Rhizolutin dissociates beta and tau aggregates
From: Wiley
November 2, 2020 -- A bacterium found
among the soil close to roots of ginseng plants could provide a new approach
for the treatment of Alzheimer's. Rhizolutin, a novel class of compounds with a
tricyclic framework, significantly dissociates the protein aggregates associated
with Alzheimer's disease both in vivo and in vitro, as reported
by scientists in the journal Angewandte Chemie.
The area around the roots of plants is a
complex ecosystem with numerous interactions between plants and diverse
microorganisms. The so-called rhizosphere has been neglected in the search for
new drugs, though it has much to offer. A team working with YoungSoo Kim
(Yonsei University, Incheon, South Korea) and Dong-Chan Oh (Seoul National University,
South Korea) has now identified a natural substance called rhizolutin that may
provide a basis for novel Alzheimer's disease treatments. Rhizolutin is
produced by a Streptomyces strain that grows in the root zone of ginseng
plants. Ginseng is an Asian plant used in traditional medicine, where it is
said to be a tonic.
Through cultivation in a medium
fortified with ginseng powder, the researchers were able to increase the
rhizolutin production of the bacterium by a factor of ten. This allowed them to
determine the structure of this novel compound, which turns out to be a unique
framework made of three rings bound together (a 7/10/6-tricyclic dilactone
flanked by a seven-membered and a six-membered lactone ring).
A screening of natural product libraries
indicated that rhizolutin is a drug lead that can dissociate amyloid-β (Aβ)
plaques and tau tangles (fiber-like aggregates of tau proteins), both of which
are typical hallmarks of Alzheimer's disease. Such deposits form when amyloid-β
proteins fold incorrectly to form β-sheets, which can aggregate to form
insoluble plaques and fibers. These lead to the death of nerve cells, nerve
inflammation, brain atrophy, and the cognitive losses these entail. No
effective treatment for Alzheimer's disease has been found.
Through a variety of in vitro and
in vivo experiments, the team was able to demonstrate that rhizolutin
leads to clear dissociation of insoluble Aβ and tau aggregates. In cultures of
neuronal and glial cells, rhizolutin was able to markedly reduce the inflammatory
processes and cell death caused by Aβ. Rhizolutin was also able to
significantly dissociate the Aβ plaques present in the brains of mice with
Alzheimer's. The process seems to be similar to the removal of incorrectly
folded proteins through immunotherapy. Computer simulations suggest that
rhizolutin enters into the hydrophobic regions of the aggregated β-sheets,
initiating the dissociation.
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