Advertisement

Animal model and in vitro studies of anti neurofilament antibodies mediated neurodegeneration in Alzheimer’s disease

  • L. Oron
  • V. Dubovik
  • L. Novitsky
  • D. Eilam
  • D. M. Michaelson
Conference paper

Summary

Alzheimer’s disease (AD) is associated with serum antibodies directed specifically against phosphorylated epitopes highly enriched in the heavy neurofilament protein NF-H of cholinergic neurons. Prolonged immunization of rats with these molecules but not with other NF-H isoforms results in cognitive impairments. This animal model, termed experimental autoimmune dementia (EAD), supports a role for such antibodies in neurodegeneration in AD.

In the present study we investigated the cellular and immunological mechanisms underlying the cognitive defects in EAD. Immunohistochemical studies revealed that IgG accumulate in the septum, hippocampus and in the entorhinal cortex of the EAD rats. This is accompanied by a marked reduction in the density of septal cholinergic neurons. An inverse correlation was observed between the level of IgG in the septum of individual EAD rats and the density of their septal cholinergic neurons. Time course studies revealed that the decrease in the density of cholinergic neurons in the septum of EAD rats and the accumulation of IgG in this brain area have the same time course and are both significant by three to four months following the initiation of immunization with cholinergic NF-H. The cognitive deficits of the EAD rats evolve more slowly and are pronounced only after six months following the initation of immunization. In vitro studies revealed that anti NF-H IgG bind to the outer surface of neurons in tissue cultures of rat forebrain and can affect neuronal viability. These AD and in vitro findings provide model systems for studying the mechanisms underlying the neuropathological effects of specific anti NF-H antibodies.

Keywords

Entorhinal Cortex Cholinergic Neuron Medial Septum Home Base Diagonal Band 
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. Chapman J, Bachar O, Korczyn AD, Wertman E, Michaelson DM (1989) Alzheimer’s disease antibodies bind specifically to a neurofilament protein in Torpedo cholinergic neurons. J Neurosci 9: 2710–2717PubMedGoogle Scholar
  2. Chapman J, Alroy G, Weiss Z, Faigon M, Feldon J, Michaelson DM (1991) Anti neuronal antibodies similar to those found in Alzheimer’s disease induce memory dysfunction in rats. Neurosci 40: 297–305CrossRefGoogle Scholar
  3. Dubovik V, Faigon M, Feldon J, Michaelson DM (1993) Decreased density of forebrain cholinergic neurons in experimental autoimmune dementia. Neuroscience 56: 75–82PubMedCrossRefGoogle Scholar
  4. Eilam D, Golani I (1990) Home base behavior of tame wild rats (Rattus norvegicus) injected with amphetamine. Behav Brain Res 36: 161–170PubMedCrossRefGoogle Scholar
  5. Eilam D, Szechtman H, Faigon M, Dubovik V, Feldon J, Michaelson DM (1993) Disintegration of the spatial organization of behavior in experimental autoimmune dementia. Neuroscience 56: 83–91PubMedCrossRefGoogle Scholar
  6. Hassin-Baer S, Wertman E, Raphael M, Stark V, Chapman J, Michaelson DM (1992) Antibodies from Down syndrome patients bind to the same cholinergic neurofilament protein recognized by Alzheimer’s disease antibodies. Neurology 42: 551–555PubMedGoogle Scholar
  7. Korsching S, Thoenen H (1983) Nerve growth factor in sympathetic ganglia and corresponding target organs of the rat: correlation with density of sympathetic innervation. Proc Natl Acad Sci USA 80: 3513–3516PubMedCrossRefGoogle Scholar
  8. Michaelson DM, Alroy G, Soussan L, Chapman J, Feldon J (1991) Experimental autoimmune dementia (EAD): an immunological model of memory dysfunction and Alzheimer’s disease. In: Giacobini E, Becker RE (eds) Pharmacological basis of cholinergic therapy in Alzheimer’s disease. Birkhäuser, Boston, pp 126–133Google Scholar
  9. Paxinos G (1985) The rat nervous system. Academic Press, Sydney, p 535Google Scholar
  10. Pelchen-Matthews A, Armes JE, Marsh M (1989) Internalization and recycling of CD4 transfected into Hela and NIH3T3 cells. EMBO J 8: 3641–3649PubMedGoogle Scholar
  11. Sadiq SA, Van-den Berg LH, Thomas FP, Kilidivias K, Hays AP, Latov N (1991) Human monoclonal antineurofilament antibody cross-reacts with a neuronal surface protein. J Neurosci Res 29: 319–325PubMedCrossRefGoogle Scholar
  12. Soussan L, Barzilai A, Michaelson DM (1994) Distinctly phosphorylated neurofilaments in different classes of neurons. J Neurochem 62: 770–776PubMedCrossRefGoogle Scholar
  13. Tchernakov K, Soussan L, Hassin-Baer S, Wertman E, Michaelson DM (1992) Alzheimer’s disease and Down’s syndrome antibodies bind to the heavy neurofilament protein of cholinergic neurons. Res Immunol 6: 583–588Google Scholar

Copyright information

© Springer-Verlag/Wien 1997

Authors and Affiliations

  • L. Oron
    • 1
  • V. Dubovik
    • 1
  • L. Novitsky
    • 1
  • D. Eilam
    • 2
  • D. M. Michaelson
    • 1
  1. 1.Department of NeurobiochemistryTel Aviv UniversityRamat AvivIsrael
  2. 2.Department of ZoologyTel Aviv UniversityRamat AvivIsrael

Personalised recommendations