NFκB-Activated Astroglial Release of Complement C3 Compromises Neuronal Morphology and Function Associated with Alzheimer's Disease

Abnormal NF kappa B activation has been implicated in Alzheimer's disease (AD). However, the signaling pathways governing NF kappa B regulation and function in the brain are poorly understood. We identify complement protein C3 as an astroglial target of NF kappa B and show that C3 release acts through neuronal C3aR to disrupt dendritic morphology and network function. Exposure to Ab activates astroglial NF kappa B and C3 release, consistent with the high levels of C3 expression in brain tissue from AD patients and APP transgenic mice, where C3aR antagonist treatment rescues cognitive impairment. Therefore, dysregulation of neuron-glia interaction through NF kappa B/C3/C3aR signaling may contribute to synaptic dysfunction in AD, and C3aR antagonists may be therapeutically beneficial.