Year: 2026
Type: preprint
Abstract: Microglia integrate local and systemic signals that can modify their response to amyloid-β (Aβ), 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 Aβ deposition and plaque-associated neuritic damage in APP NL-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 Aβ-recognition states and enhanced microglial Aβ uptake, with markedly stronger effects in females. APP NL-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 Aβ42 concentrations. Together, these findings identify microglial AhR as a metabolically responsive regulator linking systemic ligand availability, biological sex, and microglial control of amyloid pathology.
Authors: Carmen Nieto-Vaquero, Alicia Garcia-Culebras, Andrea Rubio-Ponce, David Chamoso-Sanchez, Manuel J. Gomez, F. Javier de Castro-Millan, Carlos Parra-Perez, Sandra Vazquez-Reyes, Aurora Semerano, Isabel Bravo-Ferrer, Ana Moraga-Yebenes, Coral Barbas, Hector Bueno, Estrella Morenas-Rodriguez, Fatima Sanchez-Cabo, Alberto Villarejo-Galende, Takashi Saito, Takaomi C. Saido, Pedro M. Fernandez-Salguero, Ignacio Lizasoain, Maria Isabel Cuartero, Maria Angeles Moro
Institutions: Universidad Complutense de Madrid, Spanish National Centre for Cardiovascular Research, Universidad San Pablo CEU, Harvard University, Massachusetts General Hospital, Research Institute Hospital 12 de Octubre, Hospital Universitario 12 De Octubre, The University of Tokyo, RIKEN Center for Brain Science, Universidad de Extremadura
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7225408074