Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Inflammatory mechanisms in Alzheimer's disease

Abstract

In recent years many studies have indicated an involvement of inflammatory mechanisms in Alzheimer's disease (AD). Acute-phase proteins such as α1-antichymotrypsin and c-reactive protein, elements of the complement system, and activated microglial and astroglial cells are consistently found in brains of AD patients. Most importantly, also cytokines such as interleukin-6 (IL-6) have been detected in the cortices of AD patients, indicating a local activation of components of the unspecific inflammatory system. Up to now it has remained unclear whether inflammatory mechanisms represent a primary event or only an unspecific reaction to brain tissue damage. Therefore, we investigated whether IL-6 immunoreactivity could be found in plaques prior to the onset of neuritic changes, or whether the presence of this cytokine is restricted to later stages of plaque pathology. we confirmed our previous observation that IL-6 is detectable in a significant proportion of plaques in the brains of demented patients. In AD patients IL-6 was found in diffuse plaques in a significant higher ratio as would have been expected from a random distribution of IL-6 among all plaque types. This observation suggests that IL-6 may precede neuritic changes, and that immunological mechanism may be involved both in the transformation from diffuse to neuritic plaques in AD and in the development of dementia.

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

References

  1. Abraham CR, Selkoe DJ, Potter H (1988) Immunochemical identification of the serine protease inhibitor alpha 1-antichymotrypsin in the brain amyloid deposits of Alzheimer's disease. Cell 52:487–501

  2. Aisen PS, Davis KL (1994) Inflammatory mechanisms in Alzheimer's disease: implications for therapy. Am J Psychiatry 151:1105–1113

  3. Bancher C, Braak H, Fischer P, Jellinger KA (1993) Neuropathological staging of Alzheimer lesions and intellectual status in Alzheimer's and Parkinson's disease patients. Neurosci Lett 162:179–182

  4. Bauer J (1989) Interleukin-6 and its receptor during homeostasis, inflammation and tumor growth. Klin Wochenschr 67:697–706

  5. Bauer J, Herrmann F (1991) Interleukin-6 in clinical medicine. Ann Hematol 62:203–213

  6. Bauer J, Strauss S, Schreiter-Gasser U, Ganter U, Schlegel P, Witt I, Volk B, Berger M (1991) Interleukin-6 and α2-macroglobulin indicate an acute phase state in Alzheimer's disease cortices. FEBS Lett 285:111–114

  7. Baumann H, Gauldie J (1994) The acute phase response. Immunol Today 15:74–80

  8. Berg L, McKeel DWJ, Miller JP, Baty J, Morris JC (1993) Neuropathological indexes of Alzheimer's disease in demented and nondemented persons aged 80 years and older. Arch Neurol 50:349–358

  9. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol Berl 82:239–259

  10. Breitner JCS, Gau BA, Welsh KA, Plassmann BL, McDonald WM, Helms MJ, Anthony JC (1994) Inverse association of antiinflammatory treatments and Alzheimer's disease: intial results of a co-twin control study. Neurology 44:227–232

  11. Crystal HA, Dickson DW, Sliwinski MJ, Lipton RB, Grober E, Marks-Nelson H, Antis P (1993) Pathological markers associated with normal aging and dementia in the elderly. Ann Neurol 34:1682–1687

  12. DeKosky ST, Scheff SW (1990) Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann Neurol 27:457–464

  13. DeRijk RH, Boelen A, Tilders FJH, Berkenbosch F (1994) Induction of plasma interleukin-6 by circulating adrenaline in rat. Psychoneuroendocrinology 19:155–163

  14. Dickson DW, Lee SC, Mattiace LA, Yen SC, Brosnan C (1993) Microglia and cytokines in neurological disease, with special reference to AIDS and Alzheimer's disease. Glia 7:75–83

  15. Ershler WB (1993) Interleukin-6: a cytokine for gerontologists. J Am Geriatr Soc 41:176–181

  16. Gallo P, Frei K, Rordorf C, Lazdins J, Tavolta B, Fontana A (1989) Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system: an evaluation of cytokines in the cerebrospinal fluid. J Neuroimmunol 23:109–116

  17. Gottschall PE, Tatsuno I, Arimura A (1994) Regulation of interleukin 6 (IL-6) secretion in primary cultured rat astrocytes: synergism of interleukin 1 (IL-1) and pituitary adenylate cyclase activating polypeptide (PACAP). Brain Res 637:197–203

  18. Hager K, Machein U, Krieger S, Seefried G, Bauer J (1994) Plasma concentrations of interleukin-6 and selected plasma proteins in healthy persons of different ages. Neurobiol Aging 15:771–772

  19. Helfgott DC, Tatter SB, Santhanam U, Clarick RH, Bhardwaj N, May L, Seghal BP (1989) Multiple forms of IFNβ2/IL-6 in serum and body fluids during acute bacterial infection. J Immunol 142:948–953

  20. Higuchi M, Ito T, Iwaki T, Hattori M, Kohsaka S, Niho Y, Sakaki Y (1994) Expression of the alpha-2-macroglobulin-encoding gene in rat brain and cultured astrocytes. Gene 141:155–162

  21. Jellinger K, Bancher C, Fischer P, Lassmann H (1992) Quantitative histopathologic validation of senile dementia of the Alzheimer type. Eur J Gerontol 3:146–156

  22. Khachaturian ZS (1985) Diagnosis of Alzheimer's disease. Arch Neurol 42:1097–1104

  23. Laurenzi MA, Siden A, Persson MA, Norkrans G, Hageberg L, Chiodi F (1990) Cerebrospinal fluid interleukin-6 activity in HIV infection and inflammatory and non-inflammatory diseases of the nervous system. Clin Immunol Immunopathol 57:233–241

  24. Maimone D, Cioni C, Rosa S, Macchia G, Aloisi F, Annunziata P (1993) Norepinephrine and vasoactive intestinal peptide induce IL-6 secretion by astrocytes: synergism with IL-1 beta and TN-Falpha. J Neuroimmunol 47:73–82

  25. McGeer PL, Akiyama H, Itagaki S, McGeer EG (1989) Activation of the classical complement pathway in brain tissue of Alzheimer patients. Neurosci Lett 107:341–346

  26. McGeer PL, Kawamata T, Walker DG, Akiyama H, Tooyama I, McGeer EG (1993) Microglia in degenerative neurological disease. Glia 7:84–92

  27. Minami M, Kuraishi Y, Satoh M (1991) Effects of kainic acid on mRNA levels of IL-1beta, IL-6, TNFalpha and LIF in the rat brain. Biochem Biophys Res Commun 176:593–598

  28. Murphy DGM, Bottomley PA, Salerno JA, DeCarli C, Mentis MJ, Grady CL, Teichberg D, Giacometti KR, Rosenberg JM, hardy CJ, Schapiro MB, Rapaport SI, Alger JR, Horwitz B (1993) An in vivo study of phosphorus and glucose metabolism in Alzheimer's disease using magnetic resonance spectroscopy and PET. Arch Gen Psychiatry 50:341–349

  29. Norris JG, Benveniste EN (1993) Interleukin-6 production by astrocytes: induction by the neurotransmitter norepinephrine. J Neuroimmunol 45:137–146

  30. Rich JB, Rasmusson DX, Folstein MF, Carson KA, Kawas C, Brandt J (1995) Nonsteroidal anti-inflammatory drugs in Alzheimer's disease. Neurology 45:51–55

  31. Rogers J, Kirby LC, Hempelman SR, Berry DL, McGeer PL, Kaszniak AW, Zalinski J, Cofield M, Mansukhani L, Willson P et al. (1993) Clinical trial of indomethacin in Alzheimer's disease. Neurology 43:1609–1611

  32. Sparks D, Liu H, Scheff SW, Coyne CM, Hunsaker JC (1993) Temporal sequence of plaque formation in the cerebral cortex of non-demented individuals. J Neuropathol Exp Neurol 52:135–142

  33. Strauss S, Bauer J, Ganter U, Jonas U, Berger M, Volk B (1992) Detection of interleukin 6 and alpha-2-macroglobulin immunoreactivity in cortex and hippocampus of Alzheimer's disease patients. Lab Invest 66:223–230

  34. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580

  35. Wood J, Wood P, Ryan R, Graff-Radford NR, Pilapil C, Robitaille Y, Quirion R (1993) Cytokine indices in Alzheimer's temporal cortex: no changes in mature IL-1 beta or IL-1 RA but increases in the associated acute phase proteins IL-6, alpha-2-macroglobulin and C-reactive protein. Brain Res 629:245–252

  36. Yamamoto T, Hirano A (1986) A comparative study by modified Bielschowsky, Bodian and thioflavin S stains on Alzheimer's neurofibrillary tangles. Neuropathol Appl Neurobiol 12:3–9

Download references

Author information

Correspondence to J. Bauer.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hüll, M., Berger, M., Bauer, J. et al. Inflammatory mechanisms in Alzheimer's disease. Eur Arch Psychiatry Clin Nuerosci 246, 124–128 (1996). https://doi.org/10.1007/BF02189112

Download citation

Key words

  • Senile plaques
  • Primitive plaques
  • Alzheimer's disease
  • Interleukin-6