Timing of global C1q deletion differentially regulates cognition and pathology in a mouse model of Alzheimer’s disease

The complement system, while having protective roles in the CNS, contributes to enhanced inflammation and cognitive decline in Alzheimer’s disease (AD). C1q, is required for the initiation of the classical complement cascade but also has multiple roles that are independent of the rest of the complement cascade. Previous reports showed that constitutive global deletion of C1q reduces glial activity and attenuates neuronal loss in AD mouse models with no effect on plaque load. In a separate study young adult deletion of C1q specifically in microglia resulted in improved spatial memory performance in the more aggressive Arctic (Arc) AD mouse model again without changes in plaque accumulation. Here we used the Arc model containing floxed C1qa gene with or without RosaCre ERT2 to determine if there were benefits when C1q was deleted globally in adulthood before robust amyloid accumulation or after substantial amyloid plaque accumulation vs C1q-sufficient Arc. Mice were treated with tamoxifen at either 11-wks or 20-wks of age to induce global C1q deletion. Spatial memory was tested prior to collecting brains at 10m of age. Brain sections were stained for C3/GFAP and C5aR1/Iba1 as a measure of glial activation. Superresolution microscopy was utilized to assess synaptic density of Vglut1-Psd95 synapses while confocal microscopy was used to quantify the engulfment of Vglut1 by microglia and amyloid by microglia and astrocytes. In summary, young adult global deletion of C1q in a mouse model of amyloidosis results in improved cognitive function, decreased synaptic pruning, reduced amyloid plaque accumulation and reduced astrocytic C3 expression, whereas deletion of C1q after substantial plaque deposition shows reduced C3 expression but only slight nonsignificant rescue of synaptic density, no change in amyloid accumulation and no improvement in cognitive function relative to the C1q-sufficient Arc at 10 mo of age. These findings support the role of C1q in synapse engulfment and astrocyte C3 induction and are also consistent with the hypothesis that peripheral C1q can contribute to amyloid plaque load, either directly or by modulating peripheral inflammation. The results also suggest a limited effective treatment window for targeting C1q for preservation of cognitive function.