Inhibition of tau-derived hexapeptide aggregation and toxicity by a self-assembled cyclic <scp>d</scp>,<scp>l</scp>-α-peptide conformational inhibitor

Belostozky, Anna; Richman, Michal; Lisniansky, Elvira; Tovchygrechko, A; Chill, Jordan H.; Rahimipour, Shai

doi:10.1039/c8cc01233d

Cited by 34 publications

(23 citation statements)

References 42 publications

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“…As a consequence of this detachment, there is a perturbation of cytoskeletal stability and axonal transport 4,5 . Unbound tau can self-aggregate to form soluble oligomers (TauO) that combine into paired helical filaments (PHFs) 6–8 . The PHFs then aggregate into large insoluble fibrils, known as neurofibrillary tangles (NFTs) 9 .…”

Section: Introductionmentioning

confidence: 99%

Toxic Tau Oligomers Modulated by Novel Curcumin Derivatives

Cascio

Puangmalai

Ellsworth

et al. 2019

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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.

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Section: Introductionmentioning

confidence: 99%

Toxic Tau Oligomers Modulated by Novel Curcumin Derivatives

Cascio

Puangmalai

Ellsworth

et al. 2019

Sci Rep

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“…Due to this structural mimicry, AcPHF6 and AcPHF6* stand out as model peptides to study the promotion or inhibitory effect of various ligands on Tau aggregation [27][28][29] and for the development of any peptide based Tau aggregation inhibitors. [30][31][32][33][34][35][36][37][38][39] Previous studies have shown that even shorter fragments from AcPHF6 are also capable of bril formation but with a lower rate of polymerization and only upon nucleation with known brils. 40 The aggregation properties in lysine mutants of AcPHF6 were explored by the Goux research group and the results showed variable bril formation tendency for the mutants subject to buffer and salt conditions.…”

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confidence: 99%

Residue-based propensity of aggregation in the Tau amyloidogenic hexapeptides AcPHF6* and AcPHF6

et al. 2020

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“…As result of these modifications, tau detaches from the microtubules causing their disassembly, cytoskeletal instability, and axonal transport perturbation [ 29 , 30 ]. Unbound tau can self-aggregate forming soluble tau oligomers that assemble into paired helical filaments (PHFs) [ 31 , 32 , 33 ]. The PHFs mature into fibrils that constitute the intracellular NFTs, observed in the brain of AD patients [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

Curcumin as Scaffold for Drug Discovery against Neurodegenerative Diseases

et al. 2021

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Neurodegenerative diseases (NDs) are one of major public health problems and their impact is continuously growing. Curcumin has been proposed for the treatment of several of these pathologies, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) due to the ability of this molecule to reduce inflammation and aggregation of involved proteins. Nevertheless, the poor metabolic stability and bioavailability of curcumin reduce the possibilities of its practical use. For these reasons, many curcumin derivatives were synthetized in order to overcome some limitations. In this review will be highlighted recent results on modification of curcumin scaffold in the search of new effective therapeutic agents against NDs, with particular emphasis on AD.

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Inhibition of tau-derived hexapeptide aggregation and toxicity by a self-assembled cyclic d,l-α-peptide conformational inhibitor

Cited by 34 publications

References 42 publications

Toxic Tau Oligomers Modulated by Novel Curcumin Derivatives

Toxic Tau Oligomers Modulated by Novel Curcumin Derivatives

Residue-based propensity of aggregation in the Tau amyloidogenic hexapeptides AcPHF6* and AcPHF6

Curcumin as Scaffold for Drug Discovery against Neurodegenerative Diseases

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