Microglial AhR Drives Sex-Biased Amyloid Pathology

Microglial AhR activation by indoxyl-3-sulfate (I3S) in APPNL-F mice exacerbates cortical Aβ deposition and neuritic damage, with stronger effects in females.

• Why it matters: The pathways linking microbiota- and host-derived metabolites to microglial control of amyloid pathology in Alzheimer’s disease are not fully defined, especially regarding sex bias.
• What they did: APPNL-F mice received sustained I3S, or had constitutive or inducible AhR deletion; single-cell RNA sequencing assessed microglial state changes, and serum AhR bioactivity was measured in COGNIBIO12 and H2H.
• The result: AhR loss reduced amyloid burden, promoted plaque compaction, and preserved behavior; it reprogrammed microglia toward phagolysosomal and Aβ-recognition states, increased Aβ uptake, and IAld robustly activated AhR, while higher serum AhR bioactivity related to lower CSF Aβ42 in amyloid-positive patients.

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