Identification of Aryl Hydrocarbon Receptor (AhR) as a Functional Target that Enhances Astrocytic ApoE Secretion

We discovered a chemical series that enhances ApoE secretion from human astrocytes through mechanisms independent of LXR agonism. Using chemoproteomics, photoaffinity probes, KINOMEscan analysis, and siRNA knockdowns, we identified the aryl hydrocarbon receptor (AhR), a transcription factor not previously linked to ApoE secretion, as the primary target. AhR antagonism was confirmed to increase ApoE secretion through a panel of agonists/antagonists and genetic knockdown. While chronic AhR inhibition is unsuitable for Alzheimer's treatment due to peripheral effects, these findings highlight AhR as a modulator of ApoE secretion and a pathway worth further exploration. There is two datasets deposited for this project. One dataset was generated through affinity chromatography enrichment, and the second dataset was generated through photo-affinity chromatography enrichment.