Neuroglial-mediated immunoinflammatory responses in Alzheimer's disease: complement activation and therapeutic approaches.
Increasing evidence points to A beta-containing senile plaques as primary etiological agents in Alzheimer's disease (AD). The mechanism by which these deposits cause neurotoxicity is unresolved, but there are compelling data suggesting that the activated glia found associated with senile plaques contribute to the pathology of AD. These cells appear to release a variety of immunoinflammatory molecules, including complement proteins whose activation products colocalize with senile plaques and dystrophic neurites. Previous studies showed that A beta can bind and activate complement protein C1q, providing a plausible explanation for the initiation of the complement cascade in AD. Data presented here further define the nature of A beta-C1q association, revealing key aspects of the C1q domain involved in binding the amyloid peptide. Moreover, we show that it is possible to inhibit A beta-induced complement activation without affecting the normal immunoglobulin-mediated complement pathway. This indicates that it should be feasible to develop drugs to reduce complement damage in AD without compromising this important immune-defense mechanism throughout the body.
Chen
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Gliatech Incorporated, Cleveland, OH 44122, USA.
Frederickson
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Brunden
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D000544:Alzheimer Disease / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D003167:Complement Activation / Q000187:drug effects / Q000502:physiology*; D015922:Complement C1q / Q000096:biosynthesis; D003169:Complement Inactivator Proteins / Q000494:pharmacology; D003171:Complement Pathway, Classical / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D009457:Neuroglia / Q000502:physiology*
D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003169:Complement Inactivator Proteins; D015922:Complement C1q