Acute communication between microglia and non-parenchymal immune cells in the anti-Aβ antibody injected cortex.

Anti-Aβ immunotherapy use to treat Alzheimer's disease is on the rise. While anti-Aβ antibodies provide hope in targeting Aβ plaques in the brain there still remains a lack of understanding regarding the cellular responses to these antibodies in the brain. In this study we sought to identify acute effects of anti-Aβ antibody on immune responses. To determine cellular changes due to anti-Aβ antibody exposure, we intracranially injected 14mo APP male and female mice with anti-Aβ IgG1 (6E10) or control IgG1 into the cortex. After 24hrs or 3days, we harvested the cortex and performed a glial cell enriched preparation for single cell sequencing. Cell types, proportions, and cell-to-cell signaling was evaluated between the two injection conditions and two acute timepoints. We identified 23 unique cell clusters including microglia, astrocytes, endothelial cells, neurons, oligos/OPCs, immune cells, and unknown. The anti-Aβ antibody injected cortices revealed more ligand-receptor(L-R) communications between cell types, as well as stronger communications at only 24hrs. At 3 days, while there were more L-R communications for the anti-Aβ antibody condition, the strength of these connections was stronger in the control IgG condition. We also found evidence of an initial and strong communication emphasis in microglia-to-non-parenchymal immune cells at 24hrs, specifically in the TGFβ signaling pathway. We identify several pathways that specific to anti-Aβ antibody exposure at acute timepoints. These data lay the groundwork for understanding the brain's unique response to anti-Aβ antibody. Anti-Aβ monoclonal antibody therapy is the first disease-modifying therapy to be traditionally approved by the FDA. The target population is relatively small due to the incidence of adverse vascular reactions in a significant proportion of individuals. While these adverse reactions are prevalent, our basic understanding of the cellular responses to these antibodies limits our ability to further refine this therapeutic approach to increase safety and accessibility. These studies are the first, but critical, step in understanding the brain's response to anti-Aβ antibodies.