Skip to main content

Advertisement

SpringerLink
Log in

Neuroinflammation in Alzheimer’s Disease: from Pathogenesis to a Therapeutic Target

  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

The top-down, reductionist approach of the past three decades has resulted in remarkable progress in identifying genes and proteins involved in Alzheimer’s disease (AD), including β-amyloid (Aβ) peptides and tau protein. Recently, a number of genes of the innate immune pathway have been identified as AD risk factors and several microglial proteins have been shown to be chronically activated in AD brains. Together, these observations suggest a crucial role for neuroinflammation in AD pathogenesis and emerging evidence suggests that neuroinflammation is both a cause and a consequence of AD. Epidemiological studies show that long-term users of anti-inflammatory drugs are protected from AD but anti-inflammatory treatment in mild AD patients has not been successful. These observations suggest that anti-inflammatory treatment is likely to be successful if initiated prior to the onset of neurological symptoms. Finally, after the remarkable success of the reductionist approach, a complimentary bottom-up systems approach is necessary to gain a better understanding of the highly complex, multifactorial nature of AD pathogenesis.

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

Similar content being viewed by others

References

  1. Association A’s. Alzheimer’s disease facts and figures. Chicago: Alzheimer’s Association; 2012.

    Google Scholar 

  2. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;297(5580):353–6.

    Article  CAS  PubMed  Google Scholar 

  3. Price DL, Tanzi RE, Borchelt DR, Sisodia SS. Alzheimer’s disease: genetic studies and transgenic models. Annu Rev Genet. 1998;32:461–93.

    Article  CAS  PubMed  Google Scholar 

  4. Jack Jr CR, Wiste HJ, Lesnick TG, Weigand SD, Knopman DS, Vemuri P, et al. Brain beta-amyloid load approaches a plateau. Neurology. 2013;80(10):890–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Jack Jr CR, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, et al. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013;12(2):207–16.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med. 2012;367(9):795–804.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Editorial. Why are drug trials in Alzheimer’s disease failing? Lancet. 2010; 376(9742):658.

  8. Rinne JO, Brooks DJ, Rossor MN, Fox NC, Bullock R, Klunk WE, et al. 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol. 2010;9(4):363–72.

    Article  CAS  PubMed  Google Scholar 

  9. Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, et al. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science. 2007;316(5825):750–4.

    Article  CAS  PubMed  Google Scholar 

  10. Gong CX, Iqbal K. Hyperphosphorylation of microtubule-associated protein tau: a promising therapeutic target for Alzheimer disease. Curr Med Chem. 2008;15(23):2321–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Walsh DM, Selkoe DJ. Deciphering the molecular basis of memory failure in Alzheimer’s disease. Neuron. 2004;44(1):181–93.

    Article  CAS  PubMed  Google Scholar 

  12. Iqbal K, Liu F, Gong CX, Grundke-Iqbal I. Tau in Alzheimer disease and related tauopathies. Curr Alzheimer’s Res. 2010;7(8):656–64.

    Article  CAS  Google Scholar 

  13. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, et al. The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature. 1987;325(6106):733–6.

    Article  CAS  PubMed  Google Scholar 

  14. Cruts M, Van Broeckhoven C. Presenilin mutations in Alzheimer’s disease. Hum Mutat. 1998;11(3):183–90.

    Article  CAS  PubMed  Google Scholar 

  15. Radde R, Duma C, Goedert M, Jucker M. The value of incomplete mouse models of Alzheimer’s disease. Eur J Nucl Med Mol Imaging. 2008;35 Suppl 1:S70–4.

    Article  CAS  PubMed  Google Scholar 

  16. Phinney AL, Horne P, Yang J, Janus C, Bergeron C, Westaway D. Mouse models of Alzheimer’s disease: the long and filamentous road. Neurol Res. 2003;25(6):590–600.

    Article  CAS  PubMed  Google Scholar 

  17. Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256(5054):184–5.

    Article  CAS  PubMed  Google Scholar 

  18. Selkoe DJ. The molecular pathology of Alzheimer’s disease. Neuron. 1991;6(4):487–98.

    Article  CAS  PubMed  Google Scholar 

  19. Small SA, Duff K. Linking abeta and tau in late-onset Alzheimer’s disease: a dual pathway hypothesis. Neuron. 2008;60(4):534–42.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Bloom GS. Amyloid-beta and Tau: The trigger and bullet in Alzheimer disease pathogenesis. JAMA neurology. 2014.

  21. Liu L, Drouet V, Wu JW, Witter MP, Small SA, Clelland C, et al. Trans-synaptic spread of tau pathology in vivo. PLoS One. 2012;7(2):e31302.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Khan UA, Liu L, Provenzano FA, Berman DE, Profaci CP, Sloan R, et al. Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer’s disease. Nat Neurosci. 2014;17(2):304–11.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Vossel KA, Zhang K, Brodbeck J, Daub AC, Sharma P, Finkbeiner S, et al. Tau reduction prevents abeta-induced defects in axonal transport. Science. 2010;330(6001):198.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Shipton OA, Leitz JR, Dworzak J, Acton CE, Tunbridge EM, Denk F, et al. Tau protein is required for amyloid {beta}-induced impairment of hippocampal long-term potentiation. J Neurosci. 2011;31(5):1688–92.

    Article  CAS  PubMed  Google Scholar 

  25. Brunden KR, Zhang B, Carroll J, Yao Y, Potuzak JS, Hogan AM, et al. Epothilone D improves microtubule density, axonal integrity, and cognition in a transgenic mouse model of tauopathy. J Neurosci. 2010;30(41):13861–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Barten DM, Fanara P, Andorfer C, Hoque N, Wong PY, Husted KH, et al. Hyperdynamic microtubules, cognitive deficits, and pathology are improved in Tau transgenic mice with Low doses of the microtubule-stabilizing agent BMS-241027. J Neurosci. 2012;32(21):7137–45.

    Article  CAS  PubMed  Google Scholar 

  27. Zhang B, Carroll J, Trojanowski JQ, Yao Y, Iba M, Potuzak JS, et al. The microtubule-stabilizing agent, epothilone D, reduces axonal dysfunction, neurotoxicity, cognitive deficits, and Alzheimer-like pathology in an interventional study with aged tau transgenic mice. J Neurosci. 2012;32(11):3601–11.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Pimplikar SW. Reassessing the amyloid cascade hypothesis of Alzheimer’s disease. Int J Biochem Cell Biol. 2009;41(6):1261–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Pimplikar SW, Nixon RA, Robakis NK, Shen J, Tsai LH. Amyloid-independent mechanisms in Alzheimer’s disease pathogenesis. J Neurosci. 2010;30(45):14946–54.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Storandt M, Head D, Fagan AM, Holtzman DM, Morris JC. Toward a multifactorial model of Alzheimer disease. Neurobiol Aging. 2012.

  31. Naj AC, Jun G, Beecham GW, Wang LS, Vardarajan BN, Buros J, et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat Genet. 2011;43(5):436–41.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM, et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet. 2011;43(5):429–35.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Zhang B, Gaiteri C, Bodea LG, Wang Z, McElwee J, Podtelezhnikov AA, et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell. 2013;153(3):707–20.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Miller JA, Woltjer RL, Goodenbour JM, Horvath S, Geschwind DH. Genes and pathways underlying regional and cell type changes in Alzheimer’s disease. Genome Med. 2013;5(5):48.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Vlad SC, Miller DR, Kowall NW, Felson DT. Protective effects of NSAIDs on the development of Alzheimer disease. Neurology. 2008;70(19):1672–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. McGeer PL, Schulzer M, McGeer EG. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer’s disease: a review of 17 epidemiologic studies. Neurology. 1996;47(2):425–32.

    Article  CAS  PubMed  Google Scholar 

  37. Stewart WF, Kawas C, Corrada M, Metter EJ. Risk of Alzheimer’s disease and duration of NSAID use. Neurology. 1997;48(3):626–32.

    Article  CAS  PubMed  Google Scholar 

  38. Verri M, Pastoris O, Dossena M, Aquilani R, Guerriero F, Cuzzoni G, et al. Mitochondrial alterations, oxidative stress and neuroinflammation in Alzheimer’s disease. Int J Immunopathol Pharmacol. 2012;25(2):345–53.

    CAS  PubMed  Google Scholar 

  39. Yao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT, Brinton RD. Mitochondrial bioenergetic deficit precedes Alzheimer’s pathology in female mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A. 2009;106(34):14670–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Rogers J, Webster S, Lue LF, Brachova L, Civin WH, Emmerling M, et al. Inflammation and Alzheimer’s disease pathogenesis. Neurobiol Aging. 1996;17(5):681–6.

    Article  CAS  PubMed  Google Scholar 

  41. Simard AR, Soulet D, Gowing G, Julien JP, Rivest S. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron. 2006;49(4):489–502.

    Article  CAS  PubMed  Google Scholar 

  42. Zhu SG, Sheng JG, Jones RA, Brewer MM, Zhou XQ, Mrak RE, et al. Increased interleukin-1beta converting enzyme expression and activity in Alzheimer disease. J Neuropathol Exp Neurol. 1999;58(6):582–7.

    Article  CAS  PubMed  Google Scholar 

  43. Krstic D, Madhusudan A, Doehner J, Vogel P, Notter T, Imhof C, et al. Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice. J Neuroinflammation. 2012;9:151.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Krabbe G, Halle A, Matyash V, Rinnenthal JL, Eom GD, Bernhardt U, et al. Functional impairment of microglia coincides with Beta-amyloid deposition in mice with Alzheimer-like pathology. PLoS One. 2013;8(4):e60921.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Holmes C, Cunningham C, Zotova E, Woolford J, Dean C, Kerr S, et al. Systemic inflammation and disease progression in Alzheimer disease. Neurology. 2009;73(10):768–74.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Perry VH, Cunningham C, Holmes C. Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol. 2007;7(2):161–7.

    Article  CAS  PubMed  Google Scholar 

  47. Britschgi M, Wyss-Coray T. Blood protein signature for the early diagnosis of Alzheimer disease. Arch Neurol. 2009;66(2):161–5.

    Article  PubMed  Google Scholar 

  48. Camacho-Arroyo I, Lopez-Griego L, Morales-Montor J. The role of cytokines in the regulation of neurotransmission. Neuroimmunomodulation. 2009;16(1):1–12.

    Article  CAS  PubMed  Google Scholar 

  49. McAfoose J, Baune BT. Evidence for a cytokine model of cognitive function. Neurosci Biobehav Rev. 2009;33(3):355–66.

    Article  CAS  PubMed  Google Scholar 

  50. Hein AM, O’Banion MK. Neuroinflammation and memory: the role of prostaglandins. Mol Neurobiol. 2009;40(1):15–32.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Rao JS, Kellom M, Kim HW, Rapoport SI, Reese EA. Neuroinflammation and synaptic loss. Neurochem Res. 2012;37(5):903–10.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Cameron B, Landreth GE. Inflammation, microglia, and alzheimer’s disease. Neurobiol Dis. 2009.

  53. Wyss-Coray T, Mucke L. Inflammation in neurodegenerative disease—a double-edged sword. Neuron. 2002;35(3):419–32.

    Article  CAS  PubMed  Google Scholar 

  54. Wyss-Coray T. Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med. 2006;12(9):1005–15.

    CAS  PubMed  Google Scholar 

  55. Martin BK, Szekely C, Brandt J, Piantadosi S, Breitner JC, Craft S, et al. Cognitive function over time in the Alzheimer’s disease anti-inflammatory prevention trial (ADAPT): results of a randomized, controlled trial of naproxen and celecoxib. Arch Neurol. 2008;65(7):896–905.

    Article  PubMed  Google Scholar 

  56. Nissen SE. ADAPT: the wrong way to stop a clinical trial. PLoS Clin Trials. 2006;1(7):e35.

    Article  PubMed Central  PubMed  Google Scholar 

  57. Breitner JC, Baker LD, Montine TJ, Meinert CL, Lyketsos CG, Ashe KH, et al. Extended results of the Alzheimer’s disease anti-inflammatory prevention trial. Alzheimer’s & dementia. Alzheim Dement J Alzheimer’s Assoc. 2011;7(4):402–11.

    Article  Google Scholar 

  58. Dodel R, Neff F, Noelker C, Pul R, Du Y, Bacher M, et al. Intravenous immunoglobulins as a treatment for Alzheimer’s disease: rationale and current evidence. Drugs. 2010;70(5):513–28.

    Article  CAS  PubMed  Google Scholar 

  59. Hack CE, Scheltens P. Intravenous immunoglobulins: a treatment for Alzheimer’s disease? J Neurol Neurosurg Psychiatry. 2004;75(10):1374–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Dodel RC, Du Y, Depboylu C, Hampel H, Frolich L, Haag A, et al. Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2004;75(10):1472–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Baerenwaldt A, Biburger M, Nimmerjahn F. Mechanisms of action of intravenous immunoglobulins. Expert Rev Clin Immunol. 2010;6(3):425–34.

    Article  CAS  PubMed  Google Scholar 

  62. Magga J, Puli L, Pihlaja R, Kanninen K, Neulamaa S, Malm T, et al. Human intravenous immunoglobulin provides protection against Aβ toxicity by multiple mechanisms in a mouse model of Alzheimer's disease. J Neuroinflammation. 2010;7:90. doi:10.1186/1742-2094-7-90

    Google Scholar 

  63. Sudduth TL, Greenstein A, Wilcock DM. Intracranial injection of Gammagard, a human IVIg, modulates the inflammatory response of the brain and lowers Aβ in APP/PS1 mice along a different time course than anti-Aβ antibodies. J Neurosci. 2013;33(23):9684–92.

    Google Scholar 

  64. Ryan KA, Pimplikar SW. Activation of GSK-3 and phosphorylation of CRMP2 in transgenic mice expressing APP intracellular domain. J Cell Biol. 2005;171(2):327–35.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  65. Ghosal K, Vogt DL, Liang M, Shen Y, Lamb BT, Pimplikar SW. Alzheimer’s disease-like pathological features in transgenic mice expressing the APP intracellular domain. Proc Natl Acad Sci U S A. 2009;106(43):18367–72.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Vellas B, Carrillo MC, Sampaio C, Brashear HR, Siemers E, Hampel H, et al. Designing drug trials for Alzheimer’s disease: what we have learned from the release of the phase III antibody trials: a report from the EU/US/CTAD Task Force. Alzheim Dement J Alzheimer’s Assoc. 2013;9(4):438–44.

    Article  Google Scholar 

  67. Sperling RA, Rentz DM, Johnson KA, Karlawish J, Donohue M, Salmon DP, et al. The A4 study: stopping AD before symptoms begin? Sci Transl Med. 2014;6(228):228fs13.

    Article  PubMed  Google Scholar 

  68. Lourida I, Soni M, Thompson-Coon J, Purandare N, Lang IA, Ukoumunne OC, et al. Mediterranean diet, cognitive function, and dementia: a systematic review. Epidemiology. 2013;24(4):479–89.

    Article  PubMed  Google Scholar 

  69. Balsamo S, Willardson JM, Frederico Sde S, Prestes J, Balsamo DC, da Dahan CN, et al. Effectiveness of exercise on cognitive impairment and Alzheimer’s disease. Int J Gen Med. 2013;6:387–91.

    PubMed Central  PubMed  Google Scholar 

  70. Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci. 2007;30(9):464–72.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

I thank Dr. Chris Nelson for editing the manuscript. SWP gratefully acknowledges funding support from the NIH, Alzheimer’s Association and Baxter Bioscience Foundation.

Author information

Authors and Affiliations

  1. Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA

    Sanjay W. Pimplikar

Authors
  1. Sanjay W. Pimplikar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sanjay W. Pimplikar.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pimplikar, S.W. Neuroinflammation in Alzheimer’s Disease: from Pathogenesis to a Therapeutic Target. J Clin Immunol 34 (Suppl 1), 64–69 (2014). https://doi.org/10.1007/s10875-014-0032-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-014-0032-5

Keywords

Search

Navigation