Effective suppression of the modified PHF6 peptide/1N4R Tau amyloid aggregation by intact curcumin, not its degradation products: Another evidence for the pigment as preventive/therapeutic “functional food”

Bijari, Nooshin; Balalaie, Saeed; Akbari, Vali; Golmohammadi, Farhad; Moradi, Sajad; Adibi, Hadi; Khodarahmi, Reza

doi:10.1016/j.ijbiomac.2018.08.175

Cited by 35 publications

(20 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The interactions of positron emission tomography (PET) tracers with cryo-EM structure for the Tau fibril were defined through integrated molecular docking, MD simulations, and binding free energy calculations [153]. Experimental and theoretical docking evidence suggested that curcumin displays strong inhibition effect against Tau fibril aggregation [154]. Thermodynamic and docking binding studies suggested the formation of a hairpin structure of a Tau peptide when interacts with tannic acid, which is a key structural feature required for inhibiting Tau polymerization [155].…”

Section: Cadd For the Development Of Anti-tau Inhibitorsmentioning

confidence: 99%

Computer-Aided Drug Design of β-Secretase, γ-Secretase and Anti-Tau Inhibitors for the Discovery of Novel Alzheimer’s Therapeutics

Mouchlis

Melagraki

Zacharia

et al. 2020

IJMS

View full text Add to dashboard Cite

Aging-associated neurodegenerative diseases, which are characterized by progressive neuronal death and synapses loss in human brain, are rapidly growing affecting millions of people globally. Alzheimer’s is the most common neurodegenerative disease and it can be caused by genetic and environmental risk factors. This review describes the amyloid-β and Tau hypotheses leading to amyloid plaques and neurofibrillary tangles, respectively which are the predominant pathways for the development of anti-Alzheimer’s small molecule inhibitors. The function and structure of the druggable targets of these two pathways including β-secretase, γ-secretase, and Tau are discussed in this review article. Computer-Aided Drug Design including computational structure-based design and ligand-based design have been employed successfully to develop inhibitors for biomolecular targets involved in Alzheimer’s. The application of computational molecular modeling for the discovery of small molecule inhibitors and modulators for β-secretase and γ-secretase is summarized. Examples of computational approaches employed for the development of anti-amyloid aggregation and anti-Tau phosphorylation, proteolysis and aggregation inhibitors are also reported.

show abstract

Section: Cadd For the Development Of Anti-tau Inhibitorsmentioning

confidence: 99%

Computer-Aided Drug Design of β-Secretase, γ-Secretase and Anti-Tau Inhibitors for the Discovery of Novel Alzheimer’s Therapeutics

Mouchlis

Melagraki

Zacharia

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…The accumulating fragment lacks the N-terminus and terminates at the C-terminus at E391 (108) (Figure 3). Key regions that drive filament formation are thought to be the hexapeptides 306 VQIVYK 311 (PHF6) and 275 VQIINK 280 (PHF6 * ), (highlighted in Figure 1) (87, 88). PHF6 has been suggested as essential for tau self-assembly (87, 111) and cryo-EM has revealed its presence in the core region, where it packs through a heterotypic, non-staggered interface with FIGURE 3 | In vitro tau aggregation by autocatalytic propagation.…”

Section: Tau Self-assembly In Admentioning

confidence: 99%

“…Curcumin is another compound that has been reported to exhibit TAI properties. Curcumin is a natural polyphenol isolated from the Indian spice turmeric, which has been reported to inhibit assembly of tau (273)(274)(275) and Aβ (276). However, curcumin has poor bioavailability and had no effect on cognition or cerebrospinal fluid biomarkers in a Phase 2 trial (277,278).…”

Section: Tau Aggregation Inhibitors (Tai)mentioning

confidence: 99%

Tau Filament Self-Assembly and Structure: Tau as a Therapeutic Target

et al. 2020

View full text Add to dashboard Cite

Tau plays an important pathological role in a group of neurodegenerative diseases called tauopathies, including Alzheimer's disease, Pick's disease, chronic traumatic encephalopathy and corticobasal degeneration. In each disease, tau self-assembles abnormally to form filaments that deposit in the brain. Tau is a natively unfolded protein that can adopt distinct structures in different pathological disorders. Cryo-electron microscopy has recently provided a series of structures for the core of the filaments purified from brain tissue from patients with different tauopathies and revealed that they share a common core region, while differing in their specific conformation. This structurally resolvable part of the core is contained within a proteolytically stable core region from the repeat domain initially isolated from AD tau filaments. Tau has recently become an important target for therapy. Recent work has suggested that the prevention of tau self-assembly may be effective in slowing the progression of Alzheimer's disease and other tauopathies. Here we review the work that explores the importance of tau filament structures and tau self-assembly mechanisms, as well as examining model systems that permit the exploration of the mode of action of potential inhibitors.

show abstract

“…Molecular docking showed that CUR interacts with several residues in the R1–R4 region of 0N4R, including Asp194 and Leu195 in R1, Asp225 in R2, Val255 and Ser258 in R3, and Lys285, Val292 and Val305 in R4, providing a mechanism for the inhibition of β-sheet formation by the polyphenol. Bijari et al showed through ThT fluorescence, which is sensitive to β-sheet-containing amyloid assemblies [104,105,106], that CUR inhibits the self-assembly of 1N4R tau [107]. Molecular docking revealed that CUR binds to a region close to the nucleating hexapeptide motif designated as PHF6 (V 306 QIVYK 311 ) [108] found in R3 of 1N4R [107].…”

Section: Polyphenols Inhibit Tau Self-assemblymentioning

confidence: 99%

“…Bijari et al showed through ThT fluorescence, which is sensitive to β-sheet-containing amyloid assemblies [104,105,106], that CUR inhibits the self-assembly of 1N4R tau [107]. Molecular docking revealed that CUR binds to a region close to the nucleating hexapeptide motif designated as PHF6 (V 306 QIVYK 311 ) [108] found in R3 of 1N4R [107]. Other naturally occurring polyphenols such as epicatechin 3-gallate and myricetin inhibit the heparin-induced filament formation by 1N4R [109].…”

Section: Polyphenols Inhibit Tau Self-assemblymentioning

confidence: 99%

Inhibition of the Self-Assembly of Aβ and of Tau by Polyphenols: Mechanistic Studies

et al. 2019

View full text Add to dashboard Cite

The amyloid-β (Aβ) peptide and tau protein are thought to play key neuropathogenic roles in Alzheimer’s disease (AD). Both Aβ and tau self-assemble to form the two major pathological hallmarks of AD: amyloid plaques and neurofibrillary tangles, respectively. In this review, we show that naturally occurring polyphenols abundant in fruits, vegetables, red wine, and tea possess the ability to target pathways associated with the formation of assemblies of Aβ and tau. Polyphenols modulate the enzymatic processing of the amyloid-β precursor protein and inhibit toxic Aβ oligomerization by enhancing the clearance of Aβ42 monomer, modulating monomer–monomer interactions and remodeling oligomers to non-toxic forms. Additionally, polyphenols modulate tau hyperphosphorylation and inhibit tau β-sheet formation. The anti-Aβ-self-assembly and anti-tau-self-assembly effects of polyphenols increase their potential as preventive or therapeutic agents against AD, a complex disease that involves many pathological mechanisms.

show abstract

Effective suppression of the modified PHF6 peptide/1N4R Tau amyloid aggregation by intact curcumin, not its degradation products: Another evidence for the pigment as preventive/therapeutic “functional food”

Cited by 35 publications

References 71 publications

Computer-Aided Drug Design of β-Secretase, γ-Secretase and Anti-Tau Inhibitors for the Discovery of Novel Alzheimer’s Therapeutics

Computer-Aided Drug Design of β-Secretase, γ-Secretase and Anti-Tau Inhibitors for the Discovery of Novel Alzheimer’s Therapeutics

Tau Filament Self-Assembly and Structure: Tau as a Therapeutic Target

Inhibition of the Self-Assembly of Aβ and of Tau by Polyphenols: Mechanistic Studies

Contact Info

Product

Resources

About