Advertisement

Aluminum as a CNS and Immune System Toxin Across the Life Span

  • Christopher A. Shaw
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1091)

Abstract

In the following, I will consider the impact of aluminum on two major systems, the central nervous system (CNS) and the immune system, across the life span. The article will discuss the presence of aluminum in the biosphere, its history, and the sources of the element. These include food, water cosmetics, some vaccines, and a range of other sources. I will also consider aluminum’s unique chemistry. Finally, in humans and animals, I will consider how aluminum may impact the CNS at various levels of organization and how it may be involved in various neurological disease states across the life span. These disorders include those of infancy and childhood, such as autism spectrum disorder (ASD), as well as those in adulthood, such as in Alzheimer’s disease. The bidirectional nature of CNS–immune system interactions will be considered and put into the context of neurological disorders that have an autoimmune component. I will argue that the exposure to humans and animals to this element needs to be reduced if we are to diminish some CNS and immune system disorders.

Keywords

Aluminum bioavailability Central nervous system Immune system Autoimmunity Autism spectrum disorder 

Notes

Acknowledgments

Thanks are due to Drs. Housam Eidi for constructive comments on a draft of this article. Michael Kuo provided help with references and formatting. Funding was provided by the Luther Allyn Shourds Dean estate. Some of the sections in this article were excerpted from my book, Neural Dynamics of Neurological Disease (John Wiley & Sons, 2017).

References

  1. 1.
    Agmon-Levin N, Paz Z, Israeli E, Shoenfeld Y (2009) Vaccines and autoimmunity. Nat Rev Rheumatol 5(11):648–652PubMedCrossRefGoogle Scholar
  2. 2.
    Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, ... Wyss–Coray T (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging 21(3): 383–421Google Scholar
  3. 3.
    Andrási E, Páli N, Molnár Z, Kösel S (2005) Brain aluminum, magnesium and phosphorus contents of control and Alzheimer-diseased patients. J Alzheimers Dis 7(4):273–284PubMedCrossRefGoogle Scholar
  4. 4.
    Aremu DA, Meshitsuka S (2005) Accumulation of aluminum by primary cultured astrocytes from aluminum amino acid complex and its apoptotic effect. Brain Res 1031(2):284–296PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Ashwood P, Wills S, Van de Water J (2006) The immune response in autism: a new frontier for autism research. J Leukoc Biol 80(1):1–15. https://doi.org/10.1189/jlb.1205707 PubMedCrossRefGoogle Scholar
  6. 6.
    Ashwood P, Enstrom A, Krakowiak P, Hertz-Picciotto I, Hansen RL, Croen LA, Ozonoff S, Pessah IN, Van de Water J (2008) Decreased transforming growth factor beta1 in autism: a potential link between immune dysregulation and impairment in clinical behavioral outcomes. J Neuroimmunol 204(1–2):149–153. https://doi.org/10.1016/j.jneuroim.2008.07.006 PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Ballaban-Gil K, Tuchman R (2000) Epilepsy and epileptiform EEG: association with autism and language disorders. Ment Retard Dev Disabil Res Rev 6(4):300–308. https://doi.org/10.1002/1098-2779(2000)6:4<300::AIDMRDD9>3.0.CO;2-R PubMedCrossRefGoogle Scholar
  8. 8.
    Barrientos RM, Frank MG, Watkins LR, Maier SF (2012) Aging-related changes in neuroimmune-endocrine function: implications for hippocampal-dependent cognition. Horm Behav 62(3):219–227PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Besedovsky HO, Rey A d (2007) Physiology of psychoneuroimmunology: a personal view. Brain Behav Immun 21(1):34–44PubMedCrossRefGoogle Scholar
  10. 10.
    Besedovsky HO, Rey AD (2008) Brain cytokines as integrators of the immune–neuroendocrine network. Handb Neurochem Mol Neurobiol: Neuroimmunol:3–17Google Scholar
  11. 11.
    Bilbo SD, Biedenkapp JC, Der-Avakian A, Watkins LR, Rudy JW, Maier SF (2005a) Neonatal infection-induced memory impairment after lipopolysaccharide in adulthood is prevented via caspase-1 inhibition. J Neurosci 25(35):8000–8009. https://doi.org/10.1523/JNEUROSCI.1748-05.2005 PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Bilbo SD, Levkoff LH, Mahoney JH, Watkins LR, Rudy JW, Maier SF (2005b) Neonatal infection induces memory impairments following an immune challenge in adulthood. Behav Neurosci, 119(1):293–301. https://doi.org/10.1037/0735-7044.119.1.293 PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Blaylock RL, Strunecka A (2009) Immune-glutamatergic dysfunction as a central mechanism of the autism spectrum disorders. Curr Med Chem 16(2):157–170PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Boissé L, Mouihate A, Ellis S, Pittman QJ (2004) Long-term alterations in neuroimmune responses after neonatal exposure to lipopolysaccharide. J Neurosci 24(21):4928–4934PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Bolognin S, Messori L, Drago D, Gabbiani C, Cendron L, Zatta P (2011) Aluminum, copper, iron and zinc differentially alter amyloid-Aβ1–42 aggregation and toxicity. Int J Biochem Cell Biol 43(6):877–885PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Brunner R, Jensen-Jarolim E, Pali-Schöll I (2010) The ABC of clinical and experimental adjuvants—a brief overview. Immunol Lett 128(1):29–35PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Buller KM, Day TA (2002) Systemic administration of interleukin-1β activates select populations of central amygdala afferents. J Comp Neurol 452(3):288–296PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Bush VJ, Moyer TP, Batts KP, Parisi JE (1995) Essential and toxic element concentrations in fresh and formalin-fixed human autopsy tissues. Clin Chem 41(2):284–294PubMedPubMedCentralGoogle Scholar
  19. 19.
    Exley C (2003) A biogeochemical cycle for aluminium? J Inorg Biochem 97(1):1–7PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Exley C (2004) The pro-oxidant activity of aluminum. Free Radic Biol Med 36(3):380–387. https://doi.org/10.1016/j.freeradbiomed.2003.11.017 PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Exley C, Burgess E, Day JP, Jeffery EH, Melethil S, Yokel RA (1996) Aluminum toxicokinetics. J Toxicol Environ Health 48(6):569–584Google Scholar
  22. 22.
    Children’s Hospital of Philadelphia (2013) Vaccine Education Center. Available from: http://vec.chop.edu/service/vaccine-education-center. Last accessed 23 Sept 2016
  23. 23.
    Cho I, Blaser MJ (2012) The human microbiome: at the interface of health and disease. Nat Rev Genet 13(4):260–270PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Chu J, Thomas LM, Watkins SC, Franchi L, Núñez G, Salter RD (2009) Cholesterol-dependent cytolysins induce rapid release of mature IL-1β from murine macrophages in a NLRP3 inflammasome and cathepsin B-dependent manner. J Leukoc Biol 86(5):1227–1238PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Chu Y, Jin X, Parada I, Pesic A, Stevens B, Barres B, Prince DA (2010) Enhanced synaptic connectivity and epilepsy in C1q knockout mice. Proc Natl Acad Sci U S A 107(17):7975–7980PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Cohen AD, Shoenfeld Y (1996) Vaccine-induced autoimmunity. J Autoimmun 9(6):699–703PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Conti B, Tabarean I, Andrei C, Bartfai T (2004) Cytokines and fever. Front Biosci 9:1433–1449PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Couette M, Boisse M-F, Maison P, Brugieres P, Cesaro P, Chevalier X, ..., Authier F-J (2009) Long-term persistence of vaccine-derived aluminum hydroxide is associated with chronic cognitive dysfunction. J Inorg Biochem 103(11):1571–1578PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Crepeaux G, Eidi H, David M-O, Tzavara E, Giros B, Exley C, Curmi PA, Shaw CA, Gherardi RK, Cadusseau J (2015) Highly delayed systemic translocation of aluminium-based adjuvant in CD1 mice following intramuscular injections. J Inorg Biochem 152:199–205PubMedCrossRefGoogle Scholar
  30. 30.
    Crépeaux G, Eidi H, David M-O, Baba-Amer Y, Tzavara E, Giros B et al (2016) Non-linear dose-response of aluminium hydroxide adjuvant particles: selective low dose neurotoxicity. Toxicology 375:48–57PubMedCrossRefGoogle Scholar
  31. 31.
    Davis EP, Granger DA (2009) Developmental differences in infant salivary alpha-amylase and cortisol responses to stress. Psychoneuroendocrinology 34(6):795–804PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Deployment Health Working Group Research Subcommittee (2001) Annual report to congress: federally sponsored research on gulf war veterans’ illnesses for 1999Google Scholar
  33. 33.
    Dietert RR, Dietert JM (2008) Potential for early-life immune insult including developmental immunotoxicity in autism and autism spectrum disorders: focus on critical windows of immune vulnerability. J Toxicol Environ Health B 11(8):660–680CrossRefGoogle Scholar
  34. 34.
    Dinarello CA (1999) Cytokines as endogenous pyrogens. J Infect Dis 179(Supplement 2):S294–S304PubMedCrossRefGoogle Scholar
  35. 35.
    Döllken V (1897) Über die Wirkung des Aluminiums mit besonderer Berucksichtigung der durch das Aluminium verursachten Lasionen im Centralnervensystem. Arch Exp Pathol Pharmacol:98–120Google Scholar
  36. 36.
    Duncan JA, Gao X, Huang MT-H et al (2009) Neisseria gonorrhoeae activates the proteinase cathepsin B to mediate the signaling activities of the NLRP3 and ASC-containing inflammasome. J Immunol 182(10):6460–6469PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Eisenbarth SC, Colegio OR, O’Connor W, Sutterwala FS, Flavell RA (2008) Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453(7198):1122–1126PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Elenkov IJ, Chrousos GP (1999) Stress hormones, Th1/Th2 patterns, pro/anti-inflammatory cytokines and susceptibility to disease. Trends Endocrinol Metab 10(9):359–368PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES (2000) The sympathetic nerve – an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev 52(4):595–638PubMedGoogle Scholar
  40. 40.
    Elinder CG, Ahrengart L, Lidums V, Pettersson E, Sjögren B (1991) Evidence of aluminium accumulation in aluminium welders. Br J Ind Med 48(11):735–738PubMedPubMedCentralGoogle Scholar
  41. 41.
    Eskandari F, Webster JI, Sternberg EM (2003) Neural immune pathways and their connection to inflammatory diseases. Arthritis Res Ther 5(6):251–265PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Exley C (2009a) Aluminium and medicine. Nova Biomedical Books, New York, pp 45–68Google Scholar
  43. 43.
    Exley C (2009b) Darwin, natural selection and the biological essentiality of aluminium and silicon. Trends Biochem Sci 34(12):589–593CrossRefGoogle Scholar
  44. 44.
    Exley C, Siesjö P, Eriksson H (2010) The immunobiology of aluminium adjuvants: how do they really work? Trends Immunol 31(3):103–109PubMedCrossRefGoogle Scholar
  45. 45.
    Exley C, Esiri MM (2006) Severe cerebral congophilic angiopathy coincident with increased brain aluminium in a resident of Camelford, Cornwall, UK. J Neurol Neurosurg Psychiatry 77(7):877–879PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Fombonne E (1999) The epidemiology of autism: a review. Psychol Med 29(4):769–786PubMedCrossRefGoogle Scholar
  47. 47.
    Frank MG, Miguel ZD, Watkins LR, Maier SF (2009) Prior exposure to glucocorticoids sensitizes the neuroinflammatory and peripheral inflammatory responses to E. coli lipopolysaccharide. Brain Behav Immun 24(1):19–30PubMedCrossRefGoogle Scholar
  48. 48.
    Galic MA, Riazi K, Heida JG, Mouihate A, Fournier NM, Spencer SJ, Kalynchuk LE, Teskey GC, Pittman QJ (2008) Postnatal inflammation increases seizure susceptibility in adult rats. J Neurosci, 28(27):6904–6913.  https://doi.org/10.1523/JNEUROSCI.1901-08.2008 PubMedCrossRefGoogle Scholar
  49. 49.
    Galic MA, Spencer SJ, Mouihate A, Pittman QJ (2009) Postnatal programming of the innate immune response. Integr Comp Biol 49(3):237–245PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Gherardi R, Coquet M, Cherin P., Belec L, Moretto P, Dreyfus P, ..., Authier F-J (2001) Macrophagic myofasciitis lesions assess long-term persistence of vaccine-derived aluminium hydroxide in muscle. Brain 124(9):1821–1831PubMedCrossRefGoogle Scholar
  51. 51.
    Gherardi R, Authier F (2012) Macrophagic myofasciitis: characterization and pathophysiology. Lupus 21(2):184–189PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Gies WJ (1911) Some objections to the use of alum baking-powder. J Am Med Assoc LVII(10):816–821CrossRefGoogle Scholar
  53. 53.
    Gitelman HJ, Alderman FR, Kurs-Lasky M, Rockette HE (1995) Serum and urinary aluminum levels of workers in the aluminum industry. Ann Occup Hyg 39(2):181–191PubMedCrossRefGoogle Scholar
  54. 54.
    Goodson A, Robin H, Summerfield W, Cooper I (2004) Migration of bisphenol A from can coatings – effects of damage, storage conditions and heating. Food Addit Contam 21(10):1015–1026PubMedCrossRefGoogle Scholar
  55. 55.
    Griesmaier E, Keller M (2012) Glutamate receptors—prenatal insults, long-term consequences. Pharmacol Biochem Behav 100(4):835–840PubMedCrossRefGoogle Scholar
  56. 56.
    Gunnar MR (1992) Reactivity of the hypothalamic-pituitary-adrenocortical system to stressors in normal infants and children. Pediatrics 90(3):491–497PubMedGoogle Scholar
  57. 57.
    Gunnar MR, Talge NM, Herrera A (2009) Stressor paradigms in developmental studies: what does and does not work to produce mean increases in salivary cortisol. Psychoneuroendocrinology 34(7):953–967PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, ..., Golenbock DT (2008) The NALP3 inflammasome is involved in the innate immune response to amyloid-[beta]. Nat Immunol 9(8):857–865PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Hamza TH, Zabetian CP, Tenesa A, Laederach A, Montimurro J, Yearout D, ..., Payami H (2010) Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat Genet 42(9):781–785PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Hawkes D, Benhamu J, Sidwell T, Miles R, Dunlop RA (2015) Revisiting adverse reactions to vaccines: a critical appraisal of Autoimmune Syndrome Induced by Adjuvants (ASIA). J Autoimmun 59(0):77–84PubMedCrossRefGoogle Scholar
  61. 61.
    He BP, Strong MJ (2000) Motor neuronal death in sporadic amyotrophic lateral sclerosis (ALS) is not apoptotic. A comparative study of ALS and chronic aluminium chloride neurotoxicity in New Zealand white rabbits. Neuropathol Appl Neurobiol 26(2):150–160PubMedCrossRefGoogle Scholar
  62. 62.
    Herbert MR, Ziegler DA, Deutsch CK, O’Brien LM, Lange N, Bakardjiev A, ..., Caviness VS (2003) Dissociations of cerebral cortex, subcortical and cerebral white matter volumes in autistic boys. Brain 126(5):1182–1192PubMedCrossRefGoogle Scholar
  63. 63.
    Hewitson L, Lopresti BJ, Stott C, Mason NS, Tomko J (2010) Influence of pediatric vaccines on amygdala growth and opioid ligand binding in rhesus macaque infants: a pilot study. Acta Neurobiol Exp (Wars) 70(2):147–164Google Scholar
  64. 64.
    Hoegen T, Tremel N, Klein M, Angele B, Wagner H, Kirschning C, ..., Koedel U (2011) The NLRP3 inflammasome contributes to brain injury in pneumococcal meningitis and is activated through ATP-dependent lysosomal cathepsin B release. J Immunol 187(10):5440–5451PubMedCrossRefGoogle Scholar
  65. 65.
    Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, ..., Latz E (2008) Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol 9(8):847–856PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Hotopf M, David A, Hull L, Ismail K, Unwin C, Wessely S (2000) Role of vaccinations as risk factors for ill health in veterans of the Gulf war: cross sectional study. BMJ 320(7246):1363–1367PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Ibi D, Nagai T, Kitahara Y, Mizoguchi H, Koike H, Shiraki A, Takuma K, Kamei H, Noda,Y, Nitta A, Nabeshima T, Yoneda Y, Yamada K (2009) Neonatal polyI:c treatment in mice results in schizophrenia-like behavioral and neurochemical abnormalities in adulthood. Neurosci Res 64(3):297–305.  https://doi.org/10.1016/j.neures.2009.03.015 PubMedCrossRefGoogle Scholar
  68. 68.
    Ichinohe T, Lee HK, Ogura Y et al (2009) Inflammasome recognition of influenza virus is essential for adaptive immune responses. J Exp Med 206(1):79–87PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Israeli E, Agmon-Levin N, Blank M, Shoenfeld Y (2009) Adjuvants and autoimmunity. Lupus 18(13):1217–1225PubMedCrossRefGoogle Scholar
  70. 70.
    Janeway CA, Travers P, Walport M, Capra JD (1999) Immunobiology: the immune system in health and disease, vol 157. Current Biology Publications, New YorkGoogle Scholar
  71. 71.
    Jansen LM, Gispen-de Wied CC, Van der Gaag RJ, ten Hove F, Willemsen-Swinkels SW, Harteveld E, Van Engeland H (2000) Unresponsiveness to psychosocial stress in a subgroup of autistic-like children, multiple complex developmental disorder. Psychoneuroendocrinology 25(8):753–764PubMedCrossRefGoogle Scholar
  72. 72.
    Johnson JO (1995) Neurotransmitters and vulnerability of the developing brain. Brain and Development 17(5):301–306CrossRefGoogle Scholar
  73. 73.
    Johnson R, Brooks B (1984) Possible viral etiology of amyotrophic lateral sclerosis. Neuromuscul Dis 353–359Google Scholar
  74. 74.
    Karlik SJ, Eichhorn GL, Lewis PN, Crapper DR (1980) Interaction of aluminum species with deoxyribonucleic acid. Biochemistry 19(26):5991–5998PubMedCrossRefGoogle Scholar
  75. 75.
    Keele University (2015) Keele meetings. Retrieved 19 May 2015, from http://www.keele.ac.uk/aluminium/keelemeetings/2015
  76. 76.
    Khan Z, Combadiere C, Authier F-J, Itier V, Lux F, Exley C, ..., Cadusseau J (2013) Slow CCL2-dependent translocation of biopersistent particles from muscle to brain. BMC Med 11(1):99Google Scholar
  77. 77.
    Konat GW, Lally BE, Toth AA, Salm AK (2011) Peripheral immune challenge with viral mimic during early postnatal period robustly enhances anxiety-like behavior in young adult rats. Metab Brain Dis 26(3):237–240. https://doi.org/10.1007/s11011-011-9244-z PubMedCrossRefGoogle Scholar
  78. 78.
    Krewski D, Yokel RA, Nieboer E, Borchelt D, Cohen J, Harry J, ..., Rondeau V (2007) Human health risk assessment for aluminium, aluminium oxide, and aluminium hydroxide. J Toxicol Environ Health B 10(suppl 1):1–269CrossRefGoogle Scholar
  79. 79.
    Lévesque L, Mizzen CA, McLachlan DR, Fraser PE (2000) Ligand specific effects on aluminum incorporation and toxicity in neurons and astrocytes. Brain Res 877(2):191–202PubMedCrossRefGoogle Scholar
  80. 80.
    Li H, Nookala S, Re F (2007) Aluminum hydroxide adjuvants activate caspase-1 and induce IL-1β and IL-18 release. J Immunol 178(8):5271–5276PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Li H, Willingham SB, Ting JP-Y, Re F (2008) Cutting edge: inflammasome activation by alum and alum’s adjuvant effect are mediated by NLRP3. J Immunol 181(1):17–21PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Li X-b, Zheng H, Zhang Z-r, Li M, Huang Z-y, Schluesener HJ, ..., Xu, S-q (2009) Glia activation induced by peripheral administration of aluminum oxide nanoparticles in rat brains. Nanomedicine 5(4):473–479CrossRefGoogle Scholar
  83. 83.
    Li D, Tomljenovic L, Li Y Shaw CA (2017) Activation of innate immune genes in the mouse brain by aluminum injection. J Inorg Biochem. In pressGoogle Scholar
  84. 84.
    Lidsky TI (2014) Is the aluminum hypothesis dead? J Occup Environ Med 56(5 Suppl):S73–S79PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Ljunggren KG, Lidums V, Sjögren B (1991) Blood and urine concentrations of aluminium among workers exposed to aluminium flake powders. Br J Ind Med 48(2):106–109PubMedPubMedCentralGoogle Scholar
  86. 86.
    Louis GMB, Smarr MM, Patel CJ (2017) The exposome research paradigm: an opportunity to understand the environmental basis for human health and disease. Curr Environ Health Rep 4(1):89–98CrossRefGoogle Scholar
  87. 87.
    Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, Harris TH, Kipnis J (2015) Structural and functional features of central nervous system lymphatic vessels. Nature 523(7560):337–341PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Luján L, Pérez M, Salazar E, Álvarez N, Gimeno M, Pinczowski P, ..., Chapullé J (2013) Autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA syndrome) in commercial sheep. Immunol Res 56(2–3):317–324PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Lukiw WJ, Alexandrov PN, Zhao Y, Hill JM, Bhattacharjee S (2012) Spreading of Alzheimer’s disease inflammatory signaling through soluble micro-RNA. Neuroreport 23(10):621–626PubMedPubMedCentralGoogle Scholar
  90. 90.
    Mariathasan S, Weiss DS, Newton K, McBride J, O'Rourke K, Roose-Girma M, ..., Dixit VM (2006) Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440(7081):228–232PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J (2006) Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440(7081):237–241PubMedCrossRefGoogle Scholar
  92. 92.
    Martell J (2017). The McIntyre powder project: a retrospective study of the health effects of respirable aluminium dust in a cohort of Ontario miners. The 12th Keele Meeting on Aluminum. AbstractGoogle Scholar
  93. 93.
    McLachlan DR, Kruck TP, Lukiw WJ, Krishnan SS (1991) Would decreased aluminum ingestion reduce the incidence of Alzheimer’s disease? CMAJ 145(7):793–804PubMedPubMedCentralGoogle Scholar
  94. 94.
    Meroni PL (2011) Autoimmune or auto-inflammatory syndrome induced by adjuvants (ASIA): old truths and a new syndrome? J Autoimmun 36(1):1–3PubMedCrossRefGoogle Scholar
  95. 95.
    Minshall C, Nadal J, Exley C (2014) Aluminium in human sweat. J Trace Elem Med Biol 28(1):87–88PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Molloy CA, Morrow AL, Meinzen-Derr J, Schleifer K, Dienger K, Manning-Courtney P, Altaye M, Wills-Karp M (2006) Elevated cytokine levels in children with autism spectrum disorder. J Neuroimmunol 172(1–2):198–205. https://doi.org/10.1016/j.jneuroim.2005.11.007 PubMedCrossRefGoogle Scholar
  97. 97.
    Munson J, Dawson G, Abbott R, Faja S, Webb SJ, Friedman SD, ..., Dager SR (2006) Amygdalar volume and behavioral development in autism. Arch Gen Psychiatry 63(6):686–693PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Nadeau S, Rivest S (2003) Glucocorticoids play a fundamental role in protecting the brain during innate immune response. J Neurosci 23(13):5536–5544PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Newschaffer CJ, Croen LA, Daniels J, Giarelli E, Grether JK, Levy SE, Mandell DS, Miller LA, Pinto-Martin J, Reaven J, Reynolds AM, Rice CE, Schendel D, Windham GC (2007) The epidemiology of autism spectrum disorders. Annu Rev Public Health 28:235–258. https://doi.org/10.1146/annurev.publhealth.28.021406.144007 CrossRefGoogle Scholar
  100. 100.
    Nunomura A, Tamaoki T, Motohashi N, Nakamura M, McKeel DW Jr, Tabaton M, Lee HG, Smith MA, Perry G, Zhu X (2012) The earliest stage of cognitive impairment in transition from normal aging to Alzheimer disease is marked by prominent RNA oxidation in vulnerable neurons. J Neuropathol Exp Neurol 71(3):233–241PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Nurchi V, Crisponi G, Bertolasi V, Faa G, Remelli M (2012) Aluminium-dependent human diseases and chelating properties of aluminium chelators for biomedical applications. In: Linert W, Kozlowski H (eds) Metal ions in neurological systems. Springer, Vienna, pp 103–123CrossRefGoogle Scholar
  102. 102.
    Orfila MJB (1814) Traité des Poisons: tirés des regnes minéral, végétal et animal, ou Toxicologie générale, considerée sous les rapports de la physiologie, de la pathologie et de la médicine légale: chez Crochard, libraire, rue de l’École-de-Médecine, no. 3Google Scholar
  103. 103.
    Orton SM, Herrera BM, Yee IM, Valdar W, Ramagopalan SV, Sadovnick AD, Ebers GC, Canadian Collaborative Study, Group. (2006) Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol 5(11):932–936.  https://doi.org/10.1016/S1474-4422(06)70581-6 PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Pardo CA, Vargas DL, Zimmerman AW (2005) Immunity, neuroglia and neuroinflammation in autism. Int Rev Psychiatry 17(6):485–495PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Passeri E, Villa C, Couette M, Itti E, Brugieres P, Cesaro P, ..., Authier F-J (2011) Long-term follow-up of cognitive dysfunction in patients with aluminum hydroxide-induced macrophagic myofasciitis (MMF). J Inorg Biochem 105(11):1457–1463PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Perl DP, Brody A (1980) Alzheimer’s disease: x-ray spectrometric evidence of aluminum accumulation in neurofibrillary tangle-bearing neurons. Science 208(4441):297–299PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Perl DP (1985) Relationship of aluminum to Alzheimer’s disease. Environ Health Perspect 63:149–153PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Perl DP, Good PF (1991) Aluminum, Alzheimer’s disease, and the olfactory system. Ann N Y Acad Sci 640:8–13PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Petrik MS, Wong MC, Tabata RC, Garry RF, Shaw CA (2007) Aluminum adjuvant linked to Gulf war illness induces motor neuron death in mice. Neuro Mol Med 9(1):83–100CrossRefGoogle Scholar
  110. 110.
    Petrilli V, Papin S, Dostert C, Mayor A, Martinon F, Tschopp J (2007) Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ 14(9):1583–1589PubMedCrossRefGoogle Scholar
  111. 111.
    Pickard L, Noël J, Henley JM, Collingridge GL, Molnar E (2000) Developmental changes in synaptic AMPA and NMDA receptor distribution and AMPA receptor subunit composition in living hippocampal neurons. J Neurosci 20(21):7922–7931PubMedCrossRefGoogle Scholar
  112. 112.
    Poot-Poot W, Teresa Hernandez-Sotomayor SM (2011) Aluminum stress and its role in the phospholipid signaling pathway in plants and possible biotechnological applications. IUBMB Life 63(10):864–872PubMedCrossRefGoogle Scholar
  113. 113.
    Porges SW (2005) The vagus: a mediator of behavioral and physiologic features associated with autism. In: Bauman ML, Kemper TL (eds) The neurobiology of autism, 2nd edn. Johns Hopkins University Press, Maryland, pp 65–78Google Scholar
  114. 114.
    Purcell AE, Jeon OH, Zimmerman AW, Blue ME, Pevsner J (2001) Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurology 57(9):1618–1628PubMedCrossRefGoogle Scholar
  115. 115.
    Rigolet M, Aouizerate J, Couette M, Ragunathan-Thangarajah N, Aoun-Sebaiti M, Gherardi RK, ..., Authier FJ (2014) Clinical features in patients with long-lasting macrophagic myofasciitis. Front Neurol 5:230Google Scholar
  116. 116.
    Riihimäki V, Aitio A (2012) Occupational exposure to aluminum and its biomonitoring in perspective. Crit Rev Toxicol 42(10):827–853CrossRefGoogle Scholar
  117. 117.
    Reusche E, Koch V, Friedrich HJ, Nünninghoff D, Stein P, Rob PM (1996) Correlation of drug-related aluminum intake and dialysis treatment with deposition of argyrophilic aluminum-containing inclusions in CNS and in organ systems of patients with dialysis-associated encephalopathy. Clin Neuropathol 15(6):342–347PubMedGoogle Scholar
  118. 118.
    Saiyed SM, Yokel RA (2005) Aluminium content of some foods and food products in the USA, with aluminium food additives. Food Addit Contam 22(3):234–244PubMedCrossRefGoogle Scholar
  119. 119.
    Sakamoto T, Ogasawara Y, Ishii K, Takahashi H, Tanabe S (2004) Accumulation of aluminum in ferritin isolated from rat brain. Neurosci Lett 366(3):264–267PubMedCrossRefPubMedCentralGoogle Scholar
  120. 120.
    Seneff S, Davidson R, Liu J (2012) Empirical data confirm autism symptoms related to aluminum and acetaminophen exposure. Entropy 14(11):2227–2253CrossRefGoogle Scholar
  121. 121.
    Scheperjans F, Aho V, Pereira PAB, Koskinen K, Paulin L, Pekkonen E, ..., Auvinen P (2014) Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov Disord 30(3):350–358PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Shaw CA (2017) Neural dynamics of neurological disease. Wiley, BostonCrossRefGoogle Scholar
  123. 123.
    Shaw CA, Li Y, Tomljenovic L (2013) Administration of aluminum to neonatal mice in vaccine in vaccine-relevant amounts is associated with adverse long term neurological outcomes. J Inorg Chem 128:237–244Google Scholar
  124. 124.
    Shaw CA, Petrik MS (2009) Aluminum hydroxide injections lead to motor deficits and motor neuron degeneration. J Inorg Biochem 103(11):1555–1562PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Shaw CA, Seneff S, Kette, ..., Davidson RM (2014) Aluminum-induced entropy in biological systems: implications for neurological disease. J Toxicol 2014(491316):1–27CrossRefGoogle Scholar
  126. 126.
    Shaw CA, Tomljenovic L (2013) Aluminum in the central nervous system (CNS): toxicity in humans and animals, vaccine adjuvants, and autoimmunity. Immunol Res 56(2–3):304–316PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Sheth S, Li Y, Shaw CA (2015) Effects of aluminum adjuvants on social behavior in mice. The 11th Keele Meeting on Aluminum. AbstractGoogle Scholar
  128. 128.
    Shimmura C, Suda S, Tsuchiya KJ, Hashimoto K, Ohno K, Matsuzaki H, ..., Mori N (2011) Alteration of plasma glutamate and glutamine levels in children with high-functioning autism. PLoS ONE 6(10):e25340PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Shinohe A, Hashimoto K, Nakamura K, Tsujii M, Iwata Y, Tsuchiya KJ, ..., Mori N (2006) Increased serum levels of glutamate in adult patients with autism. Prog Neuro-Psychopharmacol Biol Psychiatry 30(8):1472–1477Google Scholar
  130. 130.
    Shoenfeld Y, Agmon-Levin N (2011) ‘ASIA’ – autoimmune/inflammatory syndrome induced by adjuvants. J Autoimmun 36(1):4–8PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Sienkiewicz D, Kułak W, Okurowska-Zawada B, Paszko-Patej G (2012) Neurologic adverse events following vaccination. Prog Health Sci 2(1):129Google Scholar
  132. 132.
    Soumiya H, Fukumitsu H, Furukawa S (2011) Prenatal immune challenge compromises the normal course of neurogenesis during development of the mouse cerebral cortex. J Neurosci Res 89(10):1575–1585. https://doi.org/10.1002/jnr.22704 PubMedCrossRefGoogle Scholar
  133. 133.
    Spencer SJ, Heida JG, Pittman QJ (2005) Early life immune challenge–effects on behavioural indices of adult rat fear and anxiety. Behav Brain Res 164(2):231–238. https://doi.org/10.1016/j.bbr.2005.06.032 PubMedCrossRefGoogle Scholar
  134. 134.
    Spencer SJ, Hyland NP, Sharkey KA, Pittman QJ (2007) Neonatal immune challenge exacerbates experimental colitis in adult rats: potential role for TNF-alpha. Am J Physiol Regul Integr Comp Physiol 292(1):R308–R315. https://doi.org/10.1152/ajpregu.00398.2006 PubMedCrossRefGoogle Scholar
  135. 135.
    Strong MJ (2010) The evidence for altered RNA metabolism in amyotrophic lateral sclerosis (ALS). J Neurol Sci 288(1–2):1–12PubMedCrossRefGoogle Scholar
  136. 136.
    Strong MJ, Garruto RM (1991) Chronic aluminum-induced motor neuron degeneration: clinical, neuropathological and molecular biological aspects. Can J Neurol Sci 18(3 Suppl):428–431PubMedCrossRefGoogle Scholar
  137. 137.
    Strunecká A, Strunecky O, Patocka J (2002) Fluoride plus aluminum: useful tools in laboratory investigations, but messengers of false information. Physiol Res 51(6):557–564PubMedGoogle Scholar
  138. 138.
    Theoharides TC, Kempuraj D, Redwood, L (2009) Autism: an emerging ‘neuroimmune disorder’ in search of therapy. Expert Opin Pharmacother 10(13):2127–2143. https://doi.org/10.1517/14656560903107789 PubMedCrossRefGoogle Scholar
  139. 139.
    Tomljenovic L (2011) Aluminum and Alzheimer’s disease: after a century of controversy, is there a plausible link? J Alzheimers Dis 23(4):567–598PubMedCrossRefGoogle Scholar
  140. 140.
    Tomljenovic L, Shaw CA (2011) Do aluminum vaccine adjuvants contribute to the rising prevalence of autism? J Inorg Biochem 105(11):1489–1499PubMedCrossRefGoogle Scholar
  141. 141.
    Tomljenovic L, Shaw CA (2012) Mechanisms of aluminum adjuvant toxicity and autoimmunity in pediatric populations. Lupus 21(2):223–230PubMedCrossRefGoogle Scholar
  142. 142.
    Tschopp J, Martinon F, Burns K (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 10:417–426PubMedCrossRefGoogle Scholar
  143. 143.
    Tsumiyama K, Miyazaki Y, Shiozawa S (2009) Self-organized criticality theory of autoimmunity. PLoS One 4(12):e8382PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Tuchman R, Rapin I (2002) Epilepsy in autism. Lancet Neurol, 1(6):352–358PubMedCrossRefGoogle Scholar
  145. 145.
    Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA (2005) Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 57(1):67–81PubMedCrossRefGoogle Scholar
  146. 146.
    Varner JA, Jensen KF, Horvath W, Isaacson RL (1998) Chronic administration of aluminum-fluoride or sodium-fluoride to rats in drinking water: alterations in neuronal and cerebrovascular integrity. Brain Res 784(1–2):284–298PubMedCrossRefGoogle Scholar
  147. 147.
    Wakayama I, Nerurkar VR, Strong MJ, Garruto RM (1996) Comparative study of chronic aluminum-induced neurofilamentous aggregates with intracytoplasmic inclusions of amyotrophic lateral sclerosis. Acta Neuropathol 92(6):545–554PubMedCrossRefGoogle Scholar
  148. 148.
    Walsh JG, Muruve DA, Power C (2014) Inflammasome in the CNS. Nat Rev Neurosci 15(2):84–97PubMedCrossRefGoogle Scholar
  149. 149.
    Walton JR (2006) Aluminum in hippocampal neurons from humans with Alzheimer’s disease. Neurotoxicology 27(3):385–394PubMedCrossRefGoogle Scholar
  150. 150.
    Walton JR (2007) A longitudinal study of rats chronically exposed to aluminum at human dietary levels. Neurosci Lett 412(1):29–33PubMedCrossRefGoogle Scholar
  151. 151.
    Walton JR (2009a) Brain lesions comprised of aluminum-rich cells that lack microtubules may be associated with the cognitive deficit of Alzheimer’s disease. Neurotoxicology 30(6):1059–1069PubMedCrossRefGoogle Scholar
  152. 152.
    Walton JR (2009b) Functional impairment in aged rats chronically exposed to human range dietary aluminum equivalents. Neurotoxicology 30(2):182–193PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Walton JR, Wang MX (2009) APP expression, distribution and accumulation are altered by aluminum in a rodent model for Alzheimer’s disease. J Inorg Biochem 103(11):1548–1554PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Wilder RL (1995) Neuroendocrine-immune system interactions and autoimmunity. Annu Rev Immunol 13(1):307–338PubMedCrossRefGoogle Scholar
  155. 155.
    Xu Y, Day TA, Buller KM (1999) The central amygdala modulates hypothalamic–pituitary–adrenal axis responses to systemic interleukin-1β administration. Neuroscience 94(1):175–183PubMedCrossRefGoogle Scholar
  156. 156.
    Yokel RA (2002) Brain uptake, retention, and efflux of aluminum and manganese. Environ Health Perspect 110(Suppl 5):699–704PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Yokel RA (2006) Blood-brain barrier flux of aluminum, manganese, iron and other metals suspected to contribute to metal-induced neurodegeneration. J Alzheimers Dis 10(2–3):223–253PubMedCrossRefGoogle Scholar
  158. 158.
    Yokel RA, McNamara PJ (2001) Aluminium toxicokinetics: an updated mini review. Pharmacol Toxicol 88(4):159–167PubMedCrossRefGoogle Scholar
  159. 159.
    Zafrir Y, Agmon-Levin N, Paz Z, Shilton T, Shoenfeld Y (2012) Autoimmunity following hepatitis B vaccine as part of the spectrum of ‘autoimmune (auto-inflammatory) syndrome induced by adjuvants’ (ASIA): analysis of 93 cases. Lupus 21(2):146–152PubMedCrossRefGoogle Scholar
  160. 160.
    Zhou R, Yazdi AS, Menu P, Tschopp J (2011) A role for mitochondria in NLRP3 inflammasome activation. Nature 469(7329):221–225. https://doi.org/10.1038/nature09663 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Christopher A. Shaw
    • 1
  1. 1.Department of Ophthalmology and Visual SciencesUniversity of British ColumbiaVancouverCanada

Personalised recommendations