1,721,006 research outputs found
Toxic Tau Oligomers Modulated by Novel Curcumin Derivatives
Full text linkThe 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
Post-translational Modifications of the p53 Protein and the Impact in Alzheimer’s Disease: A Review of the Literature
No full textOur understanding of Alzheimer’s disease (AD) pathogenesis has developed with several hypotheses over the last 40 years, including the Amyloid and Tau hypotheses. More recently, the p53 protein, well-known as a genome guardian, has gained attention for its potential role in the early evolution of AD. This is due to the central involvement of p53’s in the control of oxidative stress and potential involvement in the Amyloid and Tau pathways. p53 is commonly regulated by post-translational modifications (PTMs), which affect its conformation, increasing its capacity to adopt multiple structural and functional states, including those that can affect brain processes, thus contributing to AD development. The following review will explore the impact of p53 PTMs on its function and consequential involvement in AD pathogenesis. The greater understanding of the role of p53 in the pathogenesis of AD could result in more targeted therapies benefiting the many patients of this debilitating disease
Modulating disease-relevant tau oligomeric strains by small molecules
Full text linkThe 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
A Novel Antibody Targeting Tau Phosphorylated at Serine 235 Detects Neurofibrillary Tangles
Full text linkAlzheimer's disease is characterized by two main pathological hallmarks in the human brain: the extracellular deposition of amyloid-β as plaques and the intracellular accumulation of the hyperphosphorylated protein tau as neurofibrillary tangles (NFTs). Phosphorylated tau (p-tau) specific-antibodies and silver staining have been used to reveal three morphological stages of NFT formation: pre-NFTs, intraneuronal NFTs (iNFTs), and extraneuronal NFTs (eNFTs). Here we characterize a novel monoclonal antibody, RN235, which is specific for tau phosphorylated at serine 235, and detects iNFTs and eNFTs in brain tissue, suggesting that phosphorylation at this site is indicative of late stage changes in tau
Nasal tau immunotherapy clears intracellular tau pathology and improves cognitive functions in aged tauopathy mice
No full textPathological tau aggregates cause cognitive decline in neurodegenerative tauopathies, including Alzheimer's disease (AD). These aggregates are prevalent within intracellular compartments. Current tau immunotherapies have shown limited efficacy in clearing intracellular tau aggregates and improving cognition in clinical trials. In this study, we developed toxic tau conformation-specific monoclonal antibody-2 (TTCM2), which selectively recognized pathological tau aggregates in brain tissues from patients with AD, dementia with Lewy bodies (DLB), and progressive supranuclear palsy (PSP). TTCM2 potently inhibited tau-seeding activity, an essential mechanism underlying tauopathy progression. To effectively target intracellular tau aggregates and ensure rapid delivery to the brain, TTCM2 was loaded in micelles (TTCM2-ms) and administered through the intranasal route. We found that intranasally administered TTCM2-ms efficiently entered the brain in hTau-tauopathy mice, targeting pathological tau in intracellular compartments. Moreover, a single intranasal dose of TTCM2-ms effectively cleared pathological tau, elevated synaptic proteins, and improved cognitive functions in aged tauopathy mice. Mechanistic studies revealed that TTCM2-ms cleared intracellular, synaptic, and seed-competent tau aggregates through tripartite motif-containing 21 (TRIM21), an intracellular antibody receptor and E3 ubiquitin ligase known to facilitate proteasomal degradation of cytosolic antibody-bound proteins. TRIM21 was found to be essential for TTCM2-ms-mediated clearance of tau pathology. Our study collectively provides evidence of the effectiveness of nasal tau immunotherapy in targeting and clearing intracellular tau pathology through TRIM21 and enhancing cognition in aged tauopathy mice. This study could be valuable in designing effective tau immunotherapies for AD and other tauopathies
Pre-amyloid oligomers budding:a metastatic mechanism of proteotoxicity
No full textThe pathological hallmark of misfolded protein diseases and aging is the accumulation of proteotoxic aggregates. However, the mechanisms of proteotoxicity and the dynamic changes in fiber formation and dissemination remain unclear, preventing a cure. Here we adopted a reductionist approach and used atomic force microscopy to define the temporal and spatial changes of amyloid aggregates, their modes of dissemination and the biochemical changes that may influence their growth. We show that pre-amyloid oligomers (PAO) mature to form linear and circular protofibrils, and amyloid fibers, and those can break reforming PAO that can migrate invading neighbor structures. Simulating the effect of immunotherapy modifies the dynamics of PAO formation. Anti-fibers as well as anti-PAO antibodies fragment the amyloid fibers, however the fragmentation using anti-fibers antibodies favored the migration of PAO. In conclusion, we provide evidence for the mechanisms of misfolded protein maturation and propagation and the effects of interventions on the resolution and dissemination of amyloid pathology
Growth Factors Up-Regulate Epithelial Stem Cells: Treatment Strategies for Colorectal Cancers
No full textColorectal-cancer is a leading cause of cancer deaths in United States. Accumulating evidence suggests that elevated progastrins (PG) increase the risk of colon carcinogenesis, however mechnaims involved remain ill-defined. Recently, cell-surface AnnexinA2 (CS-ANXA2) was discovered as a non-conventional receptor for progastrin. Therefore, the first goal was to examine whether ANXA2 expression is required to mediate proliferative/anti-apoptotic effects of progastrin on target cells. The studies in chapter 2, conclude that ANXA2 mediates growth effects of PG on target cells (including colonic-epithelial-cells), in vitro and in vivo, associated with up-regulation of stem/progenitor cell markers. Surprisingly, overexpression of autocrine PG in HEK-293 cells, imparted tumorigenic/metastatic potential to the cells (chapter 3). Based on these data, the second goal was to investigate the phenotypic differences between non-transformed and transformed stem cell using non-tumorigenic (HEK-C) and tumorigenic (HEK-mGAS) isogenic cells. The studies in chapter 3, conclude that transformed stem cells, unlike normal stem cells, co-express CS-ANXA2 with stem-cell-markers DCAMKL-1/CD44. Interestingly, CS-ANXA2 dictates morphology/growth characteristics of spheroidal growths, in vitro. The third goal was to identify cancer stem cell (CSC) marker(s), for developing targeted therapies against colon cancers. Since both DCAMKL-1/LGR5 have been reported as colonic CSC markers, the possible phenotypic/proliferative differences between DCAMKL-1+ve and LGR5+ve human colon CSCs was examined. Results in chapter 4 suggest that DCAMKL-1+ve cells are significantly more proliferative than either DCAMKL-1-ve or LGR5+ve stem cells. Thus targeting DCAMKL-1+ve cells may be more effective in treating/eradicating colon-cancers; this possibility was examined as part of my fourth goal.
Although several therapies are currently available for treating cancers, recurrence remains a challenge. It is believed that CSCs are resistant to radiation and chemotherapeutic treatments, and are the likely cause of cancer relapse. It is therefore important to develop novel therapies which are relatively non-toxic and specifically target CSCs. Therefore the fourth goal was to examine the inhibitory efficacy of non-toxic dietary agent (Curcumin) ± RNAi against DCAMKL-1. The results in chapter 5 suggest that combination of curcumin+siRNA-DCAMKL-1 effectively attenuates growth of colon-cancer-cells in vitro and in vivo, by synergistically augmenting autophagic/apoptotic cell-death mechanisms. It is hypothesized that the combinatorial treatment will significantly reduce the risk of relapse
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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