Aging Clinical and Experimental Research

, Volume 29, Issue 5, pp 821–831 | Cite as

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

  • F. GuerrieroEmail author
  • C. Sgarlata
  • M. Francis
  • N. Maurizi
  • A. Faragli
  • S. Perna
  • M. Rondanelli
  • M. Rollone
  • G. Ricevuti


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.


Alzheimer disease Neuroinflammation Blood brain barrier Inflammasome Signalosome Derived-microglia microvesicles 


Compliance with ethical standards

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.


  1. 1.
    American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders, 5th edn. American Psychiatric Publishing, ArlingtonGoogle Scholar
  2. 2.
    Fratiglioni L, Winblad B, von Strauss E (2007) Prevention of Alzheimer’s disease and dementia. Major findings from the Kungsholmen Project. Physiol Behav 92:98–104PubMedGoogle Scholar
  3. 3.
    Kinsella K, Velkoff VA (2002) The demographics of aging. Aging Clin Exp Res 14:159–169PubMedGoogle Scholar
  4. 4.
    Rogers J, Cooper NR, Webster S et al (1992) Complement activation by beta-amyloid in Alzheimer disease. Proc Natl Acad Sci USA 89:10016–10020PubMedGoogle Scholar
  5. 5.
    McGeer PL, McGeer EG (2013) The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy. Acta Neuropathol 126:479–497PubMedGoogle Scholar
  6. 6.
    Heneka MT, O’banion MK (2007) Inflammatory processes in Alzheimer’s disease. J Neuroimmunol 184:69–91PubMedGoogle Scholar
  7. 7.
    Damani MR, Zhao L, Fontainhas AM et al (2011) Age-related alterations in the dynamic behavior of microglia. Aging Cell 10:263–276PubMedGoogle Scholar
  8. 8.
    Sierra A, Gottfried-Blackmore AC, Mc Ewen BS et al (2007) Microglia derived from aging mice exhibit altered inflammatory profile. Glia 55:412–424PubMedGoogle Scholar
  9. 9.
    Harry GJ (2013) Microglia during development and aging. Pharmacol Ther 139:313–326PubMedPubMedCentralGoogle Scholar
  10. 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 85:1018–1032PubMedGoogle Scholar
  11. 11.
    Kierdorf K, Prinz M (2013) Factors regulating microglia activation. Front Cell Neurosci 7:44PubMedPubMedCentralGoogle Scholar
  12. 12.
    Czlonkowska A, Kurkowska-Jastrzebska I (2011) Inflammation and gliosis in neurological diseases–clinical implications. J Neuroimmunol 231:78–85PubMedGoogle Scholar
  13. 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 89:141–146PubMedGoogle Scholar
  14. 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 89:291–295PubMedGoogle Scholar
  15. 15.
    Seubert P, Vigo-Pelfrey C, Esch F et al (1992) Isolation and quantification of soluble Alzheimer’s beta-peptide from biological fluids. Nature 359:325–327PubMedGoogle Scholar
  16. 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 11:149–153PubMedGoogle Scholar
  17. 17.
    Tejera D, Heneka MT (2016) Microglia in Alzheimer’s disease: the good, the bad and the ugly. Curr Alzheimer Res 13:370–380PubMedGoogle Scholar
  18. 18.
    Abbott NJ, Patabendige AA, Dolman DE et al (2010) Structure and function of the blood brain barrier. Neurobiol Dis 37:13–25PubMedGoogle Scholar
  19. 19.
    Crane IJ, Liversidge J (2008) Mechanism of leukocyte migration across the blood–retina-barrier. Semin Immunopathol 30:165–177PubMedPubMedCentralGoogle Scholar
  20. 20.
    Sallusto F, Impellizieri D, Basso C et al (2012) T-cell trafficking in the central nervous system. Immunol Rev 248:216–227PubMedGoogle Scholar
  21. 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 8:4PubMedPubMedCentralGoogle Scholar
  22. 22.
    Lyck R, Engelhardt B (2012) Going against the tide—how encephalitogenic T cells breach the blood brain barrier. J Vasc Res 49:497–509PubMedGoogle Scholar
  23. 23.
    Von Andrian UH, Mackay CR (2000) T-cell function and migration. Two sides of the same coin. N Engl J Med 343:1020–1034Google Scholar
  24. 24.
    Hickey WF, Hsu BL, Kimura H (1991) T lymphocyte entry into the central nervous system. J Neurosci Res 28:254–260PubMedGoogle Scholar
  25. 25.
    Owens T, Bechmann I, Engelhardt B (2008) Perivascular spaces and the two steps to neuroinflammation. J Neuropathol Exp Neurol 67:1113–1121PubMedGoogle Scholar
  26. 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 185:4846–4855PubMedGoogle Scholar
  27. 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 106:1920–1925PubMedGoogle Scholar
  28. 28.
    Shattil SJ, Kim C, Ginsberg MH (2010) The final steps of integrin activation: the end game. Nat Rev Mol Cell Biol 11:288–300PubMedPubMedCentralGoogle Scholar
  29. 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 178:851–857PubMedGoogle Scholar
  30. 30.
    Cashman JR, Ghirmai S, Abel KJ et al (2008) Immune defects in Alzheimer’s disease: new medications development. BMC Neurosci 9(Suppl 2):S13PubMedPubMedCentralGoogle Scholar
  31. 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 21:927–938Google Scholar
  32. 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 23:327–332PubMedGoogle Scholar
  33. 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 17:91–103Google Scholar
  34. 34.
    Hanke ML, Kielian T (2011) Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential. Clin Sci 121:367–387PubMedPubMedCentralGoogle Scholar
  35. 35.
    Landreth GE, Reed-Geaghan EG (2009) TLRs in Alzheimer’s disease. Curr Top Microbiol Immunol 336:137–153PubMedPubMedCentralGoogle Scholar
  36. 36.
    Riazi K, Galic MA, Pittman QJ (2010) Contributions of peripheral inflammation to seizure susceptibility: cytokines and brain excitability. Epilepsy Res 89:34–42PubMedGoogle Scholar
  37. 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 5:208–212PubMedGoogle Scholar
  38. 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 22:46PubMedPubMedCentralGoogle Scholar
  39. 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 19:2799–2806PubMedGoogle Scholar
  40. 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 278:144–158PubMedGoogle Scholar
  41. 41.
    Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8:57–69PubMedPubMedCentralGoogle Scholar
  42. 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 24:1340–1349PubMedGoogle Scholar
  43. 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 32:11706–11715PubMedPubMedCentralGoogle Scholar
  44. 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 23:309–317PubMedGoogle Scholar
  45. 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 216:133–142PubMedGoogle Scholar
  46. 46.
    Turola E, Furlan R, Bianco F et al (2012) Microglial Microvesicle Secretion and Intercellular Signaling. Front Physiol 3:149PubMedPubMedCentralGoogle Scholar
  47. 47.
    Rajendran L, Honsho M, Zahn TR et al (2006) Proc Natl Acad Sci USA 2006:11172–11177Google Scholar
  48. 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 174:7268–7277PubMedGoogle Scholar
  49. 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 23:795–805PubMedGoogle Scholar
  50. 50.
    Antonucci F, Turola E, Riganti L et al (2012) Microvesicles released from microglia stimulate synaptic activity via enhanced sphingolipid metabolism. EMBO J 31:1240Google Scholar
  51. 51.
    Verderio C, Muzio L, Turola E et al (2012) Myeloid microvesicles are a marker and a therapeutic target for neuroinflammation. Ann Neurol 72:610–624PubMedGoogle Scholar
  52. 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 21:582–593PubMedGoogle Scholar
  53. 53.
    Lamkanfi M, Dixit VM (2012) Inflammasomes and their roles in health and disease. Annu Rev Cell Dev Biol 28:137–161PubMedGoogle Scholar
  54. 54.
    Kayagaki N, Warming S, Lamkanfi M et al (2011) Non-canonical inflammasome activation targets caspase-11. Nature 479:117–121PubMedGoogle Scholar
  55. 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 2:417–426Google Scholar
  56. 56.
    Martinon F, Mayor A, Tschopp J (2009) The inflammasomes: guardians of the body. Annu Rev Immunol 27:229–265PubMedGoogle Scholar
  57. 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 14:1583–1589PubMedGoogle Scholar
  58. 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 30:566–575PubMedPubMedCentralGoogle Scholar
  59. 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 9:857–865PubMedPubMedCentralGoogle Scholar
  60. 60.
    Masters SL (2012) Specific inflammasomes in complex diseases. Clin Immunol 147:223–228PubMedGoogle Scholar
  61. 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 493:674–678PubMedGoogle Scholar
  62. 62.
    Marin R (2011) Signalosomes in the brain: relevance in the development of certain neuropathologies such as Alzheimer’s disease. Front Physiol 2:23PubMedPubMedCentralGoogle Scholar
  63. 63.
    Marin R, Guerra B, Alonso R et al (2005) Estrogen activates classical and alternative mechanisms to orchestrate neuroprotection. Curr Neurovasc Res 2:287–301PubMedGoogle Scholar
  64. 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 91:99–1099PubMedGoogle Scholar
  65. 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 42:172–183PubMedGoogle Scholar
  66. 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 169:781–786PubMedGoogle Scholar
  67. 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 102:19198–19203PubMedGoogle Scholar
  68. 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 1052:210–224PubMedGoogle Scholar
  69. 69.
    Pike CJ, Carroll JC, Rosario ER et al (2009) Protective actions of sex steroid hormones in Alzheimer’s disease. Front Neuroendocrinol 30:239–258PubMedPubMedCentralGoogle Scholar
  70. 70.
    Simpkins JW, Yi KD, Yang SH et al (2010) Mitochondrial mechanisms of estrogen neuroprotection. Biochim Biophys Acta 1800:1113–1120PubMedGoogle Scholar
  71. 71.
    Pike CJ (1999) Estrogen modulates neuronal Bcl-xL expression and β-amyloid-induced apoptosis: relevance to Alzheimer’s disease. J Neurochem 72:1552–1563PubMedGoogle Scholar
  72. 72.
    Nilsen J (2008) Estradiol and neurodegenerative oxidative stress. Front Neuroendocrinol 29:463–475PubMedGoogle Scholar
  73. 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 34:546–552PubMedGoogle Scholar
  74. 74.
    Barha CK, Galea LA (2010) Influence of different estrogens on neuroplasticity and cognition in the hippocampus. Biochim Biophys Acta 1800:1056–1067PubMedGoogle Scholar
  75. 75.
    Foy MR, Baudry M, Diaz Brinton R et al (2008) Estrogen and hippocampal plasticity in rodent models. J Alzheimers Dis 15:589–603PubMedPubMedCentralGoogle Scholar
  76. 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 66:1836–1844PubMedGoogle Scholar
  77. 77.
    Morrison JH, Baxter MG (2012) The ageing cortical synapse: hallmarks and implications for cognitive decline. Nat Rev Neurosci 13:240–250PubMedPubMedCentralGoogle Scholar
  78. 78.
    Nilsen J, Irwin RW, Gallaher TK et al (2007) Estradiol in vivo regulation of brain mitochondrial proteome. J Neurosci 27:14069–14077PubMedGoogle Scholar
  79. 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 57:605–612PubMedGoogle Scholar
  80. 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 46:1580–1584PubMedGoogle Scholar
  81. 81.
    D’Andrea MR (2005) Add Alzheimer’s disease to the list of autoimmune diseases. Med Hypotheses 64:458–463PubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • F. Guerriero
    • 1
    • 2
    Email author
  • C. Sgarlata
    • 1
  • M. Francis
    • 1
  • N. Maurizi
    • 1
  • A. Faragli
    • 1
  • S. Perna
    • 3
  • M. Rondanelli
    • 3
  • M. Rollone
    • 2
  • G. Ricevuti
    • 1
  1. 1.Department of Internal Medicine and Medical Therapy, Section of GeriatricsUniversity of PaviaPaviaItaly
  2. 2.Azienda di Servizi alla PersonaIstituto di Cura Santa Margherita of PaviaPaviaItaly
  3. 3.Department of Public Health, Experimental and Forensic Medicine, Section of Human Nutrition, Endocrinology and Nutrition UnitUniversity of PaviaPaviaItaly

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