Local apoptotic-like mechanisms underlie complement-mediated synaptic pruning

Abstract

SignificanceSynaptic pruning is dominant in early ontogenesis when a large number of unnecessary synapses are eliminated, and it maintains synaptic plasticity in the mature healthy brain, e.g., in memory processes. Its malfunction is involved in degenerative diseases such as Alzheimer’s disease. C1q, a member of the immune complement system, plays a central role in the selective pruning of synapses by microglial phagocytosis. Understanding the molecular aspects of complement-mediated synapse elimination is of high importance for developing effective therapeutic interventions in the future. Our analysis on C1q-tagged synaptosomes revealed that C1q label-based synaptic pruning is linked to local apoptotic-like processes in synapses.

Phagocytic elimination of synapses by microglia during sleep

“…Similarly, MerTK recognizes the PS on the cell surface by binding with opsonins protein S or GAS6 (Brown & Neher, 2014). The term synaptic apoptosis has been proposed to indicate that synaptosomes can undergo apoptotic changes by themselves while exposing PS to the outside of the cell (Gyorffy et al, 2018;Mattson, Keller, & Begley, 1998) together with the present results, suggest a possible mechanism underlying the selective elimination of synapses by microglia during sleep: that microglia phagocytose only inactive synapses exposing PS.…”

“…Based on our immunoblotting study, we estimated that the contents of synapsin I and PSD 95 at ZT0 were reduced by 25.2% and 12.5% relative to ZT12, respectively. The predominant disappearance of synapsin I compared to PSD95 might be correlated with the preferential binding of complements to the presynapses (Gyorffy et al, ). It has been reported that glutamate receptor contents in mouse forebrain synaptosomes decrease by 20% during the sleep phase (Diering et al, ).…”

“…Similarly, MerTK recognizes the PS on the cell surface by binding with opsonins protein S or GAS6 (Brown & Neher, ). The term synaptic apoptosis has been proposed to indicate that synaptosomes can undergo apoptotic changes by themselves while exposing PS to the outside of the cell (Gyorffy et al, ; Mattson, Keller, & Begley, ). Opsonization of cleaved caspase 3‐bearing or apoptotic inactive synapses with complement C1q and subsequent elimination have been reported in the barrel cortex after removal of the whiskers (Gyorffy et al, ).…”

“…The term synaptic apoptosis has been proposed to indicate that synaptosomes can undergo apoptotic changes by themselves while exposing PS to the outside of the cell (Gyorffy et al, ; Mattson, Keller, & Begley, ). Opsonization of cleaved caspase 3‐bearing or apoptotic inactive synapses with complement C1q and subsequent elimination have been reported in the barrel cortex after removal of the whiskers (Gyorffy et al, ). These reports, together with the present results, suggest a possible mechanism underlying the selective elimination of synapses by microglia during sleep: that microglia phagocytose only inactive synapses exposing PS.…”

Microglial inflammation and phagocytosis in Alzheimer's disease: Potential therapeutic targets

“…Studies have now shown C1q to be active downstream of Aβ processing. It has also been shown that C1q binds to neuronal presynaptic terminals and triggers local apoptosis (Gyorffy et al, ). In response to complement activation, microglia further express receptors for C3a and C5a, in turn triggering inflammation.…”