Amyloid-beta induced paralysis is reduced by cholecalciferol through inhibition of the steroid-signaling pathway in an Alzheimer model of Caenorhabditis elegans

ABSTRACT

Objectives: Alzheimer’s disease (AD) is a neurodegenerative disorder resulting from the accumulation of toxic β-amyloid (Aβ) aggregates in the human brain. Epidemiological studies have shown that elevated cholesterol plasma levels are associated with the development of AD and we have previously shown that cholesterol restriction reduces the Aβ-induced paralysis in an Alzheimer model of the nematode Caenorhabditis elegans. In the present study we investigated the effects of the cholesterol homolog cholecalciferol, i.e. vitamin D, on Aβ-induced paralysis in C. elegans and its interference with the steroid-signaling pathway.

Methods: Aβ-induced paralysis was assessed in the C. elegans strain CL2006, expressing human Aβ_1-42 under control of a muscle-specific promoter. Knockdown of members of the steroid-signaling pathway was achieved by RNA interference (RNAi). Nuclear translocation of foxo transcription factor DAF-16 was visualized using the strain TJ356, carrying a daf-16::gfp transgene.

Results: Cholecalciferol at a concentration of 1 µM reduced the Aβ-induced paralysis in CL2006 significantly, which was reverted by increasing the cholesterol concentration in the medium. Knockdown of nhr-8, daf-36, daf-9 or daf-12, all reduced Aβ-induced paralysis to the same extent as cholecalciferol with no additional or synergistic effects under co-application. Functional DAF-16 proved to be crucial for the effects of cholecalciferol and DAF-16 nuclear translocation was increased by cholecalciferol and also RNAi versus nhr-8, daf-36, daf-9 or daf-12 with no additive or synergistic effects.

Conclusions: Our results suggest, that cholecalciferol inhibits Aβ-induced paralysis in C. elegans through inhibition of steroid-signaling and the concomitant nuclear translocation of DAF-16.

KEYWORDS:

• Caenorhabditis elegans
• Alzheimer's disease
• cholecalciferol
• steroid-signaling
• foxo transcription factor

ABBREVIATIONS:

• Aβ, amyloid-beta
• AD, Alzheimer's disease
• DHE, dehydroergosterol
• GFP, green fluorescent protein
• NGM, nematode growth medium
• VIT, vitellogenin

Acknowledgements

The research does not involve human or animal subjects. All authors have read and approved the final submitted manuscript and are aware of and agree to the content of the paper and their being listed as an author on the paper. There are no financial or other contractual agreements that might cause conflicts of interest or which could be perceived as causing conflicts of interest.

Disclosure statement

No potential conflict of interest was reported by the authors.

Notes on contributors

Anne Leiteritz, M.Sc. Nutrition and Ph.D. student, works on nutritional factors that might reduce the ß-amyloid-induced Alzheimer phenotype in a model of the nematode Caenorhabditis elegans. Her recent publications is: Betaine reduces ß-amyloid-induced paralysis through activation of cystathionine-ß-synthase in an Alzheimer model of Caenorhabditis elegans. Genes and Nutrition, 13, 21 (2018).

Tommy Schmiedl, M.Sc. Nutrition, is currently lecturer at the College of Higher Education in Fulda, Germany. He teaches basics in nutritional sciences.

Stefan Baumanns, M.Sc. Nutrition and Ph.D. student, works on the relevance of mitophagy and nicotinergic neurotransmission in the context of Alzheimer’s disease using the nematode C. elegans as a model.

Uwe Wenzel, a professor of molecular nutrition research, publishes on the effects of polyphenols in the context of prevention of cellular degeneration in the nematode C. elegans. Amongst his recent publications is: The polyphenol quercetin protects from glucotoxicity depending on the aggresome in Caenorhabditis elegans. European Journal of Nutrition, ahead of print (2019).