Bacterial polar metabolites modulate β-amyloid toxicity and cholinergic dysfunction in models of Alzheimer's disease.

Alzheimer's disease is characterized by progressive neurodegeneration driven by β-amyloid (Aβ) toxicity, oxidative stress, and cholinergic dysfunction. In this study, we investigated whether polar metabolites derived from a cultivable bacterial isolate could modulate Aβ-associated neurodegenerative phenotypes in complementary experimental models. A bioactivity-guided approach identified an aqueous fraction with high antioxidant capacity in DPPH, FRAP, and ORAC assays. In a transgenic Drosophila melanogaster model expressing human Aβ, treatment with this fraction significantly reduced amyloid accumulation and attenuated neurodegenerative histopathological alterations. In human SH-SY5Y neuronal cultures, the metabolites improved cell viability under therapeutic, but not preventive, conditions following exposure to aggregated Aβ. The aqueous fraction also exhibited significant inhibitory activity against acetylcholinesterase and butyrylcholinesterase. Whole-genome sequencing assigned the bioactive isolate to the genus Providencia, with comparative genomic analyses suggesting its placement within a distinct taxonomic lineage. Metabolomic profiling by LC-ESI-MS/MS revealed a diverse set of polar metabolites, including metabolites putatively annotated based on spectral matching, previously associated with neuroprotective and cholinesterase-modulating activities. Collectively, these findings demonstrate that bacterial polar metabolites can modulate key pathological features of Alzheimer's disease, supporting their relevance for mechanistic studies of Aβ toxicity and cholinergic dysfunction.