C5aR1 antagonism suppresses microglial polarization and mitigates disease progression in a mouse model of Alzheimer’s disease

Despite the discovery of PMX205 more than 20 years ago and its reported beneficial effects in Alzheimer’s disease, the specific mechanism that might be driving the improvement in cognition are still not know. Here, we used the Tg2576 mouse model of Alzheimer’s disease and treated them with PMX205 at the onset of the amyloid pathology to further determine the effects of this C5aR1 antagonist on microglial cells. The results presented in this study demonstrated a neuroprotective effect of PMX205, which rescues the excessive synaptic pruning and synapse loss associated with Alzheimer’s disease. This finding seems to be linked to the reduction of a unique microglial subpopulation associated to synaptic pruning in the PMX205 treated mice. Interestingly, we also show here that blocking C5a-C5aR1 signaling in the Tg2576 mouse model of AD results in the increase of the DAM2 microglial subpopulation, suggesting that PMX205 might be inducing a disease mitigating phenotype on microglial cells. Our data further supports the use of C5aR1 antagonists as potential therapeutic targets to treat or slow the progression of Alzheimer’s disease. Single-cell RNA-seq libraries of 2 distinct mice genotypes and 2 distinct treatments Mice were perfused with PBS and cortex was dissected. scRNA was extracted from cortex. Approximately 15,000 microglia and astrocytes were collected for scRNA-seq. Briefly, cellular viability was assessed and cells were subsequently washed with PBS prior to library preparation. scRNA-seq protocol was performed as previously described Illumina 2016).