Oligodendrocyte Dysfunction in Tauopathy: A Less Explored Area in Tau-Mediated Neurodegeneration.

Aggregation of the microtubule-associated protein tau (MAPT) is the hallmark pathology in a spectrum of neurodegenerative disorders collectively called tauopathies. Physiologically, tau is an inherent neuronal protein that plays an important role in the assembly of microtubules and axonal transport. However, disease-associated mutations of this protein reduce its binding to the microtubule components and promote self-aggregation, leading to formation of tangles in neurons. Tau is also expressed in oligodendrocytes, where it has significant developmental roles in oligodendrocyte maturation and myelin synthesis. Oligodendrocyte-specific tau pathology, in the form of fibrils and coiled coils, is evident in major tauopathies including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD). Multiple animal models of tauopathy expressing mutant forms of MAPT recapitulate oligodendroglial tau inclusions with potential to cause degeneration/malfunction of oligodendrocytes and affecting the neuronal myelin sheath. Till now, mechanistic studies heavily concentrated on elucidating neuronal tau pathology. Therefore, more investigations are warranted to comprehensively address tau-induced pathologies in oligodendrocytes. The present review provides the current knowledge available in the literature about the intricate relations between tau and oligodendrocytes in health and diseases.

Designing one-compartment H2O2 fuel cell using electroactive phenalenyl-based [Fe2(hnmh-PLY)3] complex as the cathode material.

The sustainable chemical energy of H2O2 as a fuel and an oxidant in an advantageous single-compartment fuel cell design can be converted into electric energy, which requires molecular engineering to design suitable cathodes for lowering the high overpotential associated with H2O2 reduction. The present work covers the synthesis and structural characterization of a novel cathode material, [FeIII2(hnmh-PLY)3] complex, 1, designed from a PLY-derived Schiff base ligand (E)-9-(2-((2-hydroxynaphthalen-1-yl)methylene)hydrazineyl)-1H-phenalen-1-one, hnmh-PLYH2. Complex 1, when coated on the surface of a glassy carbon electrode (GC-1) significantly catalyzed the reduction of H2O2 in an acidic medium. Therefore, a complex 1 modified glassy carbon electrode was employed in a one-compartment H2O2 fuel cell operated in 0.1 M HCl with Ni foam as the corresponding anode to produce a high open circuit potential (OCP) of 0.65 V and a peak power density (PPD) of 2.84 mW cm-2. CV studies of complex 1 revealed the crucial participation of two Fe(III) centers for initiating H2O2 reduction, and the role of coordinated redox-active PLY units is also highlighted. In the solid state, the π-conjugated network of coordinating (hnmh-PLY) ligands in complex 1 has manifested interesting face-to-face π-π stacking interactions, which have helped the reduction of the complex and facilitated the overall catalytic performance.

Design and synthesis of a solution-processed redox-active bis(formazanate) zinc complex for resistive switching applications.

In this paper, we report the synthesis and characterization of a mononuclear zinc complex (1) containing a redox-active bis(4-antipyrinyl) derivative of the 3-cyanoformazanate ligand. Complex 1 was readily obtained by refluxing zinc acetate with 3-cyano-1,5-(4-antipyrinyl)formazan (LH) in a methanolic solution. Single-crystal X-ray diffraction analysis of complex 1 shows that the formazanate ligands bind to the zinc center in a five-member chelate "open" form via the 1- and 4-positions of the 1,2,4,5-tetraazapentadienyl formazanate backbone leading to the formation of the mononuclear bis(formazanate) zinc complex exhibiting a distorted octahedral geometry. We also report the study of resistive-switching random access memory application of this solution-processable bis(formazanate) Zn(II) complex to facilitate the practical implementation of transition metal complex-based molecular memory devices. The complex demonstrated high conductance switching with a large ON-OFF ratio, good stability, and a long retention time. A trap-controlled space charge limited current mechanism is proposed for the observed resistive switching behavior of the device, wherein the role played by the [ZnIIL2] complex that comprises the extended redox-active conjugated ligand backbone is revealed by corroborating electrochemical studies, spectrochemical experiments, and DFT calculations. In addition to providing significant insights into the molecular design of transition metal complexes for memory applications, this study also presents the utilization of ZnIIL2 towards the realization of non-volatile resistive random access memory (RRAM) devices with inorganic/organic hybrid active layers that are highly cost-effective and sustainable. These devices exhibited multilevel switching and low current operation, both of which are desirable for advanced memory applications.

A closed-shell phenalenyl-based dinuclear iron(III) complex as a robust cathode for a one-compartment H2O2 fuel cell.

Closed-shell phenalenyl (PLY) systems are increasingly becoming more attractive as building blocks for developing promising catalysts and electroactive cathode materials, as they have tremendous potential to accept electrons and participate in redox reactions. Herein, we report a PLY-based dinuclear [FeIII2(hmbh-PLY)3] complex, 1, and its utility as a cathode material in a H2O2 fuel cell. Complex 1 was synthesized from a new Schiff base ligand, (E)-9-(2-(2-hydroxy-3-methoxybenzylidene)hydrazineyl)-1H-phenalen-1-one, hmbh-PLYH2, designed using a PLY precursor, Hz-PLY. The newly derived ligand and complex 1 were characterized by various analytical techniques, including single-crystal X-ray diffraction (SCXRD). The cyclic voltammetry (CV) study revealed that complex 1 undergoes five electron reductions under an applied electric potential. When the electroactive complex 1 was employed as a cathode in a membrane-less one-compartment H2O2 fuel cell, with Ni foam as the corresponding anode, the designed fuel cell exhibited an exceptionally high peak power density (PPD) of 2.41 mW cm-2, in comparison with those of all the previously reported Fe-based molecular complexes. DFT studies were performed to gain reasonable insights into the two-electron catalytic reduction (pathway I) of H2O2 by the Fe-center of complex 1 and to explore the geometries, energetics of the electrocatalyst, reactive intermediates and transition states.

Tau fibrils induce glial inflammation and neuropathology via TLR2 in Alzheimer's disease-related mouse models.

Glial activation and inflammation coincide with neurofibrillary tangle (NFT) formation in neurons. However, the mechanism behind the interaction between tau fibrils and glia is poorly understood. Here, we found that tau preformed fibrils (PFFs) caused induction of inflammation in microglia by specifically activating the TLR2/MyD88, but not the TLR4/MyD88, pathway. Accordingly, the WT TLR2-interacting domain of MyD88 (wtTIDM) peptide inhibited tau PFF-induced activation of the TLR2/MyD88/NF-κB pathway, resulting in reduced inflammation. Nasal administration of wtTIDM in P301S tau-expressing PS19 mice was found to inhibit gliosis and inflammatory markers, as well as to reduce pathogenic tau in the hippocampus, resulting in improved cognitive behavior in PS19 mice. The inhibitory effect of wtTIDM on tau pathology was absent in PS19 mice lacking TLR2, reinforcing the essential involvement of TLR2 in wtTIDM-mediated effects in vivo. Studying the mechanism further, we found that the tau promoter harbored a potential NF-κB-binding site and that proinflammatory molecules increased transcription of tau in neurons via NF-κB. These results suggest that tau-induced neuroinflammation and neuropathology require TLR2 and that neuroinflammation directly upregulates tau in neurons via NF-κB, highlighting a direct connection between inflammation and tauopathy.

A Catecholaldimine-Based NiII-Complex as an Effective Catalyst for the Direct Conversion of Alcohols to trans-Cinnamonitriles and Aldehydes.

A nickel(II) complex [Ni(HL)2] 1 was synthesized by treatment of a new catecholaldimine-based ligand with NiCl2·6H2O in methanol at room temperature. Complex 1 showed excellent catalytic activity where aromatic and heterocyclic alcohols were rapidly converted into trans-cinnamonitrile in a one-pot manner via oxidative olefination in the presence of KOH. The potential of the disclosed catalyst and the results obtained for the direct conversion of alcohols to two different functionalities (trans-cinnamonitrile and aldehydes) are well supported by DFT studies.

Redox Switching Behavior in Resistive Memory Device Designed Using a Solution-Processable Phenalenyl-Based Co(II) Complex: Experimental and DFT Studies.

We herein report a novel square-planar complex [CoIIL], which was synthesized using the electronically interesting phenalenyl-derived ligand LH2 = 9,9'-(ethane-1,2-diylbis(azanediyl))bis(1H-phenalen-1-one). The molecular structure of the complex is confirmed with the help of the single-crystal X-ray diffraction technique. [CoIIL] is a mononuclear complex where the Co(II) ion is present in the square-planar geometry coordinated by the chelating bis-phenalenone ligand. The solid-state packing of [CoIIL] complex in a crystal structure has been explained with the help of supramolecular studies, which revealed that the π···π stacking present in the [CoIIL] complex is analogous to the one present in tetrathiafulvalene/tetracyanoquinodimethane charge transfer salt, well-known materials for their unique charge carrier interfaces. The [CoIIL] complex was employed as the active material to fabricate a resistive switching memory device, indium tin oxide/CoIIL/Al, and characterized using the write-read-erase-read cycle. The device has interestingly shown a stable and reproducible switching between two different resistance states for more than 2000 s. Observed bistable resistive states of the device have been explained by corroborating the electrochemical characterizations and density functional theory studies, where the role of the CoII metal center and π-conjugated phenalenyl backbone in the redox-resistive switching mechanism is proposed.

Oxygen-Induced Dissociation of a Single Water Molecule in Confined 2-D Layers: A Semiempirical Study.

Semiempirical quantum mechanical methods provide a middle ground to molecule-surface interactions between computationally demanding full ab initio quantum chemistry calculations and force-field calculations. In the present study, the PM7 semiempirical method is used to evaluate the adsorption energy values of X@h-BN monolayer [X=O, OH, and H2 O], followed by a mechanistic study of oxygen-induced water dissociation on a free-standing h-BN monolayer. Based on oxygen adsorption configurations, two reaction pathways for water dissociation are studied that yield two distinct configurations of double OH-functionalized h-BN monolayer. The effect of a graphene cover layer on these proposed mechanistic pathways is then investigated by placing the graphene cover layer on the top of the h-BN monolayer and continuously tuning the separation (dGr/h-BN ) between these two layers.

Protection of dopaminergic neurons in hemiparkinsonian monkeys by flavouring ingredient glyceryl tribenzoate.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and this study underlines the significance of a small molecule glyceryl tribenzoate (GTB), a FDA approved food additive, in preventing parkinsonian pathologies in MPTP-induced animal models. The study conducted in MPTP-induced mice demonstrated dose-dependent protection of nigral tyrosine hydroxylase (TH) and striatal dopamine level by GTB oral treatment and the optimum dose was found to be 50 mg/kg/d. In the next phase, the study was carried out in MPTP-injected hemiparkinsonian monkeys, which recapitulate better clinical parkinsonian syndromes. GTB inhibited MPTP-driven induction of glial inflammation, which was evidenced by reduced level of GTP-p21Ras and phospho-p65 in SN of monkeys. It led to decreased expression of inflammatory markers such as IL-1ß and iNOS. Simultaneously, GTB oral treatment protected nigral TH cells, striatal dopamine, and improved motor behaviour of hemiparkinsonian monkeys. Presence of sodium benzoate, a GTB metabolite and a FDA-approved drug for urea cycle disorders and glycine encephalopathy, in the brain suggests that the neuroprotective effect imparted by GTB might be mediated by sodium benzoate. Although the mechanism of action of GTB is poorly understood, the study sheds light on the therapeutic possibility of a food additive GTB in PD.

Selective targeting of the TLR2/MyD88/NF-κB pathway reduces α-synuclein spreading in vitro and in vivo.

Pathways to control the spreading of α-synuclein (α-syn) and associated neuropathology in Parkinson's disease (PD), multiple system atrophy (MSA) and dementia with Lewy bodies (DLB) are unclear. Here, we show that preformed α-syn fibrils (PFF) increase the association between TLR2 and MyD88, resulting in microglial activation. The TLR2-interaction domain of MyD88 (wtTIDM) peptide-mediated selective inhibition of TLR2 reduces PFF-induced microglial inflammation in vitro. In PFF-seeded A53T mice, the nasal administration of the wtTIDM peptide, NEMO-binding domain (wtNBD) peptide, or genetic deletion of TLR2 reduces glial inflammation, decreases α-syn spreading, and protects dopaminergic neurons by inhibiting NF-κB. In summary, α-syn spreading depends on the TLR2/MyD88/NF-κB pathway and it can be reduced by nasal delivery of wtTIDM and wtNBD peptides.

Alleviation of Huntington pathology in mice by oral administration of food additive glyceryl tribenzoate.

Huntington's disease (HD) is a neurodegenerative disorder characterized by accumulation of mutant huntingtin protein and significant loss of neurons in striatum and cortex. Along with motor difficulties, the HD patients also manifest anxiety and loss of cognition. Unfortunately, the clinically approved drugs only offer symptomatic relief and are not free from side effects. This study underlines the importance of glyceryl tribenzoate (GTB), an FDA-approved food flavoring ingredient, in alleviating HD pathology in transgenic N171-82Q mouse model. Oral administration of GTB significantly reduced mutant huntingtin level in striatum, motor cortex as well as hippocampus and increased the integrity of viable neurons. Furthermore, we found the presence of sodium benzoate (NaB), a FDA-approved drug for urea cycle disorders and glycine encephalopathy, in the brain of GTB-fed HD mice. Accordingly, NaB administration also markedly decreased huntingtin level in striatum and cortex. Glial activation is found to coincide with neuronal death in affected regions of HD brains. Interestingly, both GTB and NaB treatment suppressed activation of glial cells and inflammation in the brain. Finally, neuroprotective effect of GTB and NaB resulted in improved motor performance of HD mice. Collectively, these results suggest that GTB and NaB may be repurposed for HD.

Chemical Dynamics Simulations of Energy Transfer for Propylbenzene Cation and He Collisions.

Intermolecular energy transfer for the vibrationally excited propylbenzene cation (C9H12+) in a helium bath was studied with chemical dynamics simulations. The bond energy bond order relationship and electronic structure calculations were used to develop an intramolecular potential for C9H12+. Spin component scaled MP2/6-311++G** calculations were used to develop an intermolecular potential for He + C9H12+. The He + He intermolecular potential was determined from a previous explicitly correlated Gaussian electronic structure calculation. For the simulations, C9H12+ was prepared with a 100.1 kcal/mol excitation energy to compare with experiment. The average energy transfer from C9H12+, ⟨ΔEc⟩, decreased as C9H12+ was vibrationally relaxed and for the initial excitation energy ⟨ΔEc⟩ = 0.64 kcal/mol. This result agrees well with the experimental ⟨ΔEc⟩ value of 0.51 ± 0.26 kcal/mol for collisions of He with the ethylbenzene cation. The ⟨ΔEc⟩ value found for He + C9H12+ collisions is compared with reported values of ⟨ΔEc⟩ for He colliding with other molecules.

Skin score correlates with global DNA methylation and GSTO1 A140D polymorphism in arsenic-affected population of Eastern India.

Arsenic is a potent environmental toxicant causing serious public health concerns in India, Bangladesh and other parts of the world. Gene- and promoter-specific hypermethylation has been reported in different arsenic-exposed cell lines, whereas whole genome DNA methylation study suggested genomic hypo- and hypermethylation after arsenic exposure in in vitro and in vivo studies. Along with other characteristic biomarkers, arsenic toxicity leads to typical skin lesions. The present study demonstrates significant correlation between severities of skin manifestations with their whole genome DNA methylation status as well as with a particular polymorphism (Ala 140 Asp) status in arsenic metabolizing enzyme Glutathione S-transferase Omega-1 (GSTO1) in arsenic-exposed population of the district of Nadia, West Bengal, India.

Highly fluorescent magnetic quantum dot probe with superior colloidal stability.

A magnetic quantum dot (MQD) based cellular nanoprobe, composed of a magnetic oxide nanoparticle component and a quantum dot component, has been synthesized and used for both imaging and separation. The successful synthesis is based on a reverse micelle based polyacrylate coating in the presence of component nanoparticles, followed by their functionalization via conjugation chemistry.