Interactions between microglia and neurons mediated by complement. Surveillance microglia may express low levels of CR1, CR3, and iC3b whilst healthy neurones do not express or produce significant complement. Phosphatidylserine is mainly expressed on the internal surface of the neuronal plasma membrane, preventing it acting as an “eat-me” signal, and complement production by the cell is low. During neuroinflammation and neurodegeneration, activated microglia, responding to the generation of complement factors, increase their expression of complement receptors, produce complement factors, and migrate towards the chemotaxic signals of C3a and C5a. Microglia may exacerbate the secretion of complement factors by secreting cytokines (following exposure to A plaques), which can feed onto astrocytes or form a feedback loop with microglia themselves, promoting glial complement factors secretion. Exposure of secreted complement factors to A plaques can lead to complement activation. Apoptotic neurones become opsonised with iC3b, C3b, and C1q deposition, the latter on apoptotic blebs, and the neurons may also shed additional complement factors. Phosphatidylserine flips to the outside of the plasma membrane where it can potentiate expression of “eat-me” signals by promoting the expression of iC3b on the cell surface [93].
