Rhizolutin, a Novel 7/10/6‐Tricyclic 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 7membered 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.

MiR-191-5p alleviates microglial cell injury by targeting Map3k12 (mitogen-activated protein kinase kinase kinase 12) to inhibit the MAPK (mitogen-activated protein kinase) signaling pathway in Alzheimer’s disease

“…All the results revealed that APP/PS1 mice in the study possess AD pathological features. Aβ accumulation induces apoptosis of neurons, which plays a pivotal role in AD development [ 50 ]. Hence, inhibiting apoptotic behavior of neurons is often considered as an approach for AD treatment [ 50 ].…”

Assigning the Origin of Microbial Natural Products by Chemical Space Map and Machine Learning

“…We therefore asked the question whether our MAP4 SVM classifier would correctly predict the origin of NPs newly reported in 2020 and which are not part of NPAtlas (Table 4). To our delight, the classifier correctly predicted the fungal origin for the newly reported epicospirocins 1 [56], penicimeroterpenoid A [57], and rhizolutin [58], as well as the bacterial origin of the recently reported bosamycin A [59]. The correct origin assignment is probably related to the presence of structurally similar NPs within the NPAtlas training set, illustrated here by the MAP4 nearest-neighbor NPs aspermicrone A [60], isocitreohybridone H [61], Monacolin K [62], and AIP I [63] (Figure 3).…”

Die Struktur des Cyclodecatriens Collinolacton, seine Biosynthese und semisynthetische Derivate: monopolare Spindeln und Schutz vor intrazellulärem oxidativem Stress

“…haben die protektiven Eigenschaften von Rhizolutin gegen Aβ‐induzierte Zytotoxizität untersucht. Für ihre Untersuchungen inkubierten sie murine hippocampale HT22‐Zellen mit bereits aggregiertem Aβ und bestimmten den Effekt auf die Zellviabilität [10] . Wir haben ähnliche Experimente mit derselben Zelllinie in einem Oxytosis‐Assay für Verbindung 1 und die Derivate 3 – 11 durchgeführt.…”

“…Wir haben die Verbindungen auf ihre Aktivität in einem bereits beschriebenen Aβ‐Aggregationsassay untersucht [31] . Collinolacton ( 1 ) zeigte ähnliche Effekte gegenüber Aβ‐Aggregation wie für Rhizolutin beschrieben [10] . Außerdem zeigte Verbindung 10 eine Reduktion der Aβ‐Aggregate um 25 %.…”