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. 2024 Jan 8:2024:10.17912/micropub.biology.000907.
doi: 10.17912/micropub.biology.000907. eCollection 2024.

Clearance of extracellular human amyloid-β aggregates in C. elegans by nutraceutical and pharmaceutical interventions

Arastu Sharma  1   2 , Collin Y Ewald  1
Affiliations

Clearance of extracellular human amyloid-β aggregates in C. elegans by nutraceutical and pharmaceutical interventions

Arastu Sharma et al. MicroPubl Biol. .

Abstract

Numerous anti-amyloid therapies have seen recent clinical development and approval, such as the monoclonal antibodies aducanumab and lecanemab. However, in Alzheimer's disease patients, amyloid-β (Aβ) plaques are found embedded in the extracellular matrix and surrounded by collagens, which might hinder these antibodies from targeting the plaques. We reasoned that various different nutraceutical and pharmaceutical agents might induce collagen and extracellular matrix turnover and removal of these collagen-embedded amyloid-β (Aβ) plaques. To address this idea, here, we used a transgenic C. elegans strain, LSD2104 , expressing fluorescent human Aβ 1-42 as an in-vivo model for secreted amyloid aggregation in the extracellular matrix. We performed a screen of various nutraceuticals and pharmaceuticals along with different combinations, and we found that quercetin 350 µM and rifampicin 75 µM successfully cleared the extracellular amyloid plaque burden compared to the 0.2% DMSO control group, with a combination of the two agents producing the maximum effect compared to either drug alone. These results may implicate the exploration of combination therapeutics of nutraceuticals and pharmaceuticals in the clearance of amyloid-β (Aβ) plaques in Alzheimer's disease.

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Conflict of interest statement

The authors declare that there are no conflicts of interest present.

Figures

Figure 1. <b> Clearance of Extracellular Human Amyloid-Beta (Aβ) Aggregates in <i>C. elegans </i> by Nutraceutical and Pharmaceutical Interventions </b>
Figure 1. Clearance of Extracellular Human Amyloid-Beta (Aβ) Aggregates in C. elegans by Nutraceutical and Pharmaceutical Interventions
A) Depiction of the transgenic strain LSD2104 with the transgene sfGFP::Aβ 1-42 under control of heat shock protein hsp-16.2 promoter. Upon 3 hours of 33°C heat shock, amyloid-beta (Aβ) induction occurred, forming aggregates in the extracellular space over 24 hours. For details, see Materials and Methods. B) Depiction of screening for drug effects on amyloid aggregation, as measured through fluorescence intensity. Results informed various dosages for the efficacy of aggregate removal. C) Results of drug screens on amyloid aggregate removal, with color-coded legend depicting the efficacy of a given intervention. D) Depiction of experimental timeline for egg laying, amyloid induction, drug administration, and fluorescent imaging. LSD2104 C. elegans were maintained at 15°C, and heat shock was performed at 33°C for 3 hours. E) Fluorescent images of successful drug candidates with strong aggregation evident in the cuticle ECM of the transgenic LSD2104 C. elegans and coelomocytes. F) Intensity over the number of pixels (I/N) after quantification of each drug group against control, indicating the amount of amyloid burden. Statistical analysis between the geometric mean of groups was performed using one-way ANOVA, with bars representing geometric SEM and a significance threshold of (P<0.05). The combination of quercetin 350 µM and rifampicin 75 µM showed superiority in reducing aggregate burden compared to either drug alone, and both drugs administered separately reduced the amyloid burden compared to the control. Additional trials and data are found in Extended Data Figures 1-2, and Source Data File 1.
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Grants and funding

Funding from the Swiss National Science Foundation Funding from the SNF P3 Project 190072 to CYE.

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