Redox modulation of the complement cascade contributes to synapse loss in Alzheimer's disease.

Abstract

Neuroinflammation is characterized by activation of the immune response in the central nervous system (CNS). In Alzheimer's disease (AD), this involves stimulation of glial cells, including microglia and astrocytes, that surround senile plaques and affected neurons. The complement system is a crucial component of the innate immune system, responsible for rapidly eliminating pathogens and dead or dying cells, while also influencing the magnitude and duration of the inflammatory immune response. Moreover, the complement system plays both neuroprotective and neurodestructive roles. In AD, dysregulation of the complement system contributes to excessive microglial phagocytosis of synapses, with such synaptic loss representing the major correlate to cognitive decline in the course of the disease. However, the detailed mechanism for complement activation in AD had remained poorly understood until the discovery that complement factors were aberrantly S-nitrosylated, representing a redox-mediated posttranslational modification that controls the complement cascade. Nitrosative stress, caused by excessive generation of reactive nitrogen species (RNS), including nitric oxide (NO)-related species, had been recognized as a critical factor in the pathogenesis and progression of AD. Recent publications highlighted in this review support the notion that the NO-related species support aberrant S-nitrosylation of complement proteins, leading to pathological activation of the complement system, thus contributing to synaptic loss in AD.