Cannabidiol Inhibits Tau Aggregation In Vitro

Alali, Soha; Riazi, Gholam Hossein; Ashrafi-Kooshk, Mohammad Reza; Meknatkhah, Sogol; Ahmadian, Shahin; Ardakani, Mohammad Hooshyari; Hosseinkhani, Baharak

doi:10.3390/cells10123521

Cited by 20 publications

(13 citation statements)

References 44 publications

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“…In addition to the amyloid β model, researchers have also investigated the effect of CBD in the tauopathy model of AD. Recently, Alali et al have reported that CBD can inhibit aggregation of tau protein ( Alali et al, 2021 ). Using in vitro and in silico biochemical methods such as circular dichroism (CD) and atomic force microscopy (AFM), the author has demonstrated that CBD molecules bind to recombinant human tau protein and inhibit its aggregation.…”

Section: Disease-specific Pathwaymentioning

confidence: 99%

Cannabidiol for neurodegenerative disorders: A comprehensive review

et al. 2022

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Despite the significant advances in neurology, the cure for neurodegenerative conditions remains a formidable task to date. Among various factors arising from the complex etiology of neurodegenerative diseases, neuroinflammation and oxidative stress play a major role in pathogenesis. To this end, some phytocannabinoids isolated from Cannabis sativa (widely known as marijuana) have attracted significant attention as potential neurotherapeutics. The profound effect of ∆9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis, has led to the discovery of the endocannabinoid system as a molecular target in the central nervous system (CNS). Cannabidiol (CBD), the major non-psychoactive component of cannabis, has recently emerged as a potential prototype for neuroprotective drug development due to its antioxidant and anti-inflammatory properties and its well-tolerated pharmacological behavior. This review briefly discusses the role of inflammation and oxidative stress in neurodegeneration and demonstrates the neuroprotective effect of cannabidiol, highlighting its general mechanism of action and disease-specific pathways in Parkinson’s disease (PD) and Alzheimer’s disease (AD). Furthermore, we have summarized the preclinical and clinical findings on the therapeutic promise of CBD in PD and AD, shed light on the importance of determining its therapeutic window, and provide insights into identifying promising new research directions.

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Section: Disease-specific Pathwaymentioning

confidence: 99%

Cannabidiol for neurodegenerative disorders: A comprehensive review

et al. 2022

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“…Plotting dbAF intensity at 456 nm against the incubation time gives rise to a typical sigmoid-like kinetic curve for the two C-TER isoforms ( Figure 6 A). Such a three-phase kinetic profile is well described in the literature and is characteristic of amyloidogenic proteins [ 77 , 78 ]. The lag phase, corresponding to structural transitions, nucleation, and assembly of oligomers, is nearly the same for the two proteins: 36 and 40 h for C-TERb and C-TERa, respectively.…”

Section: Resultsmentioning

confidence: 92%

Unveiling the Metal-Dependent Aggregation Properties of the C-terminal Region of Amyloidogenic Intrinsically Disordered Protein Isoforms DPF3b and DPF3a

Leyder

Mignon

Mottet

et al. 2022

IJMS

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Double-PHD fingers 3 (DPF3) is a BAF-associated human epigenetic regulator, which is increasingly recognised as a major contributor to various pathological contexts, such as cardiac defects, cancer, and neurodegenerative diseases. Recently, we unveiled that its two isoforms (DPF3b and DPF3a) are amyloidogenic intrinsically disordered proteins. DPF3 isoforms differ from their C-terminal region (C-TERb and C-TERa), containing zinc fingers and disordered domains. Herein, we investigated the disorder aggregation properties of C-TER isoforms. In agreement with the predictions, spectroscopy highlighted a lack of a highly ordered structure, especially for C-TERa. Over a few days, both C-TERs were shown to spontaneously assemble into similar antiparallel and parallel β-sheet-rich fibrils. Altered metal homeostasis being a neurodegeneration hallmark, we also assessed the influence of divalent metal cations, namely Cu2+, Mg2+, Ni2+, and Zn2+, on the C-TER aggregation pathway. Circular dichroism revealed that metal binding does not impair the formation of β-sheets, though metal-specific tertiary structure modifications were observed. Through intrinsic and extrinsic fluorescence, we found that metal cations differently affect C-TERb and C-TERa. Cu2+ and Ni2+ have a strong inhibitory effect on the aggregation of both isoforms, whereas Mg2+ impedes C-TERb fibrillation and, on the contrary, enhances that of C-TERa. Upon Zn2+ binding, C-TERb aggregation is also hindered, and the amyloid autofluorescence of C-TERa is remarkably red-shifted. Using electron microscopy, we confirmed that the metal-induced spectral changes are related to the morphological diversity of the aggregates. While metal-treated C-TERb formed breakable and fragmented filaments, C-TERa fibrils retained their flexibility and packing properties in the presence of Mg2+ and Zn2+ cations.

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“…Generally, the tau exhibits intrinsic fluorescence emission near 302 nm when excited at 265 nm, resulted from tyrosine (Tyr) fluorophores in the tau structure. 48,49 When 10 μM of tau was mixed with GQDs or Cys-GQDs in increasing concentrations, the fluorescence intensity of tau was significantly quenched (Fig. 7), suggesting that the π-conjugated planar structure of GQDs binds with Tyr residues in tau, probably via π-π stacking interactions.…”

Section: Resultsmentioning

confidence: 99%

Inhibition and Disassembly of Tau Aggregates by Engineered Graphene Quantum Dots

Zhu¹,

Makwana

Zhang³

et al. 2022

Preprint

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Tauopathies are a class of neurodegenerative diseases resulting in cognitive dysfunction, executive dysfunction, and motor disturbance. The primary pathological feature of tauopathies is the presence of neurofibrillary tangles in the brain composed of tau protein aggregates. Although numerous small molecules are known to inhibit tau aggregation, it is still challenging to use them for therapeutic applications due to their limitations in specific targeting and the blood-brain barrier (BBB) penetration. Graphene quantum dots (GQDs), one of graphene nanoparticles, can penetrate the BBB and are amenable to functionalization for targeted delivery. Moreover, these nanoscale biomimetic particles can self-assemble or assemble with various biomolecules including proteins. In this paper, for the first time, we showed that GQDs interacted with tau proteinsviaelectrostatic and π-π stacking interactions to inhibit the fibrillization of monomeric tau and to trigger the disaggregation of tau filaments.In vitrothioflavin T assays demonstrated that negatively charged GQDs with larger sizes inhibited tau aggregation more efficiently, while positively charged ones were more effective in the disassembly of tau fibrils. Moreover, GQDs blocked the seeding activity of tau fibrils in a cellular propagation assay. Overall, our studies indicate GQDs with engineered properties can efficiently inhibit and disassemble pathological aggregation of tau proteins, which supports their future developments as a potential treatment for tauopathies.

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Cannabidiol Inhibits Tau Aggregation In Vitro

Cited by 20 publications

References 44 publications

Cannabidiol for neurodegenerative disorders: A comprehensive review

Cannabidiol for neurodegenerative disorders: A comprehensive review

Unveiling the Metal-Dependent Aggregation Properties of the C-terminal Region of Amyloidogenic Intrinsically Disordered Protein Isoforms DPF3b and DPF3a

Inhibition and Disassembly of Tau Aggregates by Engineered Graphene Quantum Dots

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