Journal
NEUROBIOLOGY OF AGING
Volume 33, Issue 10, Pages 2237-2246Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2011.12.005
Keywords
C5b-9; Complement C9 protein; Alzheimer's disease; Macular degeneration; Paroxysmal nocturnal hemoglobinuria
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Funding
- Pacific Alzheimer Research Foundation
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Complement plays a vital role in both the innate and adaptive immune systems. It recognizes a target, opsonizes it, generates anaphylatoxins, and directly kills cells through the membrane attack complex (MAC). This final function, which assembles C5b-9(n) on viable cell surfaces, can kill host cells through bystander lysis. Here we identify for the first time compounds that can inhibit bystander lysis while not interfering with the other essential functions of complement. We show that aurin tricarboxylic acid (ATA), aurin quadracarboxylic acid (AQA), and aurin hexacarboxylic acid (AHA), block the addition of C9 to C5b-8 so that the MAC cannot form. These molecules inhibit hemolysis of human, rat, and mouse red cells with a half maximal inhibitory concentration (IC50) in the nanomolar range. When given orally to Alzheimer disease type B6SJL-Tg mice, they inhibit MAC formation in serum and improve memory retention. On autopsy, they show no evidence of harm to any organ. Aurin tricarboxylic acid, aurin quadracarboxylic acid, and aurin hexacarboxylic acid may be effective therapeutic agents in Alzheimer disease and other degenerative disorders where self damage from the MAC occurs. (c) 2012 Elsevier Inc. All rights reserved.
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