and neurotoxicity on brain structure: evidence from women’s health initiative memory study. Ann Neurol. 2015;78(3):466–76.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Wilker EH, Preis SR, Beiser AS, Wolf PA, Au R, Kloog I, et al. Long-term exposure to fine particulate matter, residential proximity to major roads and measures of brain structure. Stroke; a journal of cerebral circulation. 2015;46(5):1161–6.

    Article  CAS  PubMed Central  Google Scholar 

  30. Tzivian L, Dlugaj M, Winkler A, Weinmayr G, Hennig F, Fuks KB, et al. Long-term air pollution and traffic noise exposures and mild cognitive impairment in older adults: a cross-sectional analysis of the Heinz Nixdorf recall study. Environ Health Perspect. 2016;124(9):1361–8.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Zanobetti A, Dominici F, Wang Y, Schwartz JD. A national case-crossover analysis of the short-term effect of PM2.5 on hospitalizations and mortality in subjects with diabetes and neurological disorders. Environ Health. 2014;13(1):38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Palacios N, Fitzgerald KC, Hart JE, Weisskopf MG, Schwarzschild MA, Ascherio A, et al. Particulate matter and risk of Parkinson disease in a large prospective study of women. Environ Health. 2014;13:80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Chen JC, Schwartz J. Neurobehavioral effects of ambient air pollution on cognitive performance in US adults. Neurotoxicology. 2009;30(2):231–9.

    Article  CAS  PubMed  Google Scholar 

  34. Ranft U, Schikowski T, Sugiri D, Krutmann J, Kramer U. Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly. Environ Res. 2009;109(8):1004–11.

    Article  CAS  PubMed  Google Scholar 

  35. Chang KH, Chang MY, Muo CH, Wu TN, Chen CY, Kao CH. Increased risk of dementia in patients exposed to nitrogen dioxide and carbon monoxide: a population-based retrospective cohort study. PLoS One. 2014;9(8):e103078.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Lee PC, Liu LL, Sun Y, Chen YA, Liu CC, Li CY, et al. Traffic-related air pollution increased the risk of Parkinson’s disease in Taiwan: a nationwide study. Environ Int. 2016;96:75–81.

    Article  CAS  PubMed  Google Scholar 

  37. Finkelstein MM, Jerrett M. A study of the relationships between Parkinson’s disease and markers of traffic-derived and environmental manganese air pollution in two Canadian cities. Environ Res. 2007;104(3):420–32.

    Article  CAS  PubMed  Google Scholar 

  38. Ritz B, Lee PC, Hansen J, Lassen CF, Ketzel M, Sorensen M, et al. Traffic-related air pollution and Parkinson’s disease in Denmark: a case-control study. Environ Health Perspect. 2016;124(3):351–6.

    PubMed  Google Scholar 

  39. Angelici L, Piola M, Cavalleri T, Randi G, Cortini F, Bergamaschi R, et al. Effects of particulate matter exposure on multiple sclerosis hospital admission in Lombardy region. Italy Environ Res. 2016;145:68–73.

    Article  PubMed  CAS  Google Scholar 

  40. Oudin A, Forsberg B, Adolfsson AN, Lind N, Modig L, Nordin M, et al. Traffic-related air pollution and dementia incidence in Northern Sweden: a longitudinal study. Environ Health Perspect. 2016;124(3):306–12.

    PubMed  Google Scholar 

  41. • Chen H, Kwong JC, Copes R, Tu K, Villeneuve PJ, van Donkelaar A, et al. Living near major roads and the incidence of dementia, Parkinson’s disease, and multiple sclerosis: a population-based cohort study. Lancet. 2017;389(10070):718–26. This is a recent, large prospective study that explores whether living next to major roads/traffic associated air pollution is associated with elevated incidence of several neurodegenerative diseases. This work reports that only dementia showed a significant relationship with being located near a highly traveled roadway.

  42. Wellenius GA, Boyle LD, Coull BA, Milberg WP, Gryparis A, Schwartz J, et al. Residential proximity to nearest major roadway and cognitive function in community-dwelling seniors: results from the MOBILIZE Boston study. J Am Geriatr Soc. 2012;60(11):2075–80.

    PubMed  PubMed Central  Google Scholar 

  43. Power MC, Weisskopf MG, Alexeeff SE, Coull BA, Spiro 3rd A, Schwartz J. Traffic-related air pollution and cognitive function in a cohort of older men. Environ Health Perspect. 2011;119(5):682–7.

    Article  CAS  PubMed  Google Scholar 

  44. Bowler RM, Kornblith ES, Gocheva VV, Colledge MA, Bollweg G, Kim Y, et al. Environmental exposure to manganese in air: associations with cognitive functions. Neurotoxicology. 2015;49:139–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Palacios N, Fitzgerald K, Roberts AL, Hart JE, Weisskopf MG, Schwarzschild MA, et al. A prospective analysis of airborne metal exposures and risk of Parkinson disease in the nurses’ health study cohort. Environ Health Perspect. 2014;122(9):933–8.

    PubMed  PubMed Central  Google Scholar 

  46. Malek AM, Barchowsky A, Bowser R, Heiman-Patterson T, Lacomis D, Rana S, et al. Exposure to hazardous air pollutants and the risk of amyotrophic lateral sclerosis. Environ Pollut. 2015;197:181–6.

    Article  CAS  PubMed  Google Scholar 

  47. Zeng Y, Gu D, Purser J, Hoenig H, Christakis N. Associations of environmental factors with elderly health and mortality in China. Am J Public Health. 2010;100(2):298–305.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Hirtz D, Thurman DJ, Gwinn-Hardy K, Mohamed M, Chaudhuri AR, Zalutsky R. How common are the “common” neurologic disorders? Neurology. 2007;68(5):326–37.

    Article  CAS  PubMed  Google Scholar 

  49. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):280–92.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S, et al. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry. 2006;63(2):168–74.

    Article  PubMed  Google Scholar 

  51. Pedersen NL, Gatz M, Berg S, Johansson B. How heritable is Alzheimer’s disease late in life? Findings from Swedish twins. Ann Neurol. 2004;55(2):180–5.

    Article  PubMed  Google Scholar 

  52. Pedersen NL. Reaching the limits of genome-wide significance in Alzheimer disease: back to the environment. JAMA. 2010;303(18):1864–5.

    Article  CAS  PubMed  Google Scholar 

  53. Oudin A, Forsberg B, Adolfsson AN, Lind N, Modig L, Nordin M, et al. Traffic-related air pollution and dementia incidence in northern Sweden: a longitudinal study. Environ Health Persp. 2016;124(3):306–12.

    Google Scholar 

  54. Dorsey ER, Constantinescu R, Thompson JP, Biglan KM, Holloway RG, Kieburtz K, et al. Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology. 2007;68(5):384–6.

    Article  CAS  PubMed  Google Scholar 

  55. Kish SJ, Shannak K, Rajput A, Deck JH, Hornykiewicz O. Aging produces a specific pattern of striatal dopamine loss: implications for the etiology of idiopathic Parkinson’s disease. J Neurochem. 1992;58(2):642–8.

    Article  CAS  PubMed  Google Scholar 

  56. Schapira AH. Science, medicine, and the future: Parkinson’s disease. BMJ. 1999;318(7179):311–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wirdefeldt K, Adami HO, Cole P, Trichopoulos D, Mandel J. Epidemiology and etiology of Parkinson’s disease: a review of the evidence. Eur J Epidemiol. 2011;26(Suppl 1):S1–58.

    Article  PubMed  Google Scholar 

  58. de Lau LM, Breteler MM. Epidemiology of Parkinson’s disease. Lancet Neurol. 2006;5(6):525–35.

    Article  PubMed  Google Scholar 

  59. Lesage S, Brice A. Role of Mendelian genes in “sporadic” Parkinson’s disease. Parkinsonism Relat Disord. 2012;18(Suppl 1):S66–70.

    Article  PubMed  Google Scholar 

  60. Kieburtz K, Wunderle KB. Parkinson’s disease: evidence for environmental risk factors. Mov Disord. 2013;28(1):8–13.

    Article  CAS  PubMed  Google Scholar 

  61. Vojinovic S, Savic D, Lukic S, Savic L, Vojinovic J. Disease relapses in multiple sclerosis can be influenced by air pollution and climate seasonal conditions. Vojnosanit Pregl. 2015;72(1):44–9.

    Article  PubMed  Google Scholar 

  62. Heydarpour P, Amini H, Khoshkish S, Seidkhani H, Sahraian MA, Yunesian M. Potential impact of air pollution on multiple sclerosis in Tehran. Iran Neuroepidemiology. 2014;43(3–4):233–8.

    Article  PubMed  Google Scholar 

  63. Oikonen M, Laaksonen M, Laippala P, Oksaranta O, Lilius EM, Lindgren S, et al. Ambient air quality and occurrence of multiple sclerosis relapse. Neuroepidemiology. 2003;22(1):95–9.

    Article  CAS  PubMed  Google Scholar 

  64. Calabrese M, Magliozzi R, Ciccarelli O, Geurts JJ, Reynolds R, Martin R. Exploring the origins of grey matter damage in multiple sclerosis. Nat Rev Neurosci. 2015;16(3):147–58.

    Article  CAS  PubMed  Google Scholar 

  65. Harbo HF, Gold R, Tintore M. Sex and gender issues in multiple sclerosis. Ther Adv Neurol Disord. 2013;6(4):237–48.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Pelletier D, Hafler DA. Fingolimod for multiple sclerosis. New Engl J Med. 2012;366(4):339–47.

    Article  CAS  PubMed  Google Scholar 

  67. Olsson T, Barcellos LF, Alfredsson L. Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nat Rev Neurol. 2016.

  68. Haulcomb MM, Mesnard-Hoaglin NA, Batka RJ, Meadows RM, Miller WM, Mcmillan KP, et al. Identification of B6SJL mSOD1(G93A) mouse subgroups with different disease progression rates. J Comp Neurol. 2015;523(18):2752–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Naganska E, Matyja E. Amyotrophic lateral sclerosis—looking for pathogenesis and effective therapy. Folia Neuropathol. 2011;49(1):1–13.

    PubMed  Google Scholar 

  70. Robberecht W, Philips T. The changing scene of amyotrophic lateral sclerosis. Nat Rev Neurosci. 2013;14(4):248–64.

    Article  CAS  PubMed  Google Scholar 

  71. Taylor JP, Brown Jr RH, Cleveland DW. Decoding ALS: from genes to mechanism. Nature. 2016;539(7628):197–206.

    Article  PubMed  Google Scholar 

  72. Kristiansson M, Sorman K, Tekwe C, Calderon-Garciduenas L. Urban air pollution, poverty, violence and health - neurological and immunological aspects as mediating factors. Environ Res. 2015;140:511–3.

    Article  CAS  PubMed  Google Scholar 

  73. Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci. 2007;8(1):57–69.

    Article  CAS  PubMed  Google Scholar 

  74. Bjelobaba I, Savic D, Lavrnja I. Multiple sclerosis and neuroinflammation: the overview of current and prospective therapies. Curr Pharm Des. 2016.

  75. Joers V, Tansey MG, Mulas G, Carta AR. Microglial phenotypes in Parkinson’s disease and animal models of the disease. Prog Neurobiol. 2016; doi:10.1016/j.pneurobio.2016.04.006.

    PubMed  Google Scholar 

  76. Schwartz M, Deczkowska A. Neurological disease as a failure of brain-immune crosstalk: the multiple faces of neuroinflammation. Trends Immunol. 2016;37(10):668–79.

    Article  CAS  PubMed  Google Scholar 

  77. Sole-Domenech S, Cruz DL, Capetillo-Zarate E, Maxfield FR. The endocytic pathway in microglia during health, aging and Alzheimer’s disease. Ageing Res Rev. 2016;32:89–103.

    Article  CAS  PubMed  Google Scholar 

  78. Reemst K, Noctor SC, Lucassen PJ, Hol EM. The indispensable roles of microglia and astrocytes during brain development. Front Hum Neurosci. 2016;10:566.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Nelson LH, Lenz KM. Microglia depletion in early life programs persistent changes in social, mood-related, and locomotor behavior in male and female rats. Behav Brain Res. 2017;316:279–93.

    Article  PubMed  Google Scholar 

  80. Hong S, Dissing-Olesen L, Stevens B. New insights on the role of microglia in synaptic pruning in health and disease. Curr Opin Neurobiol. 2016;36:128–34.

    Article  CAS  PubMed  Google Scholar 

  81. Brown GC, Vilalta A. How microglia kill neurons. Brain Res. 2015;1628:288–97.

    Article  CAS  PubMed  Google Scholar 

  82. Correale J. The role of microglial activation in disease progression. Mult Scler J. 2014;20(10):1288–95.

    Article  CAS  Google Scholar 

  83. Naert G, Rivest S. The role of microglial cell subsets in Alzheimer’s disease. Curr Alzheimer Res. 2011;8(2):151–5.

    Article  CAS  PubMed  Google Scholar 

  84. Phani S, Re DB, Przedborski S. The role of the innate immune system in ALS. Front Pharmacol. 2012;3:150.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Brites D, Vaz AR. Microglia centered pathogenesis in ALS: insights in cell interconnectivity. Front Cell Neurosci. 2014;8.

  86. Doring A, Yong VW. The good, the bad and the ugly. Macrophages/microglia with a focus on myelin repair. Front Biosci (Schol Ed). 2011;3:846–56.

    Article  Google Scholar 

  87. German DC, Eagar T, Sonsalla PK. Parkinson’s disease: a role for the immune system. Curr Mol Pharmacol. 2011.

  88. Olsson B, Hertze J, Lautner R, Zetterberg H, Nagga K, Hoglund K, et al. Microglial markers are elevated in the prodromal phase of Alzheimer’s disease and vascular dementia. J Alzheimers Dis. 2013;33(1):45–53.

    CAS  PubMed  Google Scholar 

  89. Calderon-Garciduenas L, Solt AC, Henriquez-Roldan C, Torres-Jardon R, Nuse B, Herritt L, et al. Long-term air pollution exposure is associated with neuroinflammation, an altered innate immune response, disruption of the blood-brain barrier, ultrafine particulate deposition, and accumulation of amyloid beta-42 and alpha-synuclein in children and young adults. Toxicol Pathol. 2008;36(2):289–310.

    Article  CAS  PubMed  Google Scholar 

  90. Calderon-Garciduenas L, Cross JV, Franco-Lira M, Aragon-Flores M, Kavanaugh M, Torres-Jardon R, et al. Brain immune interactions and air pollution: macrophage inhibitory factor (MIF), prion cellular protein (PrPc), interleukin-6 (IL-6), interleukin 1 receptor antagonist (IL-1Ra), and interleukin-2 (IL-2) in cerebrospinal fluid and MIF in serum differentiate urban children exposed to severe vs. low air pollution. Front Neurosci-Switz. 2013;7.

  91. Calderon-Garciduenas L, Franco-Lira M, Mora-Tiscarenno A, Medina-Cortina H, Torres-Jardon R, Kavanaugh M. Early Alzheimer’s and Parkinson’s disease pathology in urban children: friend versus foe responses—it is time to face the evidence. Biomed Res Int. 2013; doi:10.1155/2013/161687.

    PubMed  PubMed Central  Google Scholar 

  92. Calderon-Garciduenas L, Mora-Tiscareno A, Gomez-Garza G, Carrasco-Portugal MD, Perez-Guille B, Flores-Murrieta FJ, et al. Effects of a cyclooxygenase-2 preferential inhibitor in young healthy dogs exposed to air pollution: a pilot study. Toxicol Pathol. 2009;37(5):644–60.

    Article  CAS  PubMed  Google Scholar 

  93. Tyler CR, Zychowski KE, Sanchez BN, Rivero V, Lucas S, Herbert G, et al. Surface area-dependence of gas-particle interactions influences pulmonary and neuroinflammatory outcomes. Part Fibre Toxicol. 2016;13(1):64.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Cheng H, Saffari A, Sioutas C, Forman HJ, Morgan TE, Finch CE. Nanoscale particulate matter from urban traffic rapidly induces oxidative stress and inflammation in olfactory epithelium with concomitant effects on brain. Environ Health Persp. 2016;124(10):1537–46.

    Article  Google Scholar 

  95. Campbell A, Araujo JA, Li H, Sioutas C, Kleinman M. Particulate matter induced enhancement of inflammatory markers in the brains of apolipoprotein E knockout mice. J Nanosci Nanotechnol. 2009;9(8):5099–104.

    Article  CAS  PubMed  Google Scholar 

  96. Campbell A, Oldham M, Becaria A, Bondy SC, Meacher D, Sioutas C, et al. Particulate matter in polluted air may increase biomarkers of inflammation in mouse brain. Neurotoxicology. 2005;26(1):133–40.

    Article  CAS  PubMed  Google Scholar 

  97. Hogan MK, Kovalycsik T, Sun QH, Rajagopalan S, Nelson RJ. Combined effects of exposure to dim light at night and fine particulate matter on C3H/HeNHsd mice. Behav Brain Res. 2015;294:81–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Santiago-Lopez D, Bautista-Martinez JA, Reyes-Hernandez CI, Aguilar-Martinez M, Rivas-Arancibia S. Oxidative stress, progressive damage in the substantia nigra and plasma dopamine oxidation, in rats chronically exposed to ozone. Toxicol Lett. 2010;197(3):193–200.

    Article  CAS  PubMed  Google Scholar 

  99. Mumaw CL, Levesque S, McGraw C, Robertson S, Lucas S, Stafflinger JE, et al. Microglial priming through the lung-brain axis: the role of air pollution-induced circulating factors. FASEB J. 2016;30(5):1880–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Rivas-Arancibia S, Zimbron LFH, Rodriguez-Martinez E, Maldonado PD, Perez GB, Sepulveda-Parada M. Oxidative stress-dependent changes in immune responses and cell death in the substantia nigra after ozone exposure in rat. Front Aging Neurosci. 2015;7:65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Gerlofs-Nijland ME, van Berlo D, Cassee FR, Schins RP, Wang K, Campbell A. Effect of prolonged exposure to diesel engine exhaust on proinflammatory markers in different regions of the rat brain. Part Fibre Toxicol. 2010;7:12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Levesque S, Taetzsch T, Lull ME, Kodavanti U, Stadler K, Wagner A, et al. Diesel exhaust activates and primes microglia: air pollution, neuroinflammation, and regulation of dopaminergic neurotoxicity. Environ Health Perspect. 2011;119(8):1149–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Levesque S, Surace MJ, McDonald J, Block ML. Air pollution and the brain: subchronic diesel exhaust exposure causes neuroinflammation and elevates early markers of neurodegenerative disease. J Neuroinflammation. 2011;8(1):105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Cole TB, Coburn J, Dao K, Roque P, Chang YC, Kalia V, et al. Sex and genetic differences in the effects of acute diesel exhaust exposure on inflammation and oxidative stress in mouse brain. Toxicology. 2016;374:1–9.

    Article  CAS  PubMed  Google Scholar 

  105. Oppenheim HA, Lucero J, Guyot AC, Herbert LM, McDonald JD, Mabondzo A, et al. Exposure to vehicle emissions results in altered blood brain barrier permeability and expression of matrix metalloproteinases and tight junction proteins in mice. Particle and Fibre Toxicology. 2013;10:62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Antonini JM, Sriram K, Benkovic SA, Roberts JR, Stone S, Chen BT, et al. Mild steel welding fume causes manganese accumulation and subtle neuroinflammatory changes but not overt neuronal damage in discrete brain regions of rats after short-term inhalation exposure. Neurotoxicology. 2009;30(6):915–25.

    Article  CAS  PubMed  Google Scholar 

  107. Elder A, Gelein R, Silva V, Feikert T, Opanashuk L, Carter J, et al. Translocation of inhaled ultrafine manganese oxide particles to the central nervous system. Environ Health Perspect. 2006;114(8):1172–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Bolton JL, Smith SH, Huff NC, Gilmour MI, Foster WM, Auten RL, et al. Prenatal air pollution exposure induces neuroinflammation and predisposes offspring to weight gain in adulthood in a sex-specific manner. FASEB J. 2012;26(11):4743–54.

    Article  CAS  PubMed  Google Scholar 

  109. Bolton JL, Huff NC, Smith SH, Mason SN, Foster WM, Auten RL, et al. Maternal stress and effects of prenatal air pollution on offspring mental health outcomes in mice. Environ Health Persp. 2013;121(9):1075–82.

    Google Scholar 

  110. Swanson KJ, Madden MC, Ghio AJ. Biodiesel exhaust: the need for health effects research. Environ Health Perspect. 2007;115(4):496–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Larcombe AN, Kicic A, Mullins BJ, Knothe G. Biodiesel exhaust: the need for a systematic approach to health effects research. Respirology. 2015;20(7):1034–45.

    Article  PubMed  Google Scholar 

  112. Prokopowicz A, Zaciera M, Sobczak A, Bielaczyc P, Woodburn J. The effects of neat biodiesel and biodiesel and HVO blends in diesel fuel on exhaust emissions from a light duty vehicle with a diesel engine. Environ Sci Technol. 2015;49(12):7473–82.

    Article  CAS  PubMed  Google Scholar 

  113. Shojaeefard MH, Etgahni MM, Meisami F, Barari A. Experimental investigation on performance and exhaust emissions of castor oil biodiesel from a diesel engine. Environ Technol. 2013;34(13–16):2019–26.

    Article  CAS  PubMed  Google Scholar 

  114. Mutlu E, Nash DG, King C, Krantz TQ, Preston WT, Kooter IM, et al. Generation and characterization of diesel engine combustion emissions from petroleum diesel and soybean biodiesel fuels and application for inhalation exposure studies. Inhal Toxicol. 2015;27(11):515–32.

    Article  CAS  PubMed  Google Scholar 

  115. Mumaw CL, Surace M, Levesque S, Kodavanti UP, Kodavanti PR, Royland JE, et al. Atypical microglial response to biodiesel exhaust in healthy and hypertensive rats. Neurotoxicology. 2016.

  116. Merino JJ, Muneton-Gomez V, Alvarez MI, Toledano-Diaz A. Effects of CX3CR1 and fractalkine chemokines in amyloid beta clearance and p-Tau accumulation in Alzheimer’s disease (AD) rodent models: is fractalkine a systemic biomarker for AD? Curr Alzheimer Res. 2015.

  117. Zanier ER, Marchesi F, Ortolano F, Perego C, Arabian M, Zoerle T, et al. Fractalkine receptor deficiency is associated with early protection but late worsening of outcome following brain trauma in mice. J Neurotrauma. 2015.

  118. Ginhoux F, Lim S, Hoeffel G, Low D, Huber T. Origin and differentiation of microglia. Front Cell Neurosci. 2013;7:45.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Ousman SS, Kubes P. Immune surveillance in the central nervous system. Nat Neurosci. 2012;15(8):1096–101.

    Article  CAS  PubMed  Google Scholar 

  120. Block ML, Hong JS. Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol. 2005;76(2):77–98.

    Article  CAS  PubMed  Google Scholar 

  121. Heusinkveld HJ, Wahle T, Campbell A, Westerink RH, Tran L, Johnston H, et al. Neurodegenerative and neurological disorders by small inhaled particles. Neurotoxicology. 2016;56:94–106.

    Article  CAS  PubMed  Google Scholar 

  122. Oberdorster G, Elder A, Rinderknecht A. Nanoparticles and the brain: cause for concern? J Nanosci Nanotechnol. 2009;9(8):4996–5007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Maher BA, Ahmed IAM, Karloukovski V, MacLaren DA, Foulds PG, Allsop D, et al. Magnetite pollution nanoparticles in the human brain. P Natl Acad Sci USA. 2016;113(39):10797–801.

    Article  CAS  Google Scholar 

  124. Plascencia-Villa G, Ponce A, Collingwood JF, Arellano-Jimenez MJ, Zhu X, Rogers JT, et al. High-resolution analytical imaging and electron holography of magnetite particles in amyloid cores of Alzheimer’s disease. Sci Rep. 2016;6:24873.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Kreyling WG. Discovery of unique and ENM-specific pathophysiologic pathways: comparison of the translocation of inhaled iridium nanoparticles from nasal epithelium versus alveolar epithelium towards the brain of rats. Toxicol Appl Pharmacol. 2016;299:41–6.

    Article  CAS  PubMed  Google Scholar 

  126. Thomson EM, Kumarathasan P, Calderon-Garciduenas L, Vincent R. Air pollution alters brain and pituitary endothelin-1 and inducible nitric oxide synthase gene expression. Environ Res. 2007;105(2):224–33.

    Article  CAS  PubMed  Google Scholar 

  127. Peters A, Veronesi B, Calderon-Garciduenas L, Gehr P, Chen LC, Geiser M, et al. Translocation and potential neurological effects of fine and ultrafine particles a critical update. Part Fibre Toxicol. 2006;3:13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Cheng H, Davis DA, Hasheminassab S, Sioutas C, Morgan TE, Finch CE. Urban traffic-derived nanoparticulate matter reduces neurite outgrowth via TNFalpha in vitro. J Neuroinflammation. 2016;13:19.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Liu F, Huang YL, Zhang F, Chen Q, Wu BQ, Rui W, et al. Macrophages treated with particulate matter PM2.5 induce selective neurotoxicity through glutaminase-mediated glutamate generation. J Neurochem. 2015;134(2):315–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Campbell A, Daher N, Solaimani P, Mendoza K, Sioutas C. Human brain derived cells respond in a type-specific manner after exposure to urban particulate matter (PM). Toxicol in Vitro. 2014;28(7):1290–5.

    Article  CAS  PubMed  Google Scholar 

  131. Gillespie P, Tajuba J, Lippmann M, Chen LC, Veronesi B. Particulate matter neurotoxicity in culture is size-dependent. Neurotoxicology. 2011.

  132. Sama P, Long TC, Hester S, Tajuba J, Parker J, Chen LC, et al. The cellular and genomic response of an immortalized microglia cell line (BV2) to concentrated ambient particulate matter. Inhal Toxicol. 2007;19(13):1079–87.

    Article  CAS  PubMed  Google Scholar 

  133. Ma JY, Ma JK. The dual effect of the particulate and organic components of diesel exhaust particles on the alteration of pulmonary immune/inflammatory responses and metabolic enzymes. J Environ Sci Health Part C Environ Carcinog Ecotoxicol Rev. 2002;20(2):117–47.

    Article  CAS  Google Scholar 

  134. Hesterberg TW, Long CM, Lapin CA, Hamade AK, Valberg PA. Diesel exhaust particulate (DEP) and nanoparticle exposures: what do DEP human clinical studies tell us about potential human health hazards of nanoparticles? Inhal Toxicol. 2010;22(8):679–94.

    Article  CAS  PubMed  Google Scholar 

  135. Mauderly JL. Diesel emissions: is more health research still needed? Toxicol Sci. 2001;62(1):6–9.

    Article  CAS  PubMed  Google Scholar 

  136. Roque PJ, Dao K, Costa LG. Microglia mediate diesel exhaust particle-induced cerebellar neuronal toxicity through neuroinflammatory mechanisms. Neurotoxicology. 2016;56:204–14.

    Article  CAS  PubMed  Google Scholar 

  137. Levesque S, Taetzsch T, Lull ME, Johnson JA, McGraw C, Block ML. The role of MAC1 in diesel exhaust particle-induced microglial activation and loss of dopaminergic neuron function. J Neurochem. 2013;125(5):756–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Block ML, Wu X, Pei Z, Li G, Wang T, Qin L, et al. Nanometer size diesel exhaust particles are selectively toxic to dopaminergic neurons: the role of microglia, phagocytosis, and NADPH oxidase. FASEB J. 2004;18(13):1618–20.

    CAS  PubMed  Google Scholar 

  139. Chen SH, Oyarzabal EA, Hong JS. Critical role of the Mac1/NOX2 pathway in mediating reactive microgliosis-generated chronic neuroinflammation and progressive neurodegeneration. Curr Opin Pharmacol. 2016;26:54–60.

    Article  CAS  PubMed  Google Scholar 

  140. Pei Z, Pang H, Qian L, Yang S, Wang T, Zhang W, et al. MAC1 mediates LPS-induced production of superoxide by microglia: the role of pattern recognition receptors in dopaminergic neurotoxicity. Glia. 2007;55(13):1362–73.

    Article  PubMed  Google Scholar 

  141. Levesque S, Wilson B, Gregoria V, Thorpe LB, Dallas S, Polikov VS, et al. Reactive microgliosis: extracellular micro-calpain and microglia-mediated dopaminergic neurotoxicity. Brain. 2010;133(Pt 3):808–21.

    Article  PubMed  PubMed Central  Google Scholar 

  142. Hu X, Zhang D, Pang H, Caudle WM, Li Y, Gao H, et al. Macrophage antigen complex-1 mediates reactive microgliosis and progressive dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease. J Immunol. 2008;181(10):7194–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Zhang W, Dallas S, Zhang D, Guo JP, Pang H, Wilson B, et al. Microglial PHOX and Mac-1 are essential to the enhanced dopaminergic neurodegeneration elicited by A30P and A53T mutant alpha-synuclein. Glia. 2007;55(11):1178–88.

    Article  PubMed  Google Scholar 

  144. Zhang D, Hu X, Qian L, Chen SH, Zhou H, Wilson B, et al. Microglial MAC1 receptor and PI3K are essential in mediating beta-amyloid peptide-induced microglial activation and subsequent neurotoxicity. J Neuroinflammation. 2011;8(1):3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, et al. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia. 2007;55(5):453–62.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Zhou J, Huang WQ, Li C, Wu GY, Li YS, Wen SH, et al. Intestinal ischemia/reperfusion enhances microglial activation and induces cerebral injury and memory dysfunction in rats. Crit Care Med. 2012;40(8):2438–48.

    Article  CAS  PubMed  Google Scholar 

  147. Tamagawa E, van Eeden SF. Impaired lung function and risk for stroke: role of the systemic inflammation response? Chest. 2006;130(6):1631–3.

    Article  PubMed  Google Scholar 

  148. Folkmann JK, Risom L, Hansen CS, Loft S, Moller P. Oxidatively damaged DNA and inflammation in the liver of dyslipidemic ApoE−/− mice exposed to diesel exhaust particles. Toxicology. 2007;237(1–3):134–44.

    Article  CAS  PubMed  Google Scholar 

  149. Steenhof M, Janssen NA, Strak M, Hoek G, Gosens I, Mudway IS, et al. Air pollution exposure affects circulating white blood cell counts in healthy subjects: the role of particle composition, oxidative potential and gaseous pollutants—the RAPTES project. Inhal Toxicol. 2014;26(3):141–65.

    Article  CAS  PubMed  Google Scholar 

  150. den Hartigh LJ, Lame MW, Ham W, Kleeman MJ, Tablin F, Wilson DW. Endotoxin and polycyclic aromatic hydrocarbons in ambient fine particulate matter from Fresno, California initiate human monocyte inflammatory responses mediated by reactive oxygen species. Toxicol in Vitro. 2010;24(7):1993–2002.

    Article  CAS  Google Scholar 

  151. Swiston JR, Davidson W, Attridge S, Li GT, Brauer M, van Eeden SF. Wood smoke exposure induces a pulmonary and systemic inflammatory response in firefighters. Eur Respir J. 2008;32(1):129–38.

    Article  CAS  PubMed  Google Scholar 

  152. Ruckerl R, Greven S, Ljungman P, Aalto P, Antoniades C, Bellander T, et al. Air pollution and inflammation (interleukin-6, C-reactive protein, fibrinogen) in myocardial infarction survivors. Environ Health Perspect. 2007;115(7):1072–80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Calderon-Garciduenas L, Cross JV, Franco-Lira M, Aragon-Flores M, Kavanaugh M, Torres-Jardon R, et al. Brain immune interactions and air pollution: macrophage inhibitory factor (MIF), prion cellular protein (PrP(C)), interleukin-6 (IL-6), interleukin 1 receptor antagonist (IL-1Ra), and interleukin-2 (IL-2) in cerebrospinal fluid and MIF in serum differentiate urban children exposed to severe vs. low air pollution. Front Neurosci. 2013;7:183.

    Article  PubMed  PubMed Central  Google Scholar 

  154. Nwokoro C, Ewin C, Harrison C, Ibrahim M, Dundas I, Dickson I, et al. Cycling to work in London and inhaled dose of black carbon. Eur Respir J. 2012;40(5):1091–7.

    Article  CAS  PubMed  Google Scholar 

  155. Calderon-Garciduenas L, Villarreal-Calderon R, Valencia-Salazar G, Henriquez-Roldan C, Gutierrez-Castrellon P, Torres-Jardon R, et al. Systemic inflammation, endothelial dysfunction, and activation in clinically healthy children exposed to air pollutants. Inhal Toxicol. 2008;20(5):499–506.

    Article  CAS  PubMed  Google Scholar 

  156. Calderon-Garciduenas L, Mora-Tiscareno A, Ontiveros E, Gomez-Garza G, Barragan-Mejia G, Broadway J, et al. Air pollution, cognitive deficits and brain abnormalities: a pilot study with children and dogs. Brain Cogn. 2008;68(2):117–27.

    Article  PubMed  Google Scholar 

  157. Cheng H, Saffari A, Sioutas C, Forman HJ, Morgan TE, Finch CE. Nanoscale particulate matter from urban traffic rapidly induces oxidative stress and inflammation in olfactory epithelium with concomitant effects on brain. Environ Health Perspect. 2016;124(10):1537–46.

    Article  PubMed  PubMed Central  Google Scholar 

  158. Chiu IM, von Hehn CA, Woolf CJ. Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nat Neurosci. 2012;15(8):1063–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Kodavanti UP. Stretching the stress boundary: linking air pollution health effects to a neurohormonal stress response. Biochim Biophys Acta. 2016;1860(12):2880–90.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Institute of Environmental Health Sciences/the National Institute of Health [Grant number 1R01ES016951].

Author information

Authors and Affiliations

  1. Department of Anatomy and Cell Biology, The Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Richard L. Jayaraj, Eric A. Rodriguez & Michelle L. Block

  2. Department of Environmental Health, Indiana University Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN, 46202, USA

    Yi Wang

Authors
  1. Richard L. Jayaraj
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eric A. Rodriguez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michelle L. Block
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michelle L. Block.

Ethics declarations

Conflict of Interest

Richard L. Jayaraj, Eric A. Rodriguez, Yi Wang, and Michelle L. Block declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Mechanisms of Toxicity

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jayaraj, R.L., Rodriguez, E.A., Wang, Y. et al. Outdoor Ambient Air Pollution and Neurodegenerative Diseases: the Neuroinflammation Hypothesis. Curr Envir Health Rpt 4, 166–179 (2017). https://doi.org/10.1007/s40572-017-0142-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40572-017-0142-3

Keywords

Search

Navigation