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Synthesis of d-amino acid peptides and their effect on beta-amyloid aggregation and toxicity in transgenic Caenorhabditis elegans

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Abstract

Genetic, biochemical, and pathological evidence supports that aggregation of amyloid-beta (Aβ) peptide into fibrillar structures rich in beta-sheets is implicated as the cause of Alzheimer’s disease. Therefore, an attractive therapeutic strategy is to prevent or alter amyloid-beta aggregation. In this work we examine the effects of the short d-peptides pgklvya, kklvffarrrra, and kklvffa on Aβ aggregation in vitro and toxicity in vivo. These peptides are based on the central hydrophobic region of Aβ (residues 16–20), which is believed to be crucial in Aβ self-association. The effect of peptides on Aβ aggregation was examined by circular dichroism spectroscopy, Thioflavin T fluorescence, and ANS binding assay. Transgenic Caenorhabditis elegans model was used to evaluate the pharmacological effect of d-peptides on Aβ-initiated toxicity. The data suggested that d-peptides are very effective at inhibiting fibrillogenesis of Aβ. Among the three peptides tested, only pgklvya and kklvffa improved survival in the transgenic C. elegans. The activity of these peptides correlates with their ability to inhibit Aβ oligomerization. These suggest that d-peptides should be considered during future design of peptide-based inhibitors of amyloid deposition and toxicity.

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Abbreviations

Aβ:

Amyloid beta

app:

Amyloid precursor protein

AD:

Alzheimer’s disease

ThT:

Thioflavin T

HFIP:

Hexafluoroisopropanol

TFA:

Trifluoroacetic acid

TFE:

Trifluoroethanol

bis-ANS:

4,4′-Bis(1-anilinonaphthalene 8-sulfonate)

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Acknowledgments

We are thankful to Dr. Asit Baran Mandal, Director, Central Leather Research Institute, Chennai for his kind support for this work. The author thanks the Council of Scientific and Industrial Research (CSIR), India, for the award of Junior and Senior Research Fellowships. We are thankful to Man-Wah Tan, Stanford University for allowing us to do C.elegans work in his lab. We are also thankful to Prof. T. Pradeep, IIT Madras for doing Maldi-MS.

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  1. Bioorganic Laboratory, Central Leather Research Institute (CSIR), Adyar, Chennai, 600 020, India

    Seema Jagota & Jayakumar Rajadas

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  1. Seema Jagota
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Correspondence to Seema Jagota.

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Jagota, S., Rajadas, J. Synthesis of d-amino acid peptides and their effect on beta-amyloid aggregation and toxicity in transgenic Caenorhabditis elegans . Med Chem Res 22, 3991–4000 (2013). https://doi.org/10.1007/s00044-012-0386-2

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