Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer's disease mouse models

In this multi-omics study, the authors identified C1q-dependent synapse elimination by both astrocytes and microglia in Alzheimer's mouse models. While astrocytes preferentially removed excitatory synapses, microglia preferred inhibitory synapses. Microglia and complement can mediate neurodegeneration in Alzheimer's disease (AD). By integrative multi-omics analysis, here we show that astrocytic and microglial proteins are increased in Tau(P301S) synapse fractions with age and in a C1q-dependent manner. In addition to microglia, we identified that astrocytes contribute substantially to synapse elimination in Tau(P301S) hippocampi. Notably, we found relatively more excitatory synapse marker proteins in astrocytic lysosomes, whereas microglial lysosomes contained more inhibitory synapse material. C1q deletion reduced astrocyte-synapse association and decreased astrocytic and microglial synapses engulfment in Tau(P301S) mice and rescued synapse density. Finally, in an AD mouse model that combines beta-amyloid and Tau pathologies, deletion of the AD risk gene Trem2 impaired microglial phagocytosis of synapses, whereas astrocytes engulfed more inhibitory synapses around plaques. Together, our data reveal that astrocytes contact and eliminate synapses in a C1q-dependent manner and thereby contribute to pathological synapse loss and that astrocytic phagocytosis can compensate for microglial dysfunction.

Automated summary

In this study, the authors found that astrocytes and microglia eliminate synapses in a C1q-dependent manner in Alzheimer's mouse models. Astrocytes preferentially remove excitatory synapses, while microglia prefer inhibitory synapses. The study also revealed the contribution of astrocytes to synapse elimination in the hippocampus of Tau(P301S) mice. The findings suggest that astrocytes play a role in pathological synapse loss and can compensate for microglial dysfunction.