Aims

The TAM (Tyro3, Axl, MerTK) receptor tyrosine kinases are known for their roles in phagocytosis and suppression of inflammation. Axl is upregulated on plaque-associated microglia and is regularly reported as a disease-associated microglial marker. Furthermore, Gas6, the primary CNS TAM ligand, has demonstrated efficacy in reducing neuroinflammation and alleviating pathology in multiple CNS diseases. We sought to determine the effects of overexpression of Gas6 on Alzheimer’s disease pathology with the following aims:

1. Determine whether overexpression of Gas6 alters behavior and plaque pathology in the APP/PS1 model of Alzheimer’s disease.

2. Determine effect of Gas6 on microglial activation using immunohistochemistry and bulk RNAseq of FACS-sorted microglia for transcriptional analyses following Gas6 overexpression.

Methods

APP/PS1 mice and nontransgenic littermates were treated with intrahippocampal injections of AAV containing Gas6 or an attenuated Gas6 protein as control. One month later, mice performed behavioral tasks including open field, novel object recognition, and fear conditioning. Immunohistochemical analyses for plaque pathology and microglial markers were completed. RNAseq was performed on FACS-sorted microglia from Gas6 and control-treated mice.

Results

Gas6 overexpression worsens performance in the contextual fear conditioning task and reduces plaque number in male APP/PS1 mice. Gas6 induces a proinflammatory microglial transcriptional signature.

Conclusions

Overexpression of Gas6 worsens behavior and reduces plaque number in male APP/PS1 mice. Contrary to literature describing an anti-inflammatory effect of Gas6, we found that overexpression of Gas6 in aged APP/PS1 mice induces a proinflammatory microglial signature, which may suggest a novel role for Gas6.