Skip to main content

Advertisement

Log in

Neuroinflammation, immune system and Alzheimer disease: searching for the missing link

  • Review
  • Published:
Aging Clinical and Experimental Research Aims and scope Submit manuscript

Abstract

Due to an increasingly aging population, Alzheimer disease (AD) represents a crucial issue for the healthcare system because of its widespread prevalence and the burden of its care needs. Several hypotheses on AD pathogenesis have been proposed and current therapeutical strategies have shown limited effectiveness. In the last decade, more evidence has supported a role for neuroinflammation and immune system dysregulation in AD. It remains unclear whether astrocytes, microglia and immune cells influence disease onset, progression or both. Amyloid-β peptides that aggregate extracellularly in the typical neuritic plaques generate a constant inflammatory environment. This causes a prolonged activation of microglial and astroglial cells that potentiate neuronal damage and provoke the alteration of the blood brain barrier (BBB), damaging the permeability of blood vessels. Recent data support the role of the BBB as a link between neuroinflammation, the immune system and AD. Hence, a thorough investigation of the neuroinflammatory and immune system pathways that impact neurodegeneration and novel exciting findings such as microglia-derived microvesicles, inflammasomes and signalosomes will ultimately enhance our understanding of the pathological process. Eventually, we should proceed with caution in defining a causal or consequential role of neuroinflammation in AD, but rather focus on identifying its exact pathological contribution.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders, 5th edn. American Psychiatric Publishing, Arlington

    Google Scholar 

  2. Fratiglioni L, Winblad B, von Strauss E (2007) Prevention of Alzheimer’s disease and dementia. Major findings from the Kungsholmen Project. Physiol Behav 92:98–104

    CAS  PubMed  Google Scholar 

  3. Kinsella K, Velkoff VA (2002) The demographics of aging. Aging Clin Exp Res 14:159–169

    PubMed  Google Scholar 

  4. Rogers J, Cooper NR, Webster S et al (1992) Complement activation by beta-amyloid in Alzheimer disease. Proc Natl Acad Sci USA 89:10016–10020

    CAS  PubMed  PubMed Central  Google Scholar 

  5. McGeer PL, McGeer EG (2013) The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy. Acta Neuropathol 126:479–497

    CAS  PubMed  Google Scholar 

  6. Heneka MT, O’banion MK (2007) Inflammatory processes in Alzheimer’s disease. J Neuroimmunol 184:69–91

    CAS  PubMed  Google Scholar 

  7. Damani MR, Zhao L, Fontainhas AM et al (2011) Age-related alterations in the dynamic behavior of microglia. Aging Cell 10:263–276

    CAS  PubMed  Google Scholar 

  8. Sierra A, Gottfried-Blackmore AC, Mc Ewen BS et al (2007) Microglia derived from aging mice exhibit altered inflammatory profile. Glia 55:412–424

    PubMed  Google Scholar 

  9. Harry GJ (2013) Microglia during development and aging. Pharmacol Ther 139:313–326

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Parihar MS, Brewer GJ (2007) Simultaneous age-related depolarization of mitochondrial membrane potential and increased mitochondrial reactive oxygen species production correlate with age-related glutamate excitotoxicity in rat hippocampal neurons. J Neurosci Res 85:1018–1032

    CAS  PubMed  Google Scholar 

  11. Kierdorf K, Prinz M (2013) Factors regulating microglia activation. Front Cell Neurosci 7:44

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Czlonkowska A, Kurkowska-Jastrzebska I (2011) Inflammation and gliosis in neurological diseases–clinical implications. J Neuroimmunol 231:78–85

    CAS  PubMed  Google Scholar 

  13. Liu W, Tang Y, Feng J (2011) Cross talk between activation of microglia and astrocytes in pathological conditions in the central nervous system. Life Sci 89:141–146

    CAS  PubMed  Google Scholar 

  14. Cras P, Smith MA, Richey PL et al (1995) Extracellular neurofibrillary tangles reflect neuronal loss and provide further evidence of extensive protein cross-linking in Alzheimer disease. Acta Neuropathol 89:291–295

    CAS  PubMed  Google Scholar 

  15. Seubert P, Vigo-Pelfrey C, Esch F et al (1992) Isolation and quantification of soluble Alzheimer’s beta-peptide from biological fluids. Nature 359:325–327

    CAS  PubMed  Google Scholar 

  16. Sardi F, Fassina L, Venturini L et al (2011) Alzheimer’s disease, autoimmunity and inflammation. The good, the bad and the ugly. Autoimmun Rev 11:149–153

    CAS  PubMed  Google Scholar 

  17. Tejera D, Heneka MT (2016) Microglia in Alzheimer’s disease: the good, the bad and the ugly. Curr Alzheimer Res 13:370–380

    CAS  PubMed  Google Scholar 

  18. Abbott NJ, Patabendige AA, Dolman DE et al (2010) Structure and function of the blood brain barrier. Neurobiol Dis 37:13–25

    CAS  PubMed  Google Scholar 

  19. Crane IJ, Liversidge J (2008) Mechanism of leukocyte migration across the blood–retina-barrier. Semin Immunopathol 30:165–177

    PubMed  PubMed Central  Google Scholar 

  20. Sallusto F, Impellizieri D, Basso C et al (2012) T-cell trafficking in the central nervous system. Immunol Rev 248:216–227

    PubMed  Google Scholar 

  21. Engelhardt B, Coisne C (2011) Fluids and barriers of the CNS establish immune privilege by confining immune surveillance to a two-walled castle moat surrounding the CNS castle. Fluids Barriers CNS 8:4

    PubMed  PubMed Central  Google Scholar 

  22. Lyck R, Engelhardt B (2012) Going against the tide—how encephalitogenic T cells breach the blood brain barrier. J Vasc Res 49:497–509

    PubMed  Google Scholar 

  23. Von Andrian UH, Mackay CR (2000) T-cell function and migration. Two sides of the same coin. N Engl J Med 343:1020–1034

    Google Scholar 

  24. Hickey WF, Hsu BL, Kimura H (1991) T lymphocyte entry into the central nervous system. J Neurosci Res 28:254–260

    CAS  PubMed  Google Scholar 

  25. Owens T, Bechmann I, Engelhardt B (2008) Perivascular spaces and the two steps to neuroinflammation. J Neuropathol Exp Neurol 67:1113–1121

    PubMed  Google Scholar 

  26. Steiner O (2010) Differential roles for endothelial ICAM-1, ICAM-2 and VCAM-1 in shear resistant T cell arrest, polarization, and directed crawling on BBB endothelium. J Immunol 185:4846–4855

    CAS  PubMed  Google Scholar 

  27. Bauer M, Brakebusch C, Coisne C et al (2009) Beta 1 integrins differentially control extravasation of inflammatory cell subsets into the CNS during autoimmunity. Proc Natl Acad Sci USA 106:1920–1925

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Shattil SJ, Kim C, Ginsberg MH (2010) The final steps of integrin activation: the end game. Nat Rev Mol Cell Biol 11:288–300

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Bullard DC, Hu X, Schoeb TR et al (2007) Intercellular adhesion molecule-1 expression is required on multiple cell types for development of experimental autoimmune encephalomyelitis. J Immunol 178:851–857

    CAS  PubMed  Google Scholar 

  30. Cashman JR, Ghirmai S, Abel KJ et al (2008) Immune defects in Alzheimer’s disease: new medications development. BMC Neurosci 9(Suppl 2):S13

    PubMed  PubMed Central  Google Scholar 

  31. Saresella M, Calabrese E, Marventano I et al (2010) PD1 negative and PD1 positive CD4+ T regulatory cells in mild cognitive impairment and Alzheimer’s disease. J Alzheimer Dis 21:927–938

    CAS  Google Scholar 

  32. Wang L, Xie Y, Zhu LJ et al (2010) An Association between immunosenescence and CD4+ CD25+ regulatory T Cells: a systematic review. Biomed Environ Sci 23:327–332

    CAS  PubMed  Google Scholar 

  33. Larbia A, Paweleca G, Witkowskib JM et al (2009) Dramatic shifts in circulating CD4 but not CD8 T cell subsets in mild Alzheimer’s disease. J Alzheimer Dis 17:91–103

    Google Scholar 

  34. Hanke ML, Kielian T (2011) Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential. Clin Sci 121:367–387

    CAS  Google Scholar 

  35. Landreth GE, Reed-Geaghan EG (2009) TLRs in Alzheimer’s disease. Curr Top Microbiol Immunol 336:137–153

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Riazi K, Galic MA, Pittman QJ (2010) Contributions of peripheral inflammation to seizure susceptibility: cytokines and brain excitability. Epilepsy Res 89:34–42

    CAS  PubMed  Google Scholar 

  37. Asari Y, Majima M, Sugimoto K et al (1996) Release site of TNF alpha after intravenous and intraperitoneal injection of LPS from Escherichia coli in rats. Shock 5:208–212

    CAS  PubMed  Google Scholar 

  38. Ho Y, Lin Y, Wu C et al (2015) Peripheral inflammation increases seizure susceptibility via the induction of neuroinflammation and oxidative stress in the hippocampus. J Biomed Sci 22:46

    PubMed  PubMed Central  Google Scholar 

  39. Goehler LE, Gaykema RP, Nguyen KT et al (1999) Interleukin-1beta in immune cells of the abdominal vagus nerve: A link between the immune and nervous systems? J Neurosci 19:2799–2806

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Nakano Y, Furube E, Morita S et al (2015) Astrocytic TLR4 expression and LPS-induced nuclear translocation of STAT3 in the sensory circumventricular organs of adult mouse brain. J Neuroimmunol 278:144–158

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  42. Nguyen MD, D’Aigle T, Gowing G et al (2004) Exacerbation of motor neuron disease by chronic stimulation of innate immunity in a mouse model of amyotrophic lateral sclerosis. J Neurosci 24:1340–1349

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Chen Z, Jalabi W, Shpargel KB et al (2012) Lipopolysaccharide-induced microglial activation and neuroprotection against experimental brain injury is independent of hematogenous TLR4. J Neurosci 32:11706–11715

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Henry CJ, Huang Y, Wynne AM et al (2009) Peripheral lipopolysaccharide challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1beta and anti-inflammatory IL-10 cytokines. Brain Behav Immun 23:309–317

    CAS  PubMed  Google Scholar 

  45. Liu X, Wu Z, Hayashi Y et al (2012) Age-dependent neuroinflammatory responses and deficits in long-term potentiation in the hippocampus during systemic inflammation. Neuroscience 216:133–142

    CAS  PubMed  Google Scholar 

  46. Turola E, Furlan R, Bianco F et al (2012) Microglial Microvesicle Secretion and Intercellular Signaling. Front Physiol 3:149

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Rajendran L, Honsho M, Zahn TR et al (2006) Proc Natl Acad Sci USA 2006:11172–11177

    Google Scholar 

  48. Bianco F, Pravettoni E, Colombo A et al (2005) Astrocyte-derived ATP induces vesicle shedding and IL-1 beta release from microglia. J Immunol 174:7268–7277

    CAS  PubMed  Google Scholar 

  49. Gonnord P, Delarasse C, Auger R et al (2009) Palmitoylation of the P2X7 receptor, an ATP-gated channel, controls its expression and association with lipid rafts. FASEB J 23:795–805

    CAS  PubMed  Google Scholar 

  50. Antonucci F, Turola E, Riganti L et al (2012) Microvesicles released from microglia stimulate synaptic activity via enhanced sphingolipid metabolism. EMBO J 31:1240

    Google Scholar 

  51. Verderio C, Muzio L, Turola E et al (2012) Myeloid microvesicles are a marker and a therapeutic target for neuroinflammation. Ann Neurol 72:610–624

    CAS  PubMed  Google Scholar 

  52. Joshi P, Turola E, Ruiz A et al (2014) Microglia convert aggregated amyloid-β into neurotoxic forms through the shedding of microvesicles. Cell Death Differ 21:582–593

    CAS  PubMed  Google Scholar 

  53. Lamkanfi M, Dixit VM (2012) Inflammasomes and their roles in health and disease. Annu Rev Cell Dev Biol 28:137–161

    CAS  PubMed  Google Scholar 

  54. Kayagaki N, Warming S, Lamkanfi M et al (2011) Non-canonical inflammasome activation targets caspase-11. Nature 479:117–121

    CAS  PubMed  Google Scholar 

  55. Martinon F, Burns K, Tschopp J (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 2:417–426

    Google Scholar 

  56. Martinon F, Mayor A, Tschopp J (2009) The inflammasomes: guardians of the body. Annu Rev Immunol 27:229–265

    CAS  PubMed  Google Scholar 

  57. Petrilli V, Papin S, Dostert C et al (2007) Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ 14:1583–1589

    CAS  PubMed  Google Scholar 

  58. Thomas PG, Dash P, Aldridge JR et al (2009) NLRP3 (NALP3/CIAS1/Cryopyrin) mediates key innate and healing responses to influenza A virus via the regulation of caspase-1. Immunity 30:566–575

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Halle A, Hornung V, Petzold GC et al (2008) The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nat Immunol 9:857–865

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Masters SL (2012) Specific inflammasomes in complex diseases. Clin Immunol 147:223–228

    PubMed  Google Scholar 

  61. Heneka MT, Kummer MP, Stutz A et al (2013) NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493:674–678

    CAS  PubMed  Google Scholar 

  62. Marin R (2011) Signalosomes in the brain: relevance in the development of certain neuropathologies such as Alzheimer’s disease. Front Physiol 2:23

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Marin R, Guerra B, Alonso R et al (2005) Estrogen activates classical and alternative mechanisms to orchestrate neuroprotection. Curr Neurovasc Res 2:287–301

    CAS  PubMed  Google Scholar 

  64. Guerra B, Diaz M, Alonso R et al (2004) Plasma membrane estrogen receptor mediates neuroprotection against β-amyloid toxicity through activation of Raf1/MEK/ERK cascade in septal-derived cholinergic SN56 cells. J Neurochem 91:99–1099

    CAS  PubMed  Google Scholar 

  65. Ramirez CM, Gonzalez M, Diaz M et al (2009) VDAC and ERα interaction in caveolae from human cortex is altered in Alzheimer’s disease. Mol Cell Neurosci 42:172–183

    CAS  PubMed  Google Scholar 

  66. Amtul Z, Wang L, Westaway D et al (2010) Neuroprotective mechanism conferred by 17beta-estradiol on the biochemical basis of Alzheimer’s disease. Neuroscience 169:781–786

    CAS  PubMed  Google Scholar 

  67. Yue X, Lu M, Lancaster T et al (2005) Brain estrogen deficiency accelerates A(beta) plaque formation in an Alzheimer’s disease animal model. Proc Natl Acad Sci USA 102:19198–19203

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Alvarez-De-La-Rosa M, Silva I, Nilsen J et al (2005) Estradiol prevents neural tau hyperphosphorylation characteristic of Alzheimer’s disease. Ann NY Acad Sci 1052:210–224

    CAS  PubMed  Google Scholar 

  69. Pike CJ, Carroll JC, Rosario ER et al (2009) Protective actions of sex steroid hormones in Alzheimer’s disease. Front Neuroendocrinol 30:239–258

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Simpkins JW, Yi KD, Yang SH et al (2010) Mitochondrial mechanisms of estrogen neuroprotection. Biochim Biophys Acta 1800:1113–1120

    CAS  PubMed  Google Scholar 

  71. Pike CJ (1999) Estrogen modulates neuronal Bcl-xL expression and β-amyloid-induced apoptosis: relevance to Alzheimer’s disease. J Neurochem 72:1552–1563

    CAS  PubMed  Google Scholar 

  72. Nilsen J (2008) Estradiol and neurodegenerative oxidative stress. Front Neuroendocrinol 29:463–475

    CAS  PubMed  Google Scholar 

  73. Borras C, Sastre J, Garcia-Sala D et al (2003) Mitochondria from females exhibit higher antioxidant gene expression and lower oxidative damage than males. Free Radic Biol Med 34:546–552

    CAS  PubMed  Google Scholar 

  74. Barha CK, Galea LA (2010) Influence of different estrogens on neuroplasticity and cognition in the hippocampus. Biochim Biophys Acta 1800:1056–1067

    CAS  PubMed  Google Scholar 

  75. Foy MR, Baudry M, Diaz Brinton R et al (2008) Estrogen and hippocampal plasticity in rodent models. J Alzheimers Dis 15:589–603

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Goodman Y, Bruce AJ, Cheng B et al (1996) Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid β-peptide toxicity in hippocampal neurons. J Neurochem 66:1836–1844

    CAS  PubMed  Google Scholar 

  77. Morrison JH, Baxter MG (2012) The ageing cortical synapse: hallmarks and implications for cognitive decline. Nat Rev Neurosci 13:240–250

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Nilsen J, Irwin RW, Gallaher TK et al (2007) Estradiol in vivo regulation of brain mitochondrial proteome. J Neurosci 27:14069–14077

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Asthana S, Baker LD, Craft S et al (2001) High-dose estradiol improves cognition for women with AD: results of a randomized study. Neurology 57:605–612

    CAS  PubMed  Google Scholar 

  80. Schneider LS, Farlow MR, Henderson VW et al (1996) Effects of estrogen replacement therapy on response to tacrine in patients with Alzheimer’s disease. Neurology 46:1580–1584

    CAS  PubMed  Google Scholar 

  81. D’Andrea MR (2005) Add Alzheimer’s disease to the list of autoimmune diseases. Med Hypotheses 64:458–463

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to F. Guerriero.

Ethics declarations

Conflict of interest

On behalf of all Authors, the corresponding author states that there is no conflict of interest.

Ethical approval

This article does not contain any studies with human participants performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guerriero, F., Sgarlata, C., Francis, M. et al. Neuroinflammation, immune system and Alzheimer disease: searching for the missing link. Aging Clin Exp Res 29, 821–831 (2017). https://doi.org/10.1007/s40520-016-0637-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40520-016-0637-z

Keywords

Navigation