Fig. 5
From: Terminal complement pathway activation drives synaptic loss in Alzheimer’s disease models
Proposed role of membrane attack complex (MAC) in complement mediated synapse loss. a In the current model for synapse elimination, C1q in the C1 complex binds an unknown tag on synapses for removal. Activated C1 then cleaves C4 and C2 to generate the C3 convertase C4b2a. The convertase cleaves C3 to C3b which binds the synapse membrane. C3b is cleaved to iC3b by factor I in the presence of cofactors. iC3b-tagged synapses are then engulfed by microglia expressing the iC3b receptor CR3. b In the revised model, complement is activated on synapses as above but proceeds through to formation of MAC, resulting in shedding of complement-opsonised synaptic fragments and “microlytic” destruction of the synapse. Microglia then phagocytose the opsonised fragments. c Peri-plaque synapses may be subject to bystander seeding of MAC precursors (C5b-7) as a result of plaque complement activation, leading to MAC formation on the synapse with consequences as in (b). Figure created with Biorender.com