Complement component C1q inhibits beta-amyloid- and serum amyloid P-induced neurotoxicity via caspase- and calpain-independent mechanisms.
Alzheimer's disease is a neurodegenerative disorder characterized by neuronal loss, beta-amyloid (Abeta) plaques, and neurofibrillary tangles. Complement protein C1q has been found associated with fibrillar Abeta deposits, however the exact contributions of C1q to Alzheimer's disease is still unknown. There is evidence that C1q, as an initiator of the inflammatory complement cascade, may accelerate disease progression. However, neuronal C1q synthesis is induced after injury/infection suggesting that it may be a beneficial response to injury. In this study, we report that C1q enhances the viability of neurons in culture and protects neurons against Abeta- and serum amyloid P (SAP)-induced neurotoxicity. Investigation of potential signaling pathways indicates that caspase and calpain are activated by Abeta, but C1q had no effect on either of these pathways. Interestingly, SAP did not induce caspase and calpain activation, suggesting that C1q neuroprotection is in distinct from caspase and calpain pathways. In contrast to Abeta- and SAP-induced neurotoxicity, neurotoxicity induced by etoposide or FCCP was unaffected by the addition of C1q, indicating pathway selectivity for C1q neuroprotection. These data support a neuroprotective role for C1q which should be further investigated to uncover mechanisms which may be therapeutically targeted to slow neurodegeneration via direct inhibition of neuronal loss.
Pisalyaput
Karntipa
K
Department of Molecular Biology and Biochemistry, Institute for Brain Aging and Dementia, Center for Immunology, University of California, Irvine, California 92697, USA.
Tenner
Andrea J
AJ
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001921:Brain / Q000166:cytology; D002154:Calpain / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015922:Complement C1q / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D005047:Etoposide / Q000494:pharmacology; D007155:Immunologic Factors / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000683:Serum Amyloid P-Component / Q000633:toxicity*
D016229:Amyloid beta-Peptides; D000972:Antineoplastic Agents, Phytogenic; D007155:Immunologic Factors; D000683:Serum Amyloid P-Component; D005047:Etoposide; D015922:Complement C1q; D002154:Calpain; D020169:Caspases