Sequential upregulation of cell adhesion molecules in degenerating rat basal forebrain cholinergic neurons and in phagocytotic microglial cells.
To study the functional role of adhesion molecules in neurodegenerative events in vivo, the basal forebrain cholinergic lesion-induced expression of the intercellular adhesion molecule (ICAM)-1 and leukocyte function-associated antigen (LFA)-1 was studied by double immunocytochemistry and Western blot analysis. A single intracerebroventricular application of the cholinergic immunotoxin, 192IgG-saporin, produced a selective cholinergic cell loss in rat basal forebrain nuclei detectable by gradual loss of choline acetyltransferase (ChAT)-immunoreactive cells starting 3 days but being nearly complete 7 days after injection of the toxin. The degeneration of cholinergic neurons was accompanied by a striking appearance of activated microglial cells in the lesioned areas. Four days following injection of 192IgG-saporin, ICAM-1 immunoreactivity was predominantly observed in ChAT-positive neurons and partly in activated microglia in the basal forebrain nuclei, while LFA-1 expression at this time point was restricted to neurons. However, 7 days after cholinergic lesion, only a few, shrunken neuronal somata were found to be immunoreactive for ICAM-1 and LFA-1, while activated microglial cells demonstrated strong immunoreactivity for ICAM-1 and LFA-1 in the lesioned forebrain areas, persisting up to 14 days after lesion while no immunoreactivity was observed in neurons at this time point. Western blot analysis demonstrated increased ICAM-1 level in the basal forebrain already detectable 4 days after surgery but being more pronounced 7 days post lesion. The data suggest that ICAM-1 and LFA-1 may act as intercellular recognition signals by which degenerating cholinergic neurons actively participate in the sequence of events leading to their targeting and elimination by phagocytotic microglia.
Paul Flechsig Institute for Brain Research, Department of Neurochemistry, University of Leipzig, Jahnallee 59, D-04109, Leipzig, Germany.
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Hartlage-Rübsamen
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Schliebs
D000818:Animals; D000911:Antibodies, Monoclonal; D018678:Cholinergic Agents; D002799:Cholinergic Fibers / Q000737:chemistry / Q000378:metabolism*; D007150:Immunohistochemistry; D000922:Immunotoxins; D007276:Injections, Intraventricular; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D008297:Male; D017628:Microglia / Q000737:chemistry / Q000378:metabolism*; D009699:N-Glycosyl Hydrolases; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D010587:Phagocytosis / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D012686:Septal Nuclei / Q000378:metabolism / Q000473:pathology; D020665:Septum of Brain / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000502:physiology
C085696:192 IgG-saporin; D000911:Antibodies, Monoclonal; D018678:Cholinergic Agents; D000922:Immunotoxins; D016169:Lymphocyte Function-Associated Antigen-1; D054789:Ribosome Inactivating Proteins, Type 1; D018799:Intercellular Adhesion Molecule-1; D009699:N-Glycosyl Hydrolases; D000076985:Saporins