Rhizolutin, a Novel 7/10/6‐Tricyclic Dilactone, Dissociates Misfolded Protein Aggregates and Reduces Apoptosis/Inflammation Associated with Alzheimer's Disease

Rhizolutin (1) was discovered as a natural product of ginseng‐rhizospheric Streptomyces sp. WON17. Its structure features an unprecedented 7/10/6‐tricyclic dilactone carbon skeleton composed of dimethylcyclodecatriene flanked by a 7‐membered and a 6‐membered lactone ring based on spectroscopic analysis. During an unbiased screening of natural product libraries, this novel compound was found to dissociate amyloid‐β (Aβ) plaques and tau tangles, which are key pathological hallmarks of Alzheimer's disease (AD). Rhizolutin treatment of APP/PS1 double transgenic mice with AD significantly dissociated hippocampal plaques. In vitro, rhizolutin substantially decreased Aβ‐induced apoptosis and inflammation in neuronal and glial cells. Our findings introduce a unique chemical entity that targets Aβ and tau concurrently by mimicking misfolded protein clearance mechanisms of immunotherapy, which is prominently investigated in clinical trials. Rhizolutin was discovered from a ginseng‐rhizospheric Streptomyces strain and structurally characterized as an unprecedented 7/10/6‐tricyclic dilactone based on spectroscopic analysis and chemical derivatizations. Rhizolutin was found to dissociate Aβ and tau aggregates and reduced Alzheimer's disease (AD)‐like pathology in APP/PS1 transgenic mice.