Toxic Tau Oligomers Modulated by Novel Curcumin Derivatives

Filippa Lo Cascio,Fabio Bucchieri,Anna Ellsworth,Antonio Palumbo Piccionello,Nicha Puangmalai,Andrea Pace,Rakez Kayed

doi:10.1038/s41598-019-55419-w

Filippa Lo Cascio, Fabio Bucchieri + Show 5 more

Open Access

https://doi.org/10.1038/s41598-019-55419-w

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Abstract

The pathological aggregation and accumulation of tau, a microtubule-associated protein, is a common feature amongst more than 18 different neurodegenerative diseases that are collectively known as tauopathies. Recently, it has been demonstrated that the soluble and hydrophobic tau oligomers are highly toxic in vitro due to their capacity towards seeding tau misfolding, thereby propagating the tau pathology seen across different neurodegenerative diseases. Modulating the aggregation state of tau oligomers through the use of small molecules could be a useful therapeutic strategy to target their toxicity, regardless of other factors involved in their formation. In this study, we screened and tested a small library of newly synthesized curcumin derivatives against preformed recombinant tau oligomers. Our results show that the curcumin derivatives affect and modulate the tau oligomer aggregation pathways, converting to a more aggregated non-toxic state as assessed in the human neuroblastoma SH-SY5Y cell line and primary cortical neuron cultures. These results provide insight into tau aggregation and may become a basis for the discovery of new therapeutic agents, as well as advance the diagnostic field for the detection of toxic tau oligomers.

Highlights

Millions of people worldwide are affected by age-related tauopathies, including Alzheimer’s disease (AD), which are characterized by the pathological accumulation of tau aggregates[1,2,3]
These results indicate that curcumin has neuroprotective effects against toxic tau oligomers
Investigations regarding treatment options should be directed toward small molecules capable of targeting the toxic tau species and promoting the formation of a non-toxic aggregation state, or perhaps conformations that can be more readily degraded by active cellular mechanisms such as autophagy and proteasomal degradation[64,65,66,67,68]

Summary

Introduction

Millions of people worldwide are affected by age-related tauopathies, including Alzheimer’s disease (AD), which are characterized by the pathological accumulation of tau aggregates[1,2,3]. Curcumin, which is a polyphenol extracted from the plant Curcuma longa, has been shown to play an important role in the prevention and treatment of many diseases, including neurodegenerative disorders[30,31,32,33].It has been demonstrated that curcumin alters the misfolding of many amyloid proteins through the disruption of π-stacking due to the presence of conjugated phenol residues[34,35] It significantly reduces amyloid beta (Aβ) and tau pathology in transgenic AD www.nature.com/scientificreports mouse models[35,36,37]. We used in vitro approaches to investigate the potential neuroprotective properties of curcumin and newly synthesized curcumin-derived small molecules by converting the aggregation state of toxic tau oligomers to a non-toxic one, as assessed by cell-based assays

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