Rhizolutin, a Novel 7/10/6-Tricyclic Dilactone, Dissociates Misfolded Protein Aggregates and Reduces Apoptosis/Inflammation Associated with Alzheimer's Disease.
Yun KwonJisu ShinKwangho NamJoon Soo AnSeung-Hoon YangSeong-Heon HongMunhyung BaeKyuho MoonYakdol ChoJiwan WooKeunwan ParkKyeonghwan KimJongheon ShinByung-Yong KimYoung Soo KimDong-Chan OhPublished in: Angewandte Chemie (International ed. in English) (2020)
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.
Keyphrases
- induced apoptosis
- oxidative stress
- endoplasmic reticulum stress
- clinical trial
- signaling pathway
- cell cycle arrest
- cognitive decline
- protein protein
- cerebrospinal fluid
- cerebral ischemia
- amino acid
- binding protein
- cell death
- mass spectrometry
- neuropathic pain
- randomized controlled trial
- small molecule
- high resolution
- spinal cord injury
- brain injury
- phase ii
- subarachnoid hemorrhage
- blood brain barrier
- placebo controlled
- replacement therapy