15 research outputs found
NOVEL SMALL MOLECULES THAT BIND AND/OR MODULATE DIFFERENT FORMS OF TAU OLIGOMERS
No full textThe present invention relates to novel small molecules of Formulas I, II, III, IIIa, IIIb, and IV and pharmaceutically acceptable salts thereof, as well as the preparation and the use thereof
Small Molecules Targeting and Modulating Toxic Tau Oligomeric Strains
No full textAlzheimer’s disease (AD) is one of over 18 different disorders known as tauopathies, characterized by the pathological aggregation and accumulation of tau, a microtubule-associated protein. Tau aggregates are heterogeneous and can be divided into two major groups: large metastable neurofibrillary tangles (NFTs) and oligomers. Recently, it has been shown that tau oligomers are highly toxic in vitro and efficient seeds for the propagation of pathology as compared to NFTs. While the toxicity of recombinant tau oligomers has been studied extensively, within the same aggregation state, tau exhibits conformational differences, termed tau oligomeric strains. Due to the dynamic nature of these strains, little is currently known about the mechanisms underlying their formation and characteristics. Therefore, modulating their aggregation states and conformations through the use of small molecules could be a powerful therapeutic strategy that targets toxicity regardless of other factors involved in the formation of tau oligomeric strains. Herein, I used biochemical and biophysical in vitro techniques to characterize preformed tau oligomers and brain-derived tau oligomers (BDTOs) in the presence and absence of small molecules, including Azure C (AC) and newly synthesized curcumin derivatives. Interestingly, AC and curcumin analogs are able to bind and modulate tau oligomers aggregation pathways resulting in the formation of tau structures with decreased toxicity as assessed in human neuroblastoma SH-SY5Y cell line and primary cortical neuron cultures.
These results provide novel insights into tau aggregation and may lead to the discovery of new compounds effective against one or more tau strains. Identification of such active compounds may lay the groundwork for developing novel therapeutic agents as well as advancing the diagnostic field for the detection of toxic tau oligomers and differential diagnosis for tauopathies
Toxic Tau Oligomers Modulated by Novel Curcumin Derivatives
No full textThe 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
Modulating disease-relevant tau oligomeric strains by small molecules
No full textThe pathological aggregation of tau plays an important role in Alzheimer's disease 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 o disease-relevant brain-derived tau oligomers (BDTOs). Herein, using well-characterized BDTOs, isolated from brain tissues of different tauopathies, including Alzheimer's disease, progressive supranuclear palsy, and dementia with Lewy bodies, we found that curcumin derivatives modulate the aggregation state of BDTOs by reshaping them and rescue neurons from BDTO-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
Small Molecules Targeting and Modulating Toxic Tau Oligomeric Strains
No full textAlzheimer’s disease (AD) is one of over 18 different disorders known as tauopathies, characterized by the pathological aggregation and accumulation of tau, a microtubule-associated protein. Tau aggregates are heterogeneous and can be divided into two major groups: large metastable neurofibrillary tangles (NFTs) and oligomers. Recently, it has been shown that tau oligomers are highly toxic in vitro and efficient seeds for the propagation of pathology as compared to NFTs. While the toxicity of recombinant tau oligomers has been studied extensively, within the same aggregation state, tau exhibits conformational differences, termed tau oligomeric strains. Due to the dynamic nature of these strains, little is currently known about the mechanisms underlying their formation and characteristics. Therefore, modulating their aggregation states and conformations through the use of small molecules could be a powerful therapeutic strategy that targets toxicity regardless of other factors involved in the formation of tau oligomeric strains. Herein, I used biochemical and biophysical in vitro techniques to characterize preformed tau oligomers and brain-derived tau oligomers (BDTOs) in the presence and absence of small molecules, including Azure C (AC) and newly synthesized compounds such as heparin like oligosaccharides and curcumin derivatives. Interestingly, AC, heparin like oligosaccharides, and curcumin analogs are able to bind and modulate tau oligomers aggregation pathways resulting in the formation of tau structures with decreased toxicity as assessed in human neuroblastoma SH-SY5Y cell line and primary cortical neuron cultures. These results provide novel insights into tau aggregation and may lead to the discovery of new compounds effective against one or more tau strains. Identification of such active compounds may lay the groundwork for developing novel therapeutic agents as well as advancing the diagnostic field for the detection of toxic tau oligomers and differential diagnosis for tauopathies
Curcumin as Scaffold for Drug Discovery against Neurodegenerative Diseases
No full textNeurodegenerative 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
Curcumin as Scaffold for Drug Discovery against Neurodegenerative Diseases
No full textNeurodegenerative 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
EXOSOMES: PROMISING NON-INVASIVE DIAGNOSTIC AND THERAPEUTIC TOOLS
No full textThis minireview provides a summary of an emerging topic of biomedical research, such as exosomes in healthcare safety. Exosomes are a group of extracellular vesicles released by human cells involved in a number of physiologic processes, but also in the pathogenesis of several human diseases. These vesicles are secreted from a variety of cell types, carry a number of proteins, nucleic acids, and lipids, and can mediate cell-cell communication. Also, they are present and can be isolated from many tissues and perhaps all biological fluids, including blood, urine, sweat, sperm, ascites fluid, bile, etc. Their properties, such as immune modulation, regeneration promotion and pathogen suppression, indicate that exosomes should be considered as a new important clinical biomarker and the majority of the current literature evidence predicts that they will become an important diagnostic and therapeutic tool in personalized healthcare
Post-translational modifications of Hsp60 and its extracellular release via exosomes are induced by the histone deacetylase inhibitor (HDACi) SAHA in the mucoepidermoid tumor H292 cells
No full textThe chaperonin Hsp60 has multiple functions, among which that of supporting the growth of some type of tumours. HDACi (histone-deacetylase inhibitors) are drugs that regulate gene expression via modulation of epigenetic mechanisms, and induce tumor-cell death. Here, we show that in the tumor cells H292 the HDACi SAHA decreases the intracellular level of Hps60 and promotes its extracellular trafficking by exosomal vesicles. SAHA caused a time- and dose-dependent decrease in cell viabil- ity with a G/2M cell-cycle arrest at 24 h and cell death at 48 h. These effects were accompanied by production of reactive oxygen species and mitochondrial membrane- potential dissipation. The marked decrease in Hsp60 level in SAHA-treated cells was not related to proteasomal degradation since it was not affected by the addition of the proteasome inhibitor MG132. Moreover, the analysis of post-translational modifica- tions of Hsp60 revealed that SAHA treatment induced a modest reduction in the ubiq- uitination of the protein, with no effect on its acetylation state, but did cause a marked increase in tyrosine-nitrated Hsp60. This effect was related to oxidative stress since it was prevented by the anti-oxidant N-acetylcysteine. Most importantly, we showed for the first time that SAHA markedly increases extracellular Hsp60 export via exosomes, which might explain the concomitant decrease of the intracellular chaperonin. Our results suggest that SAHA modifies Hsp60 by nitration and stimulates its extracellu- lar export via exosomes. Since Hsp60-bearing exosomes have been implicated in effec- tive anti-tumour responses, and since elevated intracellular levels of Hsp60 have been related to the arrest of tumour-cell death, our data offer clues to explore what might be as yet uncharacterized mechanisms by which SAHA works as antitumor drug
