Advertisement

Intranasal Aβ Vaccination as an Approach to Treating β-Amyloidosis

  • D. J. Selkoe
Conference paper
Part of the Research and Perspectives in Alzheimer’s Disease book series (ALZHEIMER)

Abstract

The cerebral accumulation of amyloid β-protein (AP) in Alzheimer’s disease (AD) is accompanied by an inflammatory reaction marked by microgliosis, astrocytosis and the release of pro-inflammatory cytokines and acute phase proteins. Mucosal administration of disease-implicated proteins can induce antigen-specific, anti-inflammatory immune responses in mucosal lymphoid tissue which subsequently act systemically. We hypothesized that chronic mucosal administration of Aβ peptide might induce an anti-inflammatory immune process in which cells induced in the mucosa would circulate to and enter brain tissue to provide a Th2-type cytokine response that could decrease local inflammation. To test this hypothesis, we treated human APP transgenic mice between the ages of ~5 and ~12 months with synthetic human Aβ1–40 peptide given mucosally (orally or intranasally) each week. In the mice treated intranasally, we found significant decreases in cerebral Aβ plaque burden as well as Aβ42 levels, compared to a control group of mice treated with myelin basic protein or left untreated. The lower Aβ burden in the nasally treated mice was associated with decreased local microglial and astrocytic activation, decreased neuritic dystrophy, serum anti-Aβ antibodies of the IgGl and IgG2b classes and a small number of mononuclear cells in the brain expressing the anti-inflammatory cytokines, IL-4, IL-10 and TGF-β. Our results demonstrate that chronic nasal administration of Aβ can induce a cellular and humoral immune response to Aβ that decreases cerebral Aβ levels, suggesting a novel mucosal immunological approach for the treatment and prevention of AD.

Keywords

Experimental Autoimmune Encephalomyelitis Myelin Basic Protein Plaque Burden Neuritic Dystrophy Nasal Administration 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Abraham CR, Selkoe DJ, Potter H (1988) Immunochemical identification of the serine protease inhibitor, al-antichymotrypsin in the brain amyloid deposits of Alzheimer’s disease. Cell 52:487–501.PubMedCrossRefGoogle Scholar
  2. Bitar DM, Whitacre CC (1988) Suppression of experimental autoimmune encephalomyelitis by the oral administration of myelin basic protein. Cell Immunol 112:364–370.PubMedCrossRefGoogle Scholar
  3. Chen Y, Kuchroo VK, Inobe J-I, Hafler DA, Weiner HL (1994) Regulatory T-cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 265:1237–1240.PubMedCrossRefGoogle Scholar
  4. Dickson DW (1997) The pathogenesis of senile plaques. J Neuropathol Exp Neurol 56:321–339.PubMedCrossRefGoogle Scholar
  5. Eikelenboom P, Stam FC (1982) Immunoglobulins and complement factors in senile plaques: an immunoperoxidase study. Acta Neuropathol 57:239–242.PubMedCrossRefGoogle Scholar
  6. Eikelenboom P, Zhan SS, van Gool WA, Allstop D (1994) Inflammatory mechanisms in Alzheimer’s disease. Trends Pharmacol Sci 15:447–450.PubMedCrossRefGoogle Scholar
  7. Faria AMC, Weiner HL (1999) Oral tolerance: mechanisms and therapeutic applications. Adv Immunol 73:153–264.PubMedCrossRefGoogle Scholar
  8. Friedman A, Weiner H (1994) Induction of anergy or active suppression following oral tolerance is determined by antigen dosage. Proc Natl Acad Sci USA 91:6688–6692.PubMedCrossRefGoogle Scholar
  9. Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F, Guido T, Hagopian S, Johnson-Wood K, Khan K, Lee M, Leibowitz P, Lieberburg I, Little S, Masliah E, McConlogue L, Montoya-Zavala M, Mucke L, Paganini L, Penniman E, Power M, schenk D, Seubert P, Snyder B, Soriano F, Tan H, Vitale J, Wadsworth S, Wolozin B, Zhao J (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 373:523–527.PubMedCrossRefGoogle Scholar
  10. Gregerson DS, Obritsch WF, Donoso LA (1993) Oral tolerance in experimental autoimmune uveoretinitis. Distinct mechanisms of resistance are induced by low dose vs high dose feeding protocols. J Immunol 151:5751–5761.Google Scholar
  11. Higgins P, Weiner HL (1988) Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin basic protein and its fragments. J Immunol 140:440–445.PubMedGoogle Scholar
  12. Itagaki S, McGeer PL, Akiyama H, Zhu S, Selkoe D (1989) Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease. J Neuroimmunol 24:173–182.PubMedCrossRefGoogle Scholar
  13. Johnson-Wood K, Lee M, Motter R, Hu K, Gordon G, Barbour R, Khan K, Gordon M, Tan H, Games D, Lieberburg I, Schenk D, Seubert P, McConlogue L (1997) Amyloid precursor protein processing and Aβ42 deposition in a transgenic mouse model of Alzheimer disease. Proc Natl Acad Sci USA 94:1550–1555.PubMedCrossRefGoogle Scholar
  14. Kalaria RN, Galloway PG, Perry G (1991) Widespread amyloid P component immunoreactivity in cortical amyloid deposits of Alzheimer’s disease and other degenerative disorders. Neu- ropathol Appl Neurobiol 17:189–201.CrossRefGoogle Scholar
  15. Lemere C, Grenfell T, Mori C, Stoltzner S, Khan K, Bales K, Games D, Selkoe DJ (1998) Temporal accrual of inflammatory proteins in the plaques of PD-APP transgenic mice between 8 and 20 months. Neurobiol. Aging 19:S279.Google Scholar
  16. Ma C-G, Zhang G-X, Xiao B-G, Olsson T, Link H (1995) Suppression of experimental autoimmune myasthenia gravis by nasal administration of acetylcholine receptor. J Neuroimmunol 58:51–60.PubMedCrossRefGoogle Scholar
  17. Masliah E, Sisk A, Mallory M, Mucke L, Schenk D, Games D (1996) Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F β-amyloid precursor protein and Alzheimer’s disease. J. Neurosci. 16:5795–5811.PubMedGoogle Scholar
  18. McGeer PL, McGeer EG (1995) The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Rev 21:195–218.PubMedCrossRefGoogle Scholar
  19. Metzler B, Wraith DC (1993) Inhibition of experimental autoimmune encephalomyelitis by inhalation but not oral administration of the encephalitogenic peptide: influence of MHC binding affinity. Int Immunol 5:1159–1165.PubMedCrossRefGoogle Scholar
  20. Moalem G, Leibowitz-Amit R, Yoles E, Mor F, Cohen IR, Schwartz M (1999) Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy. Nature Med 5:49–55.PubMedCrossRefGoogle Scholar
  21. Okumura S, Mcintosh K, Drachman DB (1994) Oral administration of acetylcholine receptor: effects on experimental myasthenia gravis. Ann Neurol 36:704–713.PubMedCrossRefGoogle Scholar
  22. Rogers J, Cooper NR, Webster S, J Schultz, PL McGeer, SD Styren, WH Civin, L Brachova, B Bradt, P Ward, I Lieberburg (1992) Complement activation by β-amyloid in Alzheimer disease. Proc Natl Acad Sci USA 89:10016–10020.PubMedCrossRefGoogle Scholar
  23. Rogers J, Kirby LC, Hempelman SR, Berry DL, McGeer PL, Kaszniak AW, Zalinski J, Cofield M, Mansukhani L, Willson P (1993) Clinical trial of indomethacin in Alzheimer’s disease. Neurology 43:1609–1611.PubMedGoogle Scholar
  24. Rogers J, Webster S, Lue L-F, Brachova L, Civin WH, Emmerling M, Shivers B, Walker D, McGeer P (1996) Inflammation and Alzheimer’s disease pathogenesis. Neurobiol Aging 17:681–686.PubMedCrossRefGoogle Scholar
  25. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P (1999) Immunization with amyloid-p attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400:173–177.PubMedCrossRefGoogle Scholar
  26. Selkoe DJ (2001) Alzheimer’s disease: genes, proteins and therapies. Physiol Rev 81:742–761.Google Scholar
  27. Seubert P, Vigo-Pelfrey C, Esch F, Lee M, Dovey H, Davis D, Sinha S, Schlossmacher M, Whaley J, Swindlehurst C, McCormack R, Wolfert R, Selkoe D, Lieberburg I, Schenk D 1992) Isolation and quantitation of soluble Alzheimer’s β-peptide from biological fluids. Nature 359:325–327.PubMedCrossRefGoogle Scholar
  28. Stewart WF, Kawas C, Corrada M, Metter EJ (1997) Risk of Alzheimer’s disease and duration of NSAID use. Neurology 48:626–632.PubMedGoogle Scholar
  29. Weiner HL, Lemere CA, Maron R, Spooner ET, Grenfell TJ, Mori C, Issazadeh S, Hancock WW, Selkoe DJ (2000) Nasal administration of amyloid-β peptide decreases cerebral amyloid burden in a mouse model of Alzheimer’s disease. Ann Neurol 48:567–579.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2003

Authors and Affiliations

  • D. J. Selkoe
    • 1
  1. 1.Center for Neurologic DiseasesHarvard Medical School and Brigham and Women’s HospitalBostonUSA

Personalised recommendations