Rhizolutin, a novel 7/10/6­tricyclic dilactone, dissociates misfolded protein aggregates and reduces apoptosis/inflammation associated with Alzheimer’s disease

Abstract

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-b (Ab) plaques and tau tangles, which are key pathological hallmarks of Alzheimers disease (AD). Rhizolutin treatment of APP/PS1 double transgenic mice with AD significantly dissociated hippocampal plaques. In vitro, rhizolutin substantially decreased Ab-induced apoptosis and inflammation in neuronal and glial cells. Our findings introduce a unique chemical entity that targets Ab and tau concurrently by mimicking misfolded protein clearance mechanisms of immunotherapy, which is prominently investigated in clinical trials.