High-throughput screening of patient iPSC-derived neurons identifies the gut microbial metabolites that attenuate Alzheimer's disease pathology (RNA-Seq HMC3-LPS-Agmatine)

ABSTRACT: Gut microbiota-derived metabolites influence the gut-brain axis and may impact Alzheimer’s disease (AD) pathology. However, the microbial metabolites involved in this process and their functional roles are largely unknown. We screened 352 gut metabolites in induced pluripotent stem cells (iPSC)-derived neurons from individuals with AD to identify compounds that reduce tau hyperphosphorylation. We identified agmatine as a lead candidate which decreased hyperphosphorylated tau in neurons and cerebral organoids. In 5xFAD mice, agmatine (100 mg/kg/day) improved cognition, reduced amyloid plaques, lowered neuroinflammation, and increased beneficial gut bacteria, including Agathobacter and Bacteroides. Transcriptomic analysis showed that agmatine downregulated complement and inflammatory genes (C1QB, C2, C3AR1, CCL3, CXCL8 and CXCL6) in patient iPSC-derived cerebral organoids. Agmatine also decreased C3aR and pSTAT3 levels in vivo, mechanistically supporting the reduced tau phosphorylation in iPSC-derived neurons. Altogether, these findings identified the therapeutic potential of gut-derived metabolites and identified agmatine as potential treatment for AD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE351598 | GEO | 2026/10/21

REPOSITORIES: GEO