Toxic Tau Oligomers Modulated by Novel Curcumin Derivatives

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

doi:10.1038/s41598-019-55419-w

Cited by 57 publications

(86 citation statements)

References 86 publications

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“…We recently showed that synthetic curcumin derivatives interact with TauO, resulting in the formation of larger tau aggregates with decreased associated neurotoxicity ( 48 ). These novel curcumin derivatives are characterized by the removal of the β-diketo moiety that exhibits keto-enol tautomerism and is thought to be responsible for the low curcumin brain bioavailability ( 48 ).…”

Section: Resultsmentioning

confidence: 99%

“…Recently, we showed that newly synthesized curcumin derivatives/analogs, with low toxicity profile, can interact with preformed toxic tau oligomers by reshaping their conformation, resulting in the formation of larger tau structures with decreased toxicity in human neuroblastoma cells and primary cortical neurons ( 48 ). In the current study, we expanded this investigation to disease-relevant tau oligomers isolated from AD, DLB, and PSP brain tissues.…”

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confidence: 99%

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Modulating disease-relevant tau oligomeric strains by small molecules

Cascio

Garcia

Montalbano

et al. 2020

Journal of Biological Chemistry

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The pathological aggregation of tau plays an important role in Alzheimer’s disease (AD) and many other related neurodegenerative diseases, collectively referred to as tauopathies. Recent evidence has demonstrated that tau oligomers, small and soluble prefibrillar aggregates, are highly toxic due to their strong ability to seed tau misfolding and propagate the pathology seen across different neurodegenerative diseases. We previously showed that novel curcumin derivatives affect preformed tau oligomer aggregation pathways by promoting the formation of more aggregated and nontoxic tau aggregates. To further investigate their therapeutic potential, we have extended our studies to disease-relevant brain-derived tau oligomers (BDTOs). Herein, using well-characterized BDTOs, isolated from brain tissues of different tauopathies, including AD, progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB), we found that curcumin derivatives modulate the aggregation state of BDTOs by reshaping them and rescue neurons from BDTOs-associated toxicity. Interestingly, compound CL3 showed an effect on the aggregation pattern of BDTOs from different tauopathies, resulting in the formation of less neurotoxic larger tau aggregates with decreased hydrophobicity and seeding propensity. Our results lay the groundwork for potential investigations of the efficacy and beneficial effects of CL3 and other promising compounds for the treatment of tauopathies. Furthermore, CL3 may aid in the development of tau imaging agent for the detection of tau oligomeric strains and differential diagnosis of the tauopathies, thus enabling earlier interventions.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Modulating disease-relevant tau oligomeric strains by small molecules

Cascio

Garcia

Montalbano

et al. 2020

Journal of Biological Chemistry

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“…This issue needs to be clarified in future research. Considering the pleotropic effect of curcumin on neurodegenerative diseases, cancers and immune disorders, curcumin is a promising substance for treating disease today without causal treatment [1,2,10,[51][52][53][54][55][56][57]. In addition, it is a safe, inexpensive substance, easily accessible and penetrates the blood-brain barrier and neuronal membranes, which is its great advantage [1][2][3]7].…”

Section: Resultsmentioning

confidence: 99%

Mutual Two-Way Interactions of Curcumin and Gut Microbiota

Pluta

Januszewski

Ułamek-Kozioł

2020

IJMS

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Curcumin, an herbal naturally occurring polyphenol, has recently been proposed for the treatment of neurodegenerative, neurological and cancer diseases due to its pleiotropic effect. Recent studies indicated that dysbiosis is associated with the abovementioned and other diseases, and gut microflora may be a new potential therapeutic target. The new working hypothesis that could explain the curative role of curcumin, despite its limited availability, is that curcumin acts indirectly on the brain, affecting the “gut–brain–microflora axis”, a complex two-way system in which the gut microbiome and its composition, are factors that preserve and determine brain health. It is therefore suspected that curcumin and its metabolites have a direct regulatory effect on gut microflora and vice versa, which may explain the paradox between curcumin’s poor bioavailability and its commonly reported therapeutic effects. Curcumin and its metabolites can have health benefits by eliminating intestinal microflora dysbiosis. In addition, curcumin undergoes enzymatic modifications by bacteria, forming pharmacologically more active metabolites than their parent, curcumin. In this review, we summarize a number of studies that highlight the interaction between curcumin and gut microbiota and vice versa, and we consider the possibility of microbiome-targeted therapies using curcumin, particularly in disease entities currently without causal treatment.

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“…The research aimed at the discovery of HSP60 inhibitors may be attractive and can lead to finding anticancer agents' adjuvants in combination with chemotherapy, thus to reduce both the adverse effects and drug resistance as well as increase the effective targeting of cancerous cells. In this field, curcumin, which is a polyphenolic compound found in turmeric, with anti-inflammatory, antioxidant, and anti-aggregation properties, has been extensively studied for its neuroprotective effects [17][18][19]. Curcumin has numerous molecular targets, and its anti-tumoral mechanisms of action, including cellular proliferation, apoptosis, autophagy, angiogenesis, immune-modulation, invasion, and metastasis, have been widely studied [20].…”

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, little is still known about its role in ameliorating the stress in cancer and its impact on the components of CS, which are the main regulators of cellular stress. On the other hand, the therapeutic benefits of curcumin, which is known to interfere with protein aggregation in neurodegenerative diseases, appear to be multifactorial and associated with the regulation of transcription factors functioning, or linked with the activity of different proteins [17][18][19][20]. Curcumin and several natural derived-products have been shown to regulate many members of HSPs.…”

Section: Introductionmentioning

confidence: 99%

Curcumin Affects HSP60 Folding Activity and Levels in Neuroblastoma Cells

Bavisotto

Gammazza

Cascio

et al. 2020

IJMS

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The fundamental challenge in fighting cancer is the development of protective agents able to interfere with the classical pathways of malignant transformation, such as extracellular matrix remodeling, epithelial–mesenchymal transition and, alteration of protein homeostasis. In the tumors of the brain, proteotoxic stress represents one of the main triggering agents for cell transformation. Curcumin is a natural compound with anti-inflammatory and anti-cancer properties with promising potential for the development of therapeutic drugs for the treatment of cancer as well as neurodegenerative diseases. Among the mediators of cancer development, HSP60 is a key factor for the maintenance of protein homeostasis and cell survival. High HSP60 levels were correlated, in particular, with cancer development and progression, and for this reason, we investigated the ability of curcumin to affect HSP60 expression, localization, and post-translational modifications using a neuroblastoma cell line. We have also looked at the ability of curcumin to interfere with the HSP60/HSP10 folding machinery. The cells were treated with 6, 12.5, and 25 µM of curcumin for 24 h, and the flow cytometry analysis showed that the compound induced apoptosis in a dose-dependent manner with a higher percentage of apoptotic cells at 25 µM. This dose of curcumin-induced a decrease in HSP60 protein levels and an upregulation of HSP60 mRNA expression. Moreover, 25 µM of curcumin reduced HSP60 ubiquitination and nitration, and the chaperonin levels were higher in the culture media compared with the untreated cells. Furthermore, curcumin at the same dose was able to favor HSP60 folding activity. The reduction of HSP60 levels, together with the increase in its folding activity and the secretion in the media led to the supposition that curcumin might interfere with cancer progression with a protective mechanism involving the chaperonin.

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Toxic Tau Oligomers Modulated by Novel Curcumin Derivatives

Cited by 57 publications

References 86 publications

Modulating disease-relevant tau oligomeric strains by small molecules

Modulating disease-relevant tau oligomeric strains by small molecules

Mutual Two-Way Interactions of Curcumin and Gut Microbiota

Curcumin Affects HSP60 Folding Activity and Levels in Neuroblastoma Cells

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