Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice

Abstract

The complement cascade not only is an innate immune response that enables removal of pathogens but also plays an important role in microglia-mediated synaptic refinement during brain development. Complement C3 is elevated in Alzheimer's disease (AD), colocalizing with neuritic plaques, and appears to contribute to clearance of Aβ by microglia in the brain. Previously, we reported that C3-deficient C57BL/6 mice were protected against age-related and region-specific loss of hippocampal synapses and cognitive decline during normal aging. Furthermore, blocking complement and downstream iC3b/CR3 signaling rescued synapses from Aβ-induced loss in young AD mice before amyloid plaques had accumulated. We assessed the effects of C3 deficiency in aged, plaque-rich APPswe/PS1dE9 transgenic mice (APP/PS1; KO). We examined the effects of C3 deficiency on cognition, Aβ plaque deposition, and plaque-related neuropathology at later AD stages in these mice. We found that 16-month-old APP/PS1; KO mice performed better on a learning and memory task than did APP/PS1 mice, despite having more cerebral Aβ plaques. Aged APP/PS1; KO mice also had fewer microglia and astrocytes localized within the center of hippocampal Aβ plaques compared to APP/PS1 mice. Several proinflammatory cytokines in the brain were reduced in APP/PS1; KO mice, consistent with an altered microglial phenotype. C3 deficiency also protected APP/PS1 mice against age-dependent loss of synapses and neurons. Our study suggests that complement C3 or downstream complement activation fragments may play an important role in Aβ plaque pathology, glial responses to plaques, and neuronal dysfunction in the brains of APP/PS1 mice.

Inhibition of Stat3‐mediated astrogliosis ameliorates pathology in an Alzheimer's disease model

“…D, E In the probe trial 24 h after the last training day, the time mice spent in the target quadrant (TQ) was different from chance in all groups except for APP/PS1-Stat3WT mice (P < 0.05, one-tailed one-sample t-test). Moreover, we also found that C3d, a characteristic product of "A1" astrocytes (Liddelow et al, 2017) that contributes to AD pathology (Shi et al, 2017), is strongly reduced by astrocyte Stat3 deletion. Importantly, the effects on cognition and network function were recapitulated by chronic treatment with a systemic Stat3 inhibitor.…”

Aminopyrimidine Class Aggregation Inhibitor Effectively Blocks Aβ–Fibrinogen Interaction and Aβ-Induced Contact System Activation

“…These complement C3-knockout AD mice performed better on learning and memory tests despite having more cerebral Aβ deposition. The reduced level of pro-inflammatory markers in these AD mice highlights the important role of inflammation in AD and suggests that targeting the inflammatory pathway could be highly beneficial in treating this disease 59 . Consistent with this finding, our group has shown that reducing neuroinflammation by depleting FXII improves the cognitive function of AD mice 25 .…”

TREM2 triggers microglial density and age‐related neuronal loss

“…Recently, complement has been linked to age‐related neurodegeneration. Complement C3‐deficient mice failed to display an age‐related hippocampal decline in the typical aging process (Shi et al, ) and displayed less neurodegeneration in aged AD model mice (Shi et al, ). Thus, decreased loss of neurons in TREM2 KO mice possibly might be related to the reduced complement expression.…”