Skip to main content

Advertisement

SpringerLink
Log in

Neuroinflammation and Neuroimmunomodulation in Alzheimer’s Disease

  • Immunology and Inflammation (W Gause and L Covey, Section Editors)
  • Published:
Current Pharmacology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

This review provides an updated summary of our current understanding of the role of neuroinflammation in Alzheimer’s disease (AD). We introduce the main cellular and molecular players in AD-related neuroinflammation, highlight the latest discovery on how inflammasome participates in the development of AD, and discuss potential neuroimmunomodulation approaches for AD prevention and therapy.

Recent Findings

AD is characterized by the abnormal accumulation or aggregation of proteins such as amyloid β (Aβ) and tau, which could act as danger-associated molecular patterns that engage pattern-recognition receptors to activate inflammatory signaling pathways and promote the production and release of a variety of inflammatory mediators. While the role of neuroinflammatory response in AD is complex and poorly understood, it is generally considered that consistent neuroinflammation has detrimental effects and facilitate the progression of AD. In particular, recent evidence suggests that targeting Nod-like receptor protein 3 (NLRP3) inflammasome could slow the deposition of Aβ plaques in the brain and improve neurological outcome in AD patients.

Summary

Neuroinflammation plays an important role in AD. Further elucidation of molecular mechanisms underlying AD-related neuroinflammatory response would help develop novel strategies for the prevention and treatment of AD.

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

Similar content being viewed by others

References

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

  1. Peng D, Shi Z, Xu J, Shen L, Xiao S, Zhang N, et al. Demographic and clinical characteristics related to cognitive decline in Alzheimer disease in China: a multicenter survey from 2011 to 2014. Medicine (Baltimore). 2016;95(26):e3727.

    Article  Google Scholar 

  2. Wang BR, Ou Z, Gu XH, Wei CS, Xu J, Shi JQ. Validation of the Chinese version of Addenbrooke's cognitive examination III for diagnosing dementia. Int J Geriatr Psychiatry. 2017;32(12):e173–9.

    Article  Google Scholar 

  3. Gandy S. The role of cerebral amyloid beta accumulation in common forms of Alzheimer disease. J Clin Invest. 2005;115:1121–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. • Bronzuoli MR, Iacomino A, Steardo L, Scuderi C. Targeting neuroinflammation in Alzheimer’s disease. J Inflamm Res. 2016;9:199–208. An excellent review on the potential of neuroinflammation as therapeutic targets of Alzheimer’s disease.

    Article  CAS  Google Scholar 

  5. Shi JQ, Chen J, Wang BR, Zhu YW, Xu Y, Wang J, et al. Short amyloid-beta immunogens show strong immunogenicity and avoid stimulating pro-inflammatory pathways in bone marrow-derived dendritic cells from C57BL/6J mice in vitro. Peptides. 2011;32(8):1617–25.

    Article  CAS  Google Scholar 

  6. Sastre M, Walter J, Gentleman SM. Interactions between APP secretases and inflammatory mediators. J Neuroinflammation. 2008;5:25.

    Article  Google Scholar 

  7. Wyss-Coray T, Mucke L. Inflammation in neurodegenerative disease: a double-edged sword. Neuron. 2002;35:419–32.

    Article  CAS  Google Scholar 

  8. Morales I, Guzmán-Martínez L, Cerda-Troncoso C, Farías GA, Maccioni RB. Neuroinflammation in the pathogenesis of Alzheimer’s disease. A rational framework for the search of novel therapeutic approaches. Front Cell Neurosci. 2014;8:112.

    PubMed  PubMed Central  Google Scholar 

  9. Ransohoff RM, Schafer D, Vincent A, Blachère NE, Bar-Or A. Neuroinflammation: ways in which the immune system affects the brain. Neurotherapeutics. 2015;12:896–909.

    Article  CAS  Google Scholar 

  10. • Ransohoff RM. How neuroinflammation contributes to neurodegeneration. Science. 2016;353:777–83. A nice review on the role of neuroinflammation in neurodegenerative diseases.

    Article  CAS  Google Scholar 

  11. Ben Haim L, Rowitch DH. Functional diversity of astrocytes in neural circuit regulation. Nat Rev Neurosci. 2017;18:31–41.

    Article  Google Scholar 

  12. Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol. 2010;119:7–35.

    Article  Google Scholar 

  13. Rodriguez-Vieitez E, Saint-Aubert L, Carter SF, Almkvist O, Farid K, Schöll M, et al. Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer’s disease. Brain. 2016;139(Pt 3):922–36.

    Article  Google Scholar 

  14. Vincent AJ, Gasperini R, Foa L, Small DH. Astrocytes in Alzheimer’s disease: emerging roles in calcium dysregulation and synaptic plasticity. J Alzheimers Dis. 2010;22(3):699–714.

    Article  Google Scholar 

  15. • Acosta C, Anderson HD, Anderson CM. Astrocyte dysfunction in Alzheimer disease. J Neurosci Res. 2017;95(12):2430–47. An updated review on the role of astrocytes in Alzheimer disease.

    Article  CAS  Google Scholar 

  16. Baroja-Mazo A, Martín-Sánchez F, Gomez AI, Martínez CM, Amores-Iniesta J, Compan V, et al. The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nat Immunol. 2014;15(8):738–48.

    Article  CAS  Google Scholar 

  17. Wilkinson K, El Khoury J. Microglial scavenger receptors and their roles in the pathogenesis of Alzheimer's disease. Int J Alzheimers Dis. 2012;2012:489456.

    PubMed  PubMed Central  Google Scholar 

  18. Hamelin L, Lagarde J, Dorothée G, Leroy C, Labit M, Comley RA, et al. Early and protective microglial activation in Alzheimer’s disease: a prospective study using 18F-DPA-714 PET imaging. Brain J Neurol. 2016;139(Pt 4):1252–64.

    Article  Google Scholar 

  19. Fan Z, Okello AA, Brooks DJ, Edison P. Longitudinal influence of microglial activation and amyloid on neuronal function in Alzheimer’s disease. Brain J Neurol. 2015;138(Pt 12):3685–98.

    Article  Google Scholar 

  20. •• Ardura-Fabregat A, Boddeke EWGM, Boza-Serrano A, Brioschi S, Castro-Gomez S, Ceyzériat K, et al. Targeting Neuroinflammation to treat Alzheimer's disease. CNS Drugs. 2017;31(12):1057–82. A comprehensive review on targeting neuroinflammation as novel avenue to treat Alzheimer's Disease.

    Article  CAS  Google Scholar 

  21. Liu S, Liu Y, Hao W, Wolf L, Kiliaan AJ, Penke B, et al. TLR2 is a primary receptor for Alzheimer’s amyloid β peptide to trigger neuroinflammatory activation. J Immunol. 2012;188:1098–107.

    Article  CAS  Google Scholar 

  22. Thundyil J, Lim KL. DAMPs and neurodegeneration. Ageing Res Rev. 2015;24(Pt A):17–28.

    Article  CAS  Google Scholar 

  23. Forlenza OV, Diniz BS, Talib LL, Mendonça VA, Ojopi EB, Gattaz WF, et al. Increased serum IL-1beta level in Alzheimer's disease and mild cognitive impairment. Dement Geriatr Cogn Disord. 2009;28(6):507–12.

    Article  CAS  Google Scholar 

  24. Yuan H, Xia Q, Ge P, Wu S. Genetic polymorphism of interleukin 1β -511C/T and susceptibility to sporadic Alzheimer’s disease: a meta-analysis. Mol Biol Rep. 2013;40(2):1827–34.

    Article  CAS  Google Scholar 

  25. Vom Berg J, Prokop S, Miller KR, Obst J, Kälin RE, Lopategui-Cabezas I, et al. Inhibition of IL-12/IL-23 signaling reduces Alzheimer’s disease-like pathology and cognitive decline. Nat Med. 2012;18(12):1812–9.

    Article  CAS  Google Scholar 

  26. Zhu XC, Tan L, Jiang T, Tan MS, Zhang W, Yu JT. Association of IL-12A and IL-12B polymorphisms with Alzheimer’s disease susceptibility in a Han Chinese population. J Neuroimmunol. 2014;274(1–2):180–4.

    Article  CAS  Google Scholar 

  27. Le Thuc O, Blondeau N, Nahon JL, Rovère C. The complex contribution of chemokines to neuroinflammation: switching from beneficial to detrimental effects. Ann N Y Acad Sci. 2015;1351:127–40.

    Article  Google Scholar 

  28. Chen P, Zhao W, Guo Y, Xu J, Yin M. CX3CL1/CX3CR1 in Alzheimer’s disease: a target for neuroprotection. Biomed Res Int. 2016;2016:8090918.

    PubMed  PubMed Central  Google Scholar 

  29. El Khoury JB, Moore KJ, Means TK, Leung J, Terada K, Toft M, et al. CD36 mediates the innate host response to beta-amyloid. J Exp Med. 2003;197(12):1657–66.

    Article  Google Scholar 

  30. Kiyota T, Morrison CM, Tu G, Dyavarshetty B, Weir RA, Zhang G, et al. Presenilin-1 familial Alzheimer’s disease mutation alters hippocampal neurogenesis and memory function in CCL2 null mice. Brain Behav Immun. 2015;49:311–21.

    Article  CAS  Google Scholar 

  31. Bagyinszky E, Giau VV, Shim K, Suk K, An SSA, Kim S. Role of inflammatory molecules in the Alzheimer’s disease progression and diagnosis. J Neurol Sci. 2017;376:242–54.

    Article  CAS  Google Scholar 

  32. •• Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002;10(2):417–26. The first report on the discovery of inflammasome.

    Article  CAS  Google Scholar 

  33. Schroder K, Tschopp J. The inflammosomes. Cell. 2010;140(6):821–32.

    Article  CAS  Google Scholar 

  34. Salminen A, Ojala J, Suuronen T, Kaarniranta K, Kauppinen A. Amyloid-beta oligomers set fire to inflammasomes and induce Alzheimer’s pathology. J Cell Mol Med. 2008;12(6A):2255–62.

    Article  CAS  Google Scholar 

  35. Saresella M, La Rosa F, Piancone F, Zoppis M, Marventano I, Calabrese E, et al. The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer’s disease. Mol Neurodegener. 2016;11:23.

    Article  Google Scholar 

  36. Wu PJ, Hung YF, Liu HY, Hsueh YP. Deletion of the inflammasome sensor Aim2 mitigates Aβ deposition and microglial activation but increases inflammatory cytokine expression in an Alzheimer disease mouse model. Neuroimmunomodulation. 2017;24(1):29–39.

    Article  CAS  Google Scholar 

  37. Pennisi M, Crupi R, Di Paola R, Ontario ML, Bella R, Calabrese EJ, et al. Inflammasomes, hormesis, and antioxidants in neuroinflammation: role of NRLP3 in Alzheimer disease. J Neurosci Res. 2017;95(7):1360–72.

    Article  CAS  Google Scholar 

  38. Parajuli B, Sonobe Y, Horiuchi H, Takeuchi H, Mizuno T, Suzumura A. Oligomeric amyloid β induces IL-1β processing via production of ROS: implication in Alzheimer’s disease. Cell Death Dis. 2013;4:e975.

    Article  CAS  Google Scholar 

  39. • Heneka MT. Inflammasome activation and innate immunity in Alzheimer’s disease. Brain Pathol. 2017;27(2):220–2. An updated review on the role of inflammasome in Alzheimer’s disease.

    Article  Google Scholar 

  40. •• Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature. 2013;493:674–8. An important study to show that NLRP3 is activated and contributes to Alzheimer's disease pathology in transgenic mouse model.

    Article  CAS  Google Scholar 

  41. •• Venegas C, Kumar S, Franklin BS, Dierkes T, Brinkschulte R, Tejera D, et al. Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer’s disease. Nature. 2017;552(7685):355–61. A very recent remarkable study to reveal that ASC adaptor of inflammasome seeds amyloid-β deposition in the brain of Alzheimer's disease patients or mouse models.

    Article  CAS  Google Scholar 

  42. White CS, Lawrence CB, Brough D, Rivers-Auty J. Inflammasomes as therapeutic targets for Alzheimer’s disease. Brain Pathol. 2017;27:223–34.

    Article  Google Scholar 

  43. Daniels MJD, Rivers-Auty J, Schilling T, Spencer NG, Watremez W, Fasolino V, et al. Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models. Nat Commun. 2016;7:12504.

    Article  CAS  Google Scholar 

  44. Sanz JM, Chiozzi P, Ferrari D, Colaianna M, Idzko M, Falzoni S, et al. Activation of microglia by amyloid β requires P2X7 receptor expression. J Immunol. 2009;182:4378–85.

    Article  CAS  Google Scholar 

  45. Coll RC, Robertson AAB, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med. 2015;21:248–55.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The study was funded by the National Natural Science Foundation of China (81271211; 81471215), Science and technology project of Jiangsu Province (BE2015665; BE2015715), and National Natural Science Foundation of Jiangsu Province (BK20151592).

Author information

Authors and Affiliations

  1. Department of Neurology, China National Clinical Research Center for Neurological Diseases, Beijing Tian Tan Hospital, Capital Medical University, Beijing, 100050, China

    Yin Hong & Jun Xu

  2. Department of Neurology, Northern Jiangsu People’s Hospital, Clinical Medical College of Yangzhou University, Yangzhou, 225001, Jiangsu Province, China

    Jun Xu, Yue Hu, Lin Li, Zhen Dong, Ting-ke Zhu & Yan-qiu Wei

  3. Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, School of Medicine, Yangzhou University, Yangzhou, 225001, Jiangsu, China

    Jun Xu

Authors
  1. Yin Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jun Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yue Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhen Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ting-ke Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yan-qiu Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jun Xu.

Ethics declarations

Conflict of Interest

The authors received no financial support in the writing of this manuscript.

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 Immunology and Inflammation

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hong, Y., Xu, J., Hu, Y. et al. Neuroinflammation and Neuroimmunomodulation in Alzheimer’s Disease. Curr Pharmacol Rep 4, 408–413 (2018). https://doi.org/10.1007/s40495-018-0148-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40495-018-0148-z

Keywords

Search

Navigation