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Dihydrophthalazinediones accelerate amyloid β peptide aggregation to nontoxic species

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Abstract

The production and accumulation of toxic amyloid plaques is one of the hallmarks of Alzheimer’s disease (AD). Amyloid beta (Aβ) peptides undergo self-aggregation to form soluble oligomers, protofibrils and insoluble fibrils. This process is termed as amyloidogenesis and is a major contributor to the observed neuronal damage and memory impairment in the AD brain. Therefore, modulation of Aβ aggregation process is considered to be an effective target to prevent neuronal damage under AD conditions. Modulation of amyloidogenesis involves inhibition of aggregation to form a toxic species or acceleration to drive the aggregation process to form species that are nontoxic by employing well-designed external ligands. In this context, we report a set of 2,3-dihydrophthalazine-1,4-dione (dihydrophthalazinedione, Phz) based small molecules (Phz 1–4) to modulate the Aβ42 aggregation and in cellular toxicity. Our detailed study (thioflavin T fluorescence assay, dot blot and transmission electron microscopy analysis) revealed fluorine containing Phz 4 as the potent modulator of Aβ42 aggregation by accelerating the process to form nontoxic aggregated species through hydrophobic and halogen interactions. Aβ42 aggregates formed in the presence of Phz 4 are mostly nontoxic when compared to the normal amyloid aggregates in the cellular milieu (PC12 cells). This study established that the hydrophobic and halogen interactions can be employed to develop anti-AD drug candidates. The excellent cell viability, effective modulation of Aβ42 aggregation to form nontoxic species and cellular (neuronal) rescue by Phz 4 offer a novel platform to develop therapeutic strategies for AD.

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Acknowledgements

We thank Prof C N R Rao, FRS, for constant support and encouragement, JNCASR, SwarnaJayanti Fellowship, the Department of Science and Technology (DST), Government of India (Grant DST/SJF/CSA-02/2015–2016), Sheikh Saqr Laboratory (SSL), ICMS-JNCASR. DG thank the JNCASR and SS thank CSIR, New Delhi for the research fellowships.

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Authors and Affiliations

  1. Bioorganic Chemistry Laboratory, New Chemistry Unit and School of Advanced Materials, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, 560064, India

    DEBASIS GHOSH, SOURAV SAMANTA & THIMMAIAH GOVINDARAJU

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  1. DEBASIS GHOSH
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  2. SOURAV SAMANTA
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  3. THIMMAIAH GOVINDARAJU
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Correspondence to THIMMAIAH GOVINDARAJU.

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This article is part of the Topical Collection: SAMat Focus Issue.

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GHOSH, D., SAMANTA, S. & GOVINDARAJU, T. Dihydrophthalazinediones accelerate amyloid β peptide aggregation to nontoxic species. Bull Mater Sci 43, 309 (2020). https://doi.org/10.1007/s12034-020-02223-2

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  • DOI: https://doi.org/10.1007/s12034-020-02223-2

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