Pathological proteins in senile plaques.
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(-4) M range).(ABSTRACT TRUNCATED AT 250 WORDS)
McGeer
P L
PL
Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, Canada.
Klegeris
A
A
Walker
D G
DG
Yasuhara
O
O
McGeer
E G
EG
D000544:Alzheimer Disease / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D000682:Amyloid / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000032:analysis; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D001923:Brain Chemistry; D003180:Complement C3b Inactivator Proteins / Q000494:pharmacology / Q000627:therapeutic use; D015938:Complement Membrane Attack Complex / Q000032:analysis; D003171:Complement Pathway, Classical; D003165:Complement System Proteins / Q000032:analysis; D016326:Extracellular Matrix Proteins / Q000032:analysis; D006801:Humans; D017628:Microglia / Q000737:chemistry / Q000276:immunology / Q000473:pathology*; D008959:Models, Neurological; D009419:Nerve Tissue Proteins / Q000032:analysis*; D016501:Neurites / Q000473:pathology; D009895:Opsonin Proteins / Q000276:immunology; D016897:Respiratory Burst / Q000187:drug effects; D015054:Zymosan / Q000037:antagonists & inhibitors / Q000276:immunology
D000682:Amyloid; D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D003180:Complement C3b Inactivator Proteins; D015938:Complement Membrane Attack Complex; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D009895:Opsonin Proteins; D003165:Complement System Proteins; D015054:Zymosan