Contribution of Neurons and Glial Cells to Complement-Mediated Synapse Removal during Development, Aging and in Alzheimer’s Disease

Figure 1

Model of complement-mediated synapse elimination during development, adulthood, and Alzheimer’s disease. (a) During early postnatal development, synaptic pruning takes place in order to eliminate excessive or weak synapses. Astrocytes induce the expression of C1q in neurons through TGF-β, and C1q colocalizes with synapses. The complement protein C3, which also colocalizes with synaptic puncta, is enzymatically cleaved to smaller fragments C3a and C3b. Finally, microglia engulf the synapse through the interaction of iC3b, the cleavage product of C3b, with its CR3 receptors. (b) In the healthy brain, synaptic pruning decreases with age to basal levels and complement protein expression is reduced. Nonetheless, microglia and astrocytes continuously survey surrounding synapses. (c) AD brain is characterized by progressive accumulation of extracellular and intracellular Aβ, gliosis, and neuroinflammation. Some studies have reported the role of microglia and complement pathway on synapse loss in AD models. Neuron-derived C1q and microglia-derived C1q are recruited to synapses and interact with Aβ. This triggers the activation of complement protein C3, expressed by both astrocytes and microglia. C3 is cleaved to smaller fragments such as C3b and iC3b that tag synapses and bind to CR3 on microglia. All these events lead to the removal of tagged synapses by the latter.

(a) Normal development

(b) Healthy brain

(c) Alzheimer’s disease