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Cultured rat microglia express C1q and receptor for C1q: implications for amyloid effects on microglia
A R Korotzer1, J Watt, D Cribbs
1IRU in Brain Aging, University of California at Irvine 92717, USA.
Abstract:
Senile plaques, the pathological hallmark of Alzheimer's disease (AD), are associated with complement components, including C1q. Reactive microglia appear to be involved in the later stages of plaque development. Since tissue macrophages are known to synthesize C1q, cultured rat microglia were examined for C1q immunoreactivity. Anti-C1q staining was detected, particularly in process-bearing microglia, indicating constitutive expression of C1q. Thus, microglia could provide a source of C1q for plaques even before becoming reactive. Since it has been previously shown that C1q binds beta 1-42, the major constituent of senile plaques, and since beta 1-42 is toxic to microglia in vitro, we asked if preincubation of beta 1-42 with C1q alters either metabolic indices of amyloid-induced degeneration in microglial cultures or the formation of amyloid deposits on these cells. While electron microscopic analysis of negatively stained amyloid fibrils confirmed that pre-incubation with C1q induced the association of C1q with the fibrils, no effect of the binding of C1q to beta 1-42 on beta 1-42 toxicity in microglia was observed. Interestingly, immunoreactivity for the C1q receptor that is known to modulate phagocytosis was found and was up-regulated in non-process-bearing microglia by interferon-gamma. While these data exclude a role for the C1q receptor in beta 1-42 toxicity in microglia, the observed expression and up-regulation of C1q receptor on microglia by interferon-gamma would be consistent with a role for C1q in complement-mediated inflammatory responses in AD and as a potential activator of microglial function in plaques.
Insights
Microglia constitutively express C1q, a complement component found in Alzheimer's disease plaques. C1q binding to amyloid-beta did not alter its toxicity to microglia, but C1q receptor expression suggests a role in inflammation.
Area of Science:
- Neuroimmunology
- Alzheimer's Disease Pathogenesis
- Complement System
Background:
- Senile plaques in Alzheimer's disease (AD) contain complement component C1q.
- Microglia, the brain's immune cells, are implicated in later stages of plaque development.
- Tissue macrophages synthesize C1q, prompting investigation into microglial C1q production.
Purpose of the Study:
- To determine if cultured rat microglia express C1q.
- To investigate if C1q binding to amyloid-beta (Aβ) affects its toxicity to microglia.
- To examine the expression and regulation of the C1q receptor on microglia.
Main Methods:
- Cultured rat microglia were analyzed for C1q immunoreactivity.
- Electron microscopy was used to assess C1q association with amyloid fibrils.
- Metabolic indices and amyloid deposition were measured in microglial cultures exposed to Aβ.
Main Results:
- Cultured microglia exhibited constitutive C1q immunoreactivity, particularly in process-bearing cells.
- Pre-incubation of Aβ with C1q led to C1q association with amyloid fibrils.
- No alteration in Aβ toxicity to microglia was observed upon C1q binding.
- C1q receptor immunoreactivity was detected and upregulated by interferon-gamma in non-process-bearing microglia.
Conclusions:
- Microglia represent a potential endogenous source of C1q in Alzheimer's disease plaques.
- C1q binding to Aβ does not mediate Aβ toxicity in microglial cultures.
- C1q receptor expression and upregulation suggest a role for C1q in microglial inflammatory responses and activation within plaques.