Microglial AhR Drives Sex-Biased Amyloid Pathology

Abstract

Microglia integrate local and systemic signals that can modify their response to amyloid-{beta} (A{beta}), but the molecular pathways connecting these signals to Alzheimer's disease (AD) pathology remain incompletely understood. Here, we identify the aryl hydrocarbon receptor (AhR), a sensor of microbiota- and host-derived metabolites, as a microglial regulator of amyloid pathology. Sustained administration of the AhR agonist indoxyl-3-sulfate (I3S) exacerbated cortical A{beta} deposition and plaque-associated neuritic damage in APPNL-F mice. Conversely, constitutive AhR deficiency reduced amyloid burden, promoted plaque compaction, and preserved behavioural performance, whereas inducible deletion of AhR in microglia was sufficient to reduce plaque accumulation. Single-cell RNA sequencing revealed that AhR loss reprogrammed microglia toward phagolysosomal and A{beta}-recognition states and enhanced microglial A{beta} uptake, with markedly stronger effects in females. APPNL-F mice also exhibited sex-dependent remodelling of the gut microbiota and tryptophan-derived metabolites. Circulating indole-3-aldehyde (IAld) robustly activated AhR and was associated with cortical amyloid pathology. AhR-activating bioactivity was increased in mouse serum, cortex and faecal extracts and was higher in serum from the COGNIBIO12 analytical subcohort than in independently recruited cognitively unimpaired H2H participants. Among amyloid-positive patients, higher serum AhR bioactivity was associated with lower CSF A{beta}42 concentrations. Together, these findings identify microglial AhR as a metabolically responsive regulator linking systemic ligand availability, biological sex, and microglial control of amyloid pathology.