Participation of Glial Cells in the Pathogenesis of AD: A Different View on Neuroinflammation

  • Rommy von Bernhardi


Inflammation has been linked to Alzheimer's disease (AD). The accepted view is that inflammation is secondary to amyloid-β (Aβ) accumulation or neurodegeneration. However, I propose that glial dysfunction and the resulting imbalance between the cytotoxic inflammatory and neuroprotective-modulator activity could be the pathological mechanism behind AD. Such unbalance could be promoted by conditions like hypoxia and inflammation, which are frequently observed in aged individuals. A strong inflammatory response can promote defective processing of the amyloid-β protein precursor (AβPP) and the handling of Aβ by glial cells, resulting in the accumulation of Aβ and further inflammation. Proinflammatory conditions also enhance microglial cell activation by AβPP and Aβ and reduce astrocytes-mediated inhibition of microglial activation. These observations indicate that glial cell response to Aβ can be critically dependent on the priming of glial cells by proinflammatory factors. Astrocytes play a major role in the pathophysiology of AD, both promoting damage and mediating neuroprotection. Persistent inflammation can impair modulation and promote microglia-mediated neurotoxicity. Altogether, I propose that dysfunctional glia could result in both neuroinflammation and impaired neuronal function in AD.


Nitric Oxide Glial Cell Microglial Cell Amyloid Plaque Glial Activation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.




amyloid-β protein precursor


Alzheimer's disease


β-secretase cleaving enzyme 1


central nervous system




inducible form of cyclooxygenase


extracellular signal-regulated kinases








inducible nitric oxide synthase


jun N-terminal kinase




long-term potentiation


mitogen-activated protein kinases


monocyte chemotactic protein-1

MHC-class II

major histocompatibility complex class II


MAPK phosphatase type 1


nuclear factor-κ B;


nerve growth factor


nitric oxide


nonsteroidal anti-inflammatory drugs


reactive oxygen species


scavenger receptors


signal-transducer and activator of transcription-1


transforming growth factor-β


tumor necrosis factor-α



I thank Dr. Jaime Eugenín for his longstanding support and his critical reading of the manuscript. I gratefully acknowledge technical support of G. Ramírez and support by grant 1040831 from FONDECYT to RvB.


  1. 1.
    Duyckaerts C, Colle MA, Dessi F, Crignon Y, Piette F, Hauw JJ (1998) The progression of the lesions in Alzheimer disease - insights from a prospective clinicopathological study. J Neural Trans Suppl 53: 119–126Google Scholar
  2. 2.
    de la Torre JC (2002) Alzheimer's disease as a vascular disorder: nosological evidence. Stroke 33: 1152–1162PubMedCrossRefGoogle Scholar
  3. 3.
    Letiembre M, Hao W, Liu Y et al (2007) Innate immune receptor expression in normal brain aging. Neuroscience 146: 248–254PubMedCrossRefGoogle Scholar
  4. 4.
    Fassbender K, Walter S, Kuhl S et al (2004) The LPS receptor (CD14) links innate immunity with Alzheimer's disease. FASEB J 18:203–205PubMedGoogle Scholar
  5. 5.
    Streit WJ, Sammons NW, Kuhns AJ, Sparks DL (2004) Dystrophic microglia in the aging human brain. Glia 45: 208–212PubMedCrossRefGoogle Scholar
  6. 6.
    Alarcón R, Fuenzalida C, Santibañez M, von Bernhardi R (2005) Expression of scavenger receptors in glial cells: comparing the adhesion of astrocytes and microglia from neonatal rats to surface-bound β-amyloid. J Biol Chem 280: 30406–30415PubMedCrossRefGoogle Scholar
  7. 7.
    J, Wegiel , Imaki H, Wang KC, Wronska A, Osuchowski M, Rubenstein R (2003)) Origin and turnover of microglial cells in fibrillar plaques of APPsw transgenic mice. Acta Neuropathol (Berlin) 105: 393–402Google Scholar
  8. 8.
    Simard AR, Soulet D, Gowing G, Julien JP, Rivest S (2006) Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease. Neuron 49: 489–502PubMedCrossRefGoogle Scholar
  9. 9.
    Husemann J, Loike JD, Anankov R, Febbraio M, Silverstein SC (2002) Scavenger receptors in neurobiology and neuropathology: their role on microglia and other cells of the nervous system. Glia 40: 195–205PubMedCrossRefGoogle Scholar
  10. 10.
    Mantovani A, Sica A, Locati M (2007) New vistas on macrophage differentiation and activation. Eur J Immunol 37: 14–16PubMedCrossRefGoogle Scholar
  11. 11.
    Wyss-Coray T, Loike JD, Brionne TC, et al (2003) Adult mouse astrocytes degrade amyloid-β in vitro and in situ. Nat Med 9: 453–457PubMedCrossRefGoogle Scholar
  12. 12.
    von Bernhardi R (2007) Glial cell dysregulation: a new perspective on Alzheimer disease. Neurotoxicity Res 12: 1–18CrossRefGoogle Scholar
  13. 13.
    von Bernhardi R, Eugenín J (2004) Microglia - astrocyte interaction in Alzheimer's disease: modulation of cell reactivity to Aβ. Brain Res 1025: 186–193PubMedCrossRefGoogle Scholar
  14. 14.
    Selkoe DJ (2002) Alzheimer's disease is a synaptic failure. Science 298: 789–791PubMedCrossRefGoogle Scholar
  15. 15.
    von Bernhardi R, Ramírez G, Toro R, Eugenín J (2007) Pro-inflammatory conditions promote neuronal damage mediated by Amyloid Precursor Protein and degradation by microglial cells in culture. Neurobiol Dis 26: 153–164PubMedCrossRefGoogle Scholar
  16. 16.
    Zhu X, Raina AK, Perry G, Smith MA (2004) Alzheimer's disease: the two-hit hypothesis. Lancet Neurol 3: 219–226PubMedCrossRefGoogle Scholar
  17. 17.
    Eikelenboom P, van Gool WA (2004) Neuroinflammatory perspectives on the two faces of Alzheimer's disease. J Neural Transm 111: 281–294PubMedCrossRefGoogle Scholar
  18. 18.
    Etminan M, Gill S, Samii A (2003) Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer's disease: systematic review and meta-analysis of observational studies. BMJ 327: 128–131PubMedCrossRefGoogle Scholar
  19. 19.
    Lim GP, Yang F, Chu T et al (2000) Ibuprofen suppresses plaque pathology and inflammation in a mouse model of Alzheimer's disease. J Neurosci 20: 5709–5714PubMedGoogle Scholar
  20. 20.
    Rogers JT, Leiter LM, McPhee J et al (1999) Translation of the Alzheimer amyloid precursor protein mRNA is up-regulated by interleukin-1 through 5′-untranslated region sequences. J Biol Chem 274: 6421–6431PubMedCrossRefGoogle Scholar
  21. 21.
    Sheng JG, Bora SH, Xu G, Borchelt DR, Price DL, Koliatos VE (2003) Lipopolysaccharide-induced-neuroinflammation increases intracellular accumulation of amyloid precursor protein and amyloid beta peptide in APPswe transgenic mice. Neurobiol Dis 14: 133–145PubMedCrossRefGoogle Scholar
  22. 22.
    Bal-Price A, Brown C (2001) Inflammatory neurodegeneration mediated by nitric oxide from activated glia-inhibiting neuronal respiration, causing glutamate release and excitotoxicity. J Neurosci 17: 6480–6491Google Scholar
  23. 23.
    McGeer PL, McGeer ED (1995) The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Rev 21: 195–218PubMedCrossRefGoogle Scholar
  24. 24.
    Herrera-Molina R, von Bernhardi R (2005) Transforming growth factor-α1 produced by hippocampal cells modulates glial reactivity in culture. Neurobiol Dis 19: 229–236PubMedCrossRefGoogle Scholar
  25. 25.
    Nguyen MD, Julien J-P, Rivest S (2002) Innate immunity: the missing link in neuroprotection and neurodegeneration? Nat Rev Neurosci 3: 216–227PubMedCrossRefGoogle Scholar
  26. 26.
    Sierra A, Gottfried-Blackmore AC, McEwen BS, Bulloch K (2007) Microglia derived from aging mice exhibit an altered inflammatory profile. Glia 55: 412–424PubMedCrossRefGoogle Scholar
  27. 27.
    Smits HA, van Beelen AJ, de Vos NM et al (2001) Activation of human macrophages by amyloid-beta is attenuated by astrocytes. J Immunol 166: 6869–6876PubMedGoogle Scholar
  28. 28.
    Sudo S, Tanaka J, Toku K et al (1998) Neurons induce the activation of microglial cell in vitro. Exp Neurol 154: 499–510PubMedCrossRefGoogle Scholar
  29. 29.
    Basu A, Krady J, Levinson S (2004) Interleukin-1: a master regulator of neuroinflammation. J Neurosci Res 78: 151–156PubMedCrossRefGoogle Scholar
  30. 30.
    Dhandapani KM, Hadman M, De Sevilla L, Wade MF, Mahesh VB, Brann DW (2003) Astrocyte protection of neurons. Role of transforming growth factor-β signaling via c-jun-Ap-1 protective pathway. J Biol Chem 278: 43329–43339PubMedCrossRefGoogle Scholar
  31. 31.
    McCarty MF (2006) Down-regulation of microglial activation may represent a practical strategy for combating neurodegenerative disorders. Med Hypotheses 67: 251–269PubMedCrossRefGoogle Scholar
  32. 32.
    Garcia-Alloza M, Ferrara BJ, Dodwell SA, Hickey GA, Hy-man BT, Bacskai BJ (2007) A limited role for microglia in anti-body mediated plaque clearance in APP mice. Neurobiol Dis doi:10.1016/j.nbd.2007.07.019Google Scholar
  33. 33.
    El Khuory J, Toft M, Hickman SE et al (2007) Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med 13: 432–438CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of NeurologyFaculty of Medicine, Pontificia Universidad Católica de ChileSantiago

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