Metabolites of soil microorganisms modulate amyloid \u03b2 production in Alzheimer\u2019s neurons

Takayuki Kondo,Tsuyoshi Yamamoto,Haruhisa Inoue,Kaoru Okayama,Hideki Narumi

doi:10.1038/s41598-022-06513-z

Abstract

Microbial flora is investigated to be related with neuropathological conditions in Alzheimer’s disease (AD), and is attracting attention as a drug discovery resource. However, the relevance between the soil microbiota and the pathological condition has not been fully clarified due to the difficulty in isolation culture and the component complexity. In this study, we established a library of secondly metabolites produced in microorganism to investigate the potential effect of microorganisms on the production of amyloid β (Aβ), one of the most representative pathogens of AD. We conducted a library screening to quantify Aβ and neuronal toxicity by using cortical neurons from human induced pluripotent stem cells (iPSCs) of AD patients after adding secondary metabolites. Screening results and following assessment of dose-dependency identified Verrucarin A, produced in Myrothecium spp., showed 80% decrease in Aβ production. Furthermore, addition of Mer-A2026A, produced in Streptomyces pactum, showed increase in Aβ42/40 ratio at the low concentration, and decrease in Aβ production at the higher concentration. As a result, established library and iPSC-based phenotyping assay clarified a direct link between Aβ production and soil microorganisms. These results suggest that Aβ-microorganism interaction may provide insight into the AD pathophysiology with potential therapeutics.

Highlights

Microbial flora is investigated to be related with neuropathological conditions in Alzheimer’s disease (AD), and is attracting attention as a drug discovery resource
These results indicate that the established library of compounds derived from soil microorganisms will be a new human-cell-based approach for investigating therapeutic agents, and will provide a direct clue to understanding the interaction potential of amyloid β (Aβ) in AD with microbiota
We utilized a chemical library consisting of 98 compounds, all secondary metabolites originating from soil microbiota (Table 1, Fig. 1b)

Summary

Introduction

Microbial flora is investigated to be related with neuropathological conditions in Alzheimer’s disease (AD), and is attracting attention as a drug discovery resource. As combinatorial chemistry technology has become more sophisticated, drug discovery based on natural products, including microorganisms, went downhill temporarily, and has received attention again in the 2000s4,5. We established a secondary metabolites library originating from soil microbiota, and applied the established library to the human-induced pluripotent stem cells (iPSCs) model which can recapitulate the Aβ metabolism, including altered Aβ production or Aβ42/40 ratio in iPSC-derived neurons from a patient with PSEN1 mutation, and reasonable responsiveness to known Aβ-modifying agents[20,21]. Library screening clarified that one secondary metabolite accelerated and two metabolites could improve Aβ production in AD neurons These results indicate that the established library of compounds derived from soil microorganisms will be a new human-cell-based approach for investigating therapeutic agents, and will provide a direct clue to understanding the interaction potential of Aβ in AD with microbiota

Results

Discussion

Conclusion