Inhibition of C1q-beta-amyloid binding protects hippocampal cells against complement mediated toxicity.
Activation of complement by beta-amyloid (A beta) contributes to the pathology of Alzheimer's disease (AD). Here, we show that C1-Inhibitor (C1-Inh) protects cultured rat hippocampal cells against beta-amyloid induced complement lysis indicating a classical pathway-mediated activation mechanism. We report on screening of compound libraries to identify compounds that inhibit C1q binding to beta-amyloid. Characterization of these compounds revealed that C1q possessed distinct binding sites for beta-amyloid and antibodies. One selected compound protected cultured hippocampal cells against complement-dependent beta-amyloid toxicity. These results provide evidence that complement has the potential to damage hippocampal cells, and C1q is a relevant target to suspend this deleterious mechanism in Alzheimer's disease.
Sárvári
M
M
Department of Molecular Biology, Gedeon Richter Ltd., Gyomroi u. 19-21, Budapest 10, POB27, 1103, Hungary.
Vágó
I
I
Wéber
C S
CS
Nagy
J
J
Gál
P
P
Mák
M
M
Kósa
J P
JP
Závodszky
P
P
Pázmány
T
T
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D015922:Complement C1q / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D003171:Complement Pathway, Classical / Q000187:drug effects / Q000276:immunology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity*; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D051381:Rats; D017208:Rats, Wistar
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D015922:Complement C1q