High throughput screening of patient's iPSC-derived neurons identifies gut microbial metabolites as a potential treatment for Alzheimer's disease.

Altered gut microbial composition observed in Alzheimer's disease patients drive microbial metabolome changes associated with AD pathogenesis; however, key microbial metabolites involved in this process and their functional roles are unknown. Here, we screened library of 352 gut metabolites in AD patient iPSC derived neurons for their ability to reduce phosphorylation of tau. We identified 4-methylcatechol, menaquinone-4 and agmatine as candidate metabolites associated with decreased tau phosphorylation and chose agmatine for further validatory studies. We demonstrated that Agmatine significantly reduce tau hyperphosphorylations (pTau181, pTau205 and pTau231) in AD patient iPSC-derived neurons and cerebral organoids. We also observed that agmatine treatment enhances learning and memory, reduces amyloid burden and neuroinflammation in a 5xFAD mouse model. Transcriptomics analysis from patient iPSC derived brain organoids suggested decreased expression of complement system pathway genes (e.g. C1S, C2, C3AR1, C5AR1) by agmatine treatment. The study also highlights agmatine as an important modulator of AD pathology via regulating C3aR-STAT3 axis and implicates it as a novel therapeutic target for AD. Overall design: We screened library of 352 gut metabolites in AD patient iPSC derived neurons for their ability to reduce phosphorylation of tau. We performed comparative transcriptomics analysis from patient iPSC derived brain organoids treated with DMSO and 100 µM agmatine at day 1 and day 3, in triplicates..