1994 Volume 174 Issue 3 Pages 269-277
MCGEER, P.L., KLEGERIS, A., WALKER, D.G., YASUHARA, O. and MCGEER, E.G. Pathological Proteins in Senile Plaques. Tohoku J. Exp. Med., 1994, 174 (3), 269-277 - The beta-amyloid protein deposits of Alzheimer disease, whether in diffuse or consoliated form, are an agglomeration of many extracellular proteins. At least 35 have been reported as components of senile plaques, most of which also occur in diffuse deposits. More than half of these proteins are directly associated with the immune system. Since diffuse deposits are believed to be the precursors of senile plaques, it is important to define the precise molecular events that lead to the transition. Diffuse deposits share with senile plaques the presence of opsonizing components of complement, the complement activators beta-amyloid protein, amyloid P, thrombin, and apolipoprotein E. However, senile plaques contain, in addition, dystrophic neurites, agglomerates of activated microglia, components of the membrane attack complex, and the inhibitors of the membrane attack complex, clusterin, protectin and vitronectin. Microglial cells are professional phagocytes which possess the respiratory burst apparatus when activated. It produces extracellular superoxide molecules which can then form additional toxic products such as hydrogen peroxide and hydroxyl free radicals. It has long been known that opsonized zymosan is a powerful activator of the respiratory burst system. We found this activation could be inhibited by antibodies to complement receptors in the nanomolar range. Dapsone and indomethacin, two antiinflammatory agents that may have therapeutic potential in Alzheimer disease, were weakly inhibitory (10-4M range). These data suggest that complement activation to a level where the membrane attack complex is generated, and respiratory burst toxins are produced, may underlie an autodestructive mechanism in Alzheimer disease, and further imply that intervention in this activation may have therapeutic possibilities.
