Abstract
Previous studies suggest that microglial-expressed Apolipoprotein E (ApoE) is necessary to shift microglia into a neurodegenerative transcriptional state in Alzheimer's disease (AD) mouse models. On the other hand, elimination of microglia shifts amyloid beta (Aβ) accumulation from parenchymal plaques to cerebral amyloid angiopathy (CAA), mimicking the effects of global APOE*4 knock-in. Here, we specifically knock-out microglial-expressed ApoE while keeping astrocytic-expressed ApoE intact. When microglial-specific ApoE is knocked-out of a 5xFAD mouse model of AD, we found a ~35% increase in average Aβ plaque size, but no changes in plaque load, microglial number, microglial clustering around Aβ plaques, nor the formation of CAA. Immunostaining revealed ApoE protein present in plaque-associated microglia in 5xFAD mice with microglial-specific ApoE knockout, suggesting that microglia can take up ApoE from other cellular sources. Mice with Apoe knocked-out of microglia had lower synaptic protein levels than control mice, indicating that microglial-expressed ApoE may have a role in synapse maintenance. Surprisingly, microglial-specific ApoE knock-out resulted in few differentially expressed genes in both 5xFAD and control mice; however, some rescue of 5xFAD associated neuronal networks may occur with microglial-specific ApoE knock-out as shown by weighted gene co-expression analysis. Altogether, our data indicates that microglial-expressed ApoE may not be necessary for plaque formation or for the microglial transcriptional shift into a Disease Associated Microglia state that is associated with reactivity to plaques but may be necessary for plaque homeostasis in disease and synaptic maintenance under normal conditions.