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Inflammation and Alzheimer disease

  • Part IV Immune Mechanisms in Neurodegenerative and Neuropsychiatric Disorders
  • Published:
Molecular and chemical neuropathology

Abstract

Inflammatory mechanisms are active in patients with Alzheimer disease. Serum elevations of acute phase proteins such as α1-antichymotrypsin, along with deposition of inflammatory cytokines in the brain, suggest a “cerebral acute phase response” contributing to amyloid deposition and tissue destruction. Activated microglia possessing HLA-DR surface markers accumulate around amyloid plaques. The complement cascade leads to generation of the membrane attack complex, which may directly damage neuronal membranes. This growing body of evidence suggests that empirical trials of anti-inflammatory drugs are now appropriate to test the hypothesis that suppression of these mechanisms will slow the rate of progression of Alzheimer disease. Several drugs useful in the treatment of rheumatic diseases are candidates for study in Alzheimer disease, including glucocorticoids, antimalarial drugs, and colchicine. Pilot studies of the synthetic glucocorticoid prednisone indicate that treatment with a moderate dose is well tolerated in patients with Alzheimer disease, and suppresses serum levels of acute phase proteins. Based on this experience, a multicenter parallel-design placebo-controlled trial has been initiated with the Alzheimer's Disease Cooperative Study to determine whether treatment with prednisone can slow the rate of progression of Alzheimer disease.

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References

  • Abraham C. R., Selkoe D. J., and Potter H. (1988) Immunohistochemical identification of the serine protease inhibitor alpha-1 antichymotrypsin in the brain amyloid deposits of Alzheimer's disease.Cell 52, 487–501.

    Article  CAS  Google Scholar 

  • Abraham C. R., Shirahama T., and Potter H. (1990) The protease inhibitor α1-antichymotrypsin is associated solely with amyloid deposits containing the β-protein and is localized in specific cells of both normal and diseased brain.Neurobiol. Aging 11, 123–129.

    Article  CAS  Google Scholar 

  • Aisen P. S., Marin D., Altstiel L., Goodwin C., Baruch B., Jacobson R., Ryan T., and Davis K. L. A pilot study of prednisone in Alzheimer's disease.Dementia, in press.

  • Aisen P. S. and Davis K. L. (1994) Inflammatory mechanisms in Alzheimer's disease: Implications for therapy.Am. J. Psychiatry 151, 1105–1113.

    Article  CAS  Google Scholar 

  • Altstiel L. and Sperber K. (1991) Cytokines in Alzheimer's disease.Prog. Neuro. Psychopharmacol. Biol. Psychiat. 15, 481–495.

    Article  CAS  Google Scholar 

  • Altstiel L. D., Lawlor B., Mohs R., Schmeidler J., Dalton A., Mehta P., and Davis K. (1995) Elevated alpha 1-antichymotrypsin serum levels in a subset of nondemented first-degree relatives of Alzheimer's disease patients.Dementia 6, 17–20.

    CAS  PubMed  Google Scholar 

  • Breitner J. C., Gau B. A., Welsh K. A., Plassman B. L., McDonald W. M., Helms M. J., and Anthony J. C. (1994) Inverse association of anti-inflammatory treatments and Alzheimer's disease: initial results of a co-twin control study.Neurology 44, 227–232.

    Article  CAS  Google Scholar 

  • Brugge K., Katzman R., Hill L. R., Hansen L. A., and Saitoh T. (1992) Serological α1-antichymotrypsin in Down's syndrome and Alzheimer's disease.Ann. Neurol. 32, 193–197.

    Article  CAS  Google Scholar 

  • Campbell I. L., Abraham C. R., Masliah E., Kemper P., Inglis J. D., Oldstone M. B. A., and Mucke L. (1993) Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6.Proc. Natl. Acad. Sci. USA 90 10,061–10,065.

    Article  CAS  Google Scholar 

  • Chang Y.-H., Silverman S. L., and Paulus H. E. (1987) Colchicine, inDrugs for Rheumatic Disease (Paulus H. E., Furst D. E., and Droomgoole, eds.), pp. 431, Churchhill Livingstone, New York.

    Google Scholar 

  • DeDuve C., DeBarsy T., Poole B., Trouet A., Tulkens P., and van Hoof F. (1974) Lysosomotropic agents.Biochem. Pharmac. 23, 2495–2531.

    Article  CAS  Google Scholar 

  • Eikelenboom P. and Stam F. C. (1982) Immunoglobulins and complement factors in senile plaques. An immunohistochemical study.Acta Neuropath. (Berl)57, 239–242.

    Article  CAS  Google Scholar 

  • Goldgaber D., Harris H., Hla T., Maciag T., Donnelly R. J., Jacobsen J. S., Vitek M. P., Guiroy D., and Gajdusek D. C. (1989) Interleukin-1 regulates synthesis of amyloid beta protein precursor mRNA in human endothelial cell.Proc. Natl. Acad. Sci. USA 86, 7606–7610.

    Article  CAS  Google Scholar 

  • Griffin W. S., Sheng J. G., Roberts G. W., and Mrak R. E. (1995) Interleukin-1 expression in different plaque types in Alzheimer's diseases: significance in plaque evolution.J. Neuropathol. Exp. Neurol. 54, 276–281.

    Article  CAS  Google Scholar 

  • Grinde B. and Seglen P. O. (1981) Role of microtubuli in lysosomal protein degradation, Hoppe-Seyler's Z.Physiol. Chem. 362, 549–556.

    Article  CAS  Google Scholar 

  • Haga S., Akai K., and Ishii T. (1989) Demonstration of microglial cells in and around senile (neuritic) plaques in the Alzheimer brain: an immunohistochemical study using a novel monoclonal antibody.Acta Neuropathol. 77, 569–575.

    Article  CAS  Google Scholar 

  • HERA Study Group (1995) A randomized trial of hydroxychloroquine in early rheumatoid arthritis: The HERA Study.Am. J. Med. 98, 156–168.

    Article  Google Scholar 

  • Hinds T. R., Kukull W. A., Van Belle G., Schellenberg G. D., Villacres E. C., and Larson E. B. (1994) Relationship between serum α1-antichymotrypsin and Alzheimer's disease.Neurobiol. Aging 15, 21–27.

    Article  CAS  Google Scholar 

  • Kisilevsky R., Boudreau L., and Foster D. (1983) Kinetics of amyloid deposition. II. The effects of dimethylsulfoxide and colchicine therapy.Lab. Invest. 48, 60–67.

    CAS  PubMed  Google Scholar 

  • Lucca U., Tettamanti M., Forloni G., and Spagnoli A. (1994) Nonsteroidal anti-inflammatory Drug Use in Alzheimer's Disease.Biol. Psychiatry. 36, 854–856.

    Article  CAS  Google Scholar 

  • Matsubara E., Hirai S., Amari H., Shoji M., Yamaguchi H., Okamoto K., Ishiguro K., Harigaya Y., and Wakabayashi W. (1990) Alpha-1-antichymotrypsin as a possible biochemical marker for Alzheimer-type dementia.Ann. Neurol. 28, 561–567.

    Article  CAS  Google Scholar 

  • McGeer P. L., Itagaki S., Tago H., and McGeer E. G. (1987) Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR.Neurosci. Lett. 79, 195–200.

    Article  CAS  Google Scholar 

  • McGeer P. L., Akiyama H., Itagaki S., and McGeer E. G. (1989) Activation of the classical complement pathway in brain tissue of Alzheimer patients.Neurosci. Lett. 107, 341–346.

    Article  CAS  Google Scholar 

  • McGeer P. L. and Rogers J. (1992) Medical hypothesis: antiinflammatory agents as a therapeutic approach to Alzheimer's disease.Neurology 42, 447–449.

    Article  CAS  Google Scholar 

  • Mullins J. F., Watts F. L., and Wilson C. J. (1956) Plaquenil in the treatment of lupus erythematosus.J. Amer. Med. Assoc. 161, 879–888.

    Article  CAS  Google Scholar 

  • Refolo L. M., Sambamurti K., Efthimiopoulos S., Pappolla M. A., and Robakis N. K. (1995) Evidence that secretase cleavage of cell surface Alzheimer amyloid precursor occurs after normal endocytotic internalization.J. Neurosci. Res. 40, 694–706.

    Article  CAS  Google Scholar 

  • Rich J. B., Rasmusson D. X., Folstein M. F., Carson K. A., Kawas C., and Brandt J. (1995) Nonsteroidal anti-inflammatory drugs in Alzheimer's disease.Neurology 45, 51–55.

    Article  CAS  Google Scholar 

  • Rogers J., Kirby L. C., Hempelman S. R., Berry D. L., McGeer P. L., Kaszniak A. W., Zalinski J., Cofield M., Mansukhani L., Willson P., and Kogan F. (1993) Clinical trial of indomethacin in Alzheimer's disease.Neurology 43, 1609–1611.

    Article  CAS  Google Scholar 

  • Rogers J. (1995) Inflammation as a pathogenic mechanism in Alzheimer's disease.Arzneim-Forsch/Drug Res. 45, 439–442.

    CAS  Google Scholar 

  • Rozemuller J. M., Stam F. C., and Eikelenboom P. (1990) Acute phase proteins are present in amorphous plaques in the cerebral but not in the cerebellar cortex of patients with Alzheimer's disease.Neurosci. Lett. 109, 75–78.

    Article  Google Scholar 

  • Salmeron G. and Lipsky P. E. (1983) Immunosuppressive potential of antimalarials.Am. J. Med. 75(1A), 19–24.

    Article  CAS  Google Scholar 

  • Shirahama T. and Cohen A. S. (1974) Blockage of amyloid induction by colchicine in an animal model.J. Exp. Med. 140, 1102–1107.

    Article  CAS  Google Scholar 

  • Sperber K., Quraishi H., Kalb T. H., Panja A., Stecher V., and Mayer L. (1993) Selective regulation of cytokine secretion by hydroxychloroquine: Inhibition of interleukin 1 alpha (IL-1-α) and IL-6 in human monocytes and T cells.J. Rheumatol. 20, 803–808.

    CAS  PubMed  Google Scholar 

  • Vandenabeele P. and Fiers W. (1991) Is amyloidogenesis during Alzheimer's disease due to an IL-1/IL-6-mediated ‘acute phase response’ in the brain?Immunol. Today 12, 217–219.

    Article  CAS  Google Scholar 

  • Wisniewski H., Wegiel J., Strojny P., Wang K.-C., Kim K.-S., and Burrage T. (1991) Ultrastructural morphology and immunocytochemistry of beta amyloid classical, primitive and diffuse plaques, inFrontiers of Alzheimer Research (Ishii T., ed.), pp. 99–108, Elsevier, Amsterdam.

    Google Scholar 

  • Zemer D., Pras M., Sohar E., Modon M., Cabili S., and Gafni J. (1986) Colchicine in the prevention and treatment of amyloidosis of familial Mediterranean fever.N. Engl. J. Med. 314, 1001–1005.

    Article  CAS  Google Scholar 

  • Zemer D., Livneh A., and Langevitz P. (1992) Reversal of the nephrotic syndrome by colchicine in amyloidosis of familial Mediterranean fever.Ann. Intern. Med. 116, 426.

    Article  CAS  Google Scholar 

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  1. Department of Psychiatry, Mount Sinai School of Medicine, One Gustave Levy Place, Box 1230, 10029, New York, NY

    Paul S. Aisen

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Aisen, P.S. Inflammation and Alzheimer disease. Molecular and Chemical Neuropathology 28, 83–88 (1996). https://doi.org/10.1007/BF02815208

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  • DOI: https://doi.org/10.1007/BF02815208

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