Curcumin as scaffold for drug discovery against neurodegenerative diseases

Neurodegenerative 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

2-(3-Eth­oxy-2-hy­droxy­benz­ylidene)-N-phenyl­hydrazinecarboxamide

The title compound, C16H17N3O3, exists in the E configuration with respect to the azomethine double bond. The mol­ecule is close to planar, with a dihedral angle of 6.7 (1)° between the aromatic rings. The phenolic O atom functions as donor and acceptor by forming intramolec­ular O—H⋯O and inter­molecular N—H⋯O hydrogen bonds, respectively. Two-dimensional packing is fashioned through an inter­molecular hydrogen bonding network in an offset manner

Tau oligomers in cerebrospinal fluid in Alzheimer's disease

OBJECTIVE: With an increasing incidence of Alzheimer's disease (AD) and neurodegenerative tauopathies, there is an urgent need to develop reliable biomarkers for the diagnosis and monitoring of the disease, such as the recently discovered toxic tau oligomers. Here, we aimed to demonstrate the presence of tau oligomers in the cerebrospinal fluid (CSF) of patients with cognitive deficits, and to determine whether tau oligomers could serve as a potential biomarker for AD. METHODS: A multicentric collaborative study involving a double-blinded analysis with a total of 98 subjects with moderate to severe AD (N = 41), mild AD (N = 31), and nondemented control subjects (N = 26), and two pilot studies of 33 total patients with AD (N = 19) and control (N = 14) subjects were performed. We carried out biochemical assays to measure oligomeric tau from CSF of these patients with various degrees of cognitive impairment as well as cognitively normal controls. RESULTS: Using a highly reproducible indirect ELISA method, we found elevated levels of tau oligomers in AD patients compared to age-matched controls. Western blot analysis confirmed the presence of oligomeric forms of tau in CSF. In addition, the ratio of oligomeric to total tau increased in the order: moderate to severe AD, mild AD, and controls. CONCLUSION: These assays are suitable for the analysis of human CSF samples. These results here suggest that CSF tau oligomer measurements could be optimized and added to the panel of CSF biomarkers for the accurate and early detection of AD

Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice

<p>Abstract</p> <p>Background</p> <p>The correlation between neurofibrillary tangles of tau and disease progression in the brains of Alzheimer's disease (AD) patients remains an area of contention. Innovative data are emerging from biochemical, cell-based and transgenic mouse studies that suggest that tau oligomers, a pre-filament form of tau, may be the most toxic and pathologically significant tau aggregate.</p> <p>Results</p> <p>Here we report that oligomers of recombinant full-length human tau protein are neurotoxic in vivo after subcortical stereotaxic injection into mice. Tau oligomers impaired memory consolidation, whereas tau fibrils and monomers did not. Additionally, tau oligomers induced synaptic dysfunction by reducing the levels of synaptic vesicle-associated proteins synaptophysin and septin-11. Tau oligomers produced mitochondrial dysfunction by decreasing the levels of NADH-ubiquinone oxidoreductase (electron transport chain complex I), and activated caspase-9, which is related to the apoptotic mitochondrial pathway.</p> <p>Conclusions</p> <p>This study identifies tau oligomers as an acutely toxic tau species in vivo, and suggests that tau oligomers induce neurodegeneration by affecting mitochondrial and synaptic function, both of which are early hallmarks in AD and other tauopathies. These results open new avenues for neuroprotective intervention strategies of tauopathies by targeting tau oligomers.</p

Analysis and design of dispersion-engineered cascaded channel waveguide for mid-infrared supercontinuum generation employing pump source at telecommunication wavelength

We theoretically investigate and propose a promising 8-mm-long cascade planar waveguide made of Si3N4 and As2Se3 glass system for mid-infrared supercontinuum generation by employing a commercially available femtosecond pump source operating at 1550 nm wavelength. A rigorous numerical investigation has been performed considering three different dispersion regions of the optimized cascade waveguide for expanding the SC coverage far into the mid-infrared. Based on the tailored dispersion region whether the anomalous or normal, the pump pulse is applied at the input of the initial waveguide segment of Si3N4 and the output of which is then coupled into the final waveguide segment made of As2Se3 glass system. The output supercontinuum spectrum for all-anomalous dispersion region expanded up to 10 µm by one of the best reported so far using cascade design with coherency of unity over the entire spectrum region predicted. This would be the widest spectral coverage expanded into the mid-infrared, to the best of the authors’ knowledge, by the cascade planar waveguide design employing a commercially available pump source in telecommunication window with a peak power of 5 kW. Such a highly coherent cascade planar waveguide, designed and proposed based on the concatenating principle for a broadband mid-infrared supercontinuum generation using the two-step process, would be highly suitable for many mid-infrared based applications such as sensing and biological imaging

3-[(E)-(4-Chloro­benzyl­idene)amino]-1-phenyl­thio­urea

In the title compound, C14H12ClN3S, the dihedral angle between the terminal benzene rings is 56.6 (2)°; the benzene rings lie to the same side of the mol­ecule. The major twist in the mol­ecule occurs around the Car—N bond (ar is aromatic) [C—N—C—C = 49.9 (5)°]. The configuration about the N=C bond [1.271 (4) Å] is E. The amine H atoms lie on opposite sides of the mol­ecule with one forming an intra­molecular N—H⋯N(imine) hydrogen bond and an S(5) ring. In the crystal, centrosymmetric dimers are formed via {⋯HNC=S}2 synthons

Molecular Origin of Polyglutamine Aggregation in Neurodegenerative Diseases

Expansion of polyglutamine (polyQ) tracts in proteins results in protein aggregation and is associated with cell death in at least nine neurodegenerative diseases. Disease age of onset is correlated with the polyQ insert length above a critical value of 35–40 glutamines. The aggregation kinetics of isolated polyQ peptides in vitro also shows a similar critical-length dependence. While recent experimental work has provided considerable insights into polyQ aggregation, the molecular mechanism of aggregation is not well understood. Here, using computer simulations of isolated polyQ peptides, we show that a mechanism of aggregation is the conformational transition in a single polyQ peptide chain from random coil to a parallel β-helix. This transition occurs selectively in peptides longer than 37 glutamines. In the β-helices observed in simulations, all residues adopt β-strand backbone dihedral angles, and the polypeptide chain coils around a central helical axis with 18.5 ± 2 residues per turn. We also find that mutant polyQ peptides with proline-glycine inserts show formation of antiparallel β-hairpins in their ground state, in agreement with experiments. The lower stability of mutant β-helices explains their lower aggregation rates compared to wild type. Our results provide a molecular mechanism for polyQ-mediated aggregation

Generic Mechanism of Emergence of Amyloid Protofilaments from Disordered Oligomeric aggregates

The presence of oligomeric aggregates, which is often observed during the process of amyloid formation, has recently attracted much attention since it has been associated with neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. We provide a description of a sequence-indepedent mechanism by which polypeptide chains aggregate by forming metastable oligomeric intermediate states prior to converting into fibrillar structures. Our results illustrate how the formation of ordered arrays of hydrogen bonds drives the formation of beta-sheets within the disordered oligomeric aggregates that form early under the effect of hydrophobic forces. Initially individual beta-sheets form with random orientations, which subsequently tend to align into protofilaments as their lengths increases. Our results suggest that amyloid aggregation represents an example of the Ostwald step rule of first order phase transitions by showing that ordered cross-beta structures emerge preferentially from disordered compact dynamical intermediate assemblies.Comment: 14 pages, 4 figure

PrP(Sc)-specific antibodies with the ability to immunodetect prion oligomers.

The development of antibodies with binding capacity towards soluble oligomeric forms of PrPSc recognised in the aggregation process in early stage of the disease would be of paramount importance in diagnosing prion diseases before extensive neuropathology has ensued. As blood transfusion appears to be efficient in the transmission of the infectious prion agent, there is an urgent need to develop reagents that would specifically recognize oligomeric forms of the abnormally folded prion protein, PrPSc.To that end, we show that anti-PrP monoclonal antibodies (called PRIOC mAbs) derived from mice immunised with native PrP-coated microbeads are able to immunodetect oligomers/multimers of PrPSc. Oligomer-specific immunoreactivity displayed by these PRIOC mAbs was demonstrated as large aggregates of immunoreactive deposits in prion-permissive neuroblastoma cell lines but not in equivalent non-infected or prn-p(0/0) cell lines. In contrast, an anti-monomer PrP antibody displayed diffuse immunoreactivity restricted to the cell membrane. Furthermore, our PRIOC mAbs did not display any binding with monomeric recombinant and cellular prion proteins but strongly detected PrPSc oligomers as shown by a newly developed sensitive and specific ELISA. Finally, PrioC antibodies were also able to bind soluble oligomers formed of Aβ and α-synuclein. These findings demonstrate the potential use of anti-prion antibodies that bind PrPSc oligomers, recognised in early stage of the disease, for the diagnosis of prion diseases in blood and other body fluids

Dirac and Weyl Equations on a Lattice as Quantum Cellular Automata

A discretized time evolution of the wave function for a Dirac particle on a cubic lattice is represented by a very simple quantum cellular automaton. In each evolution step the updated value of the wave function at a given site depends only on the values at the nearest sites, the evolution is unitary and preserves chiral symmetry. Moreover, it is shown that the relationship between Dirac particles and cellular automata operating on two component objects on a lattice is indeed very close. Every local and unitary automaton on a cubic lattice, under some natural assumptions, leads in the continuum limit to the Weyl equation. The sum over histories is evaluated and its connection with path integrals and theories of fermions on a lattice is outlined.Comment: 6, RevTe