Borrelidin from Saltern-Derived Halophilic Nocardiopsis sp. Dissociates Amyloid-? and Tau Fibrils.

ABSTRACT:

Background

Alzheimer's disease (AD) is characterized by the aggregation of two pathological proteins, amyloid-? (A?) and tau, leading to neuronal and cognitive dysfunction. Clearance of either A? or tau aggregates by immunotherapy has become a potential therapy, as these aggregates are found in the brain ahead of the symptom onset. Given that A? and tau independently and cooperatively play critical roles in AD development, AD treatments might require therapeutic approaches to eliminate both aggregates together.

Objective

We aimed to discover a chemical drug candidate from natural sources for direct dissociation of both insoluble A? and tau aggregates through in vitro assessments.

Methods

We isolated four borrelidin chemicals from a saltern-derived halophilic actinomycete strain of rare genus Nocardiopsis and simulated their docking interactions with A? fibrils. Then, anti-cytotoxic, anti-A?, and anti-tau effects of borrelidins were examined by MTT assays with HT22 hippocampal cell line, thioflavin T assays, and gel electrophoresis.

Results

When HT22 cells were exposed to A? aggregates, the treatment of borrelidins alleviates the A?-induced toxicity. These anti-cytotoxic effects can be derived from the inhibitory functions of borrelidins against the A? aggregation as shown in thioflavin T and gel electrophoretic analyses. Among them, especially borrelidin, which exhibits the highest probability of docking, not only dissociates A? aggregates but also directly regulates tau aggregation.

Conclusion

Borrelidin dissociates insoluble A? and tau aggregates together and our findings support the view that it is possible to develop an alternative chemical approach mimicking anti-A? or anti-tau immunotherapy for clearance of both aggregates.

SUBMITTER: Shin J 

PROVIDER: S-EPMC7903018 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature