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Impaired clearance of cerebral amyloid-β (Aβ) across the blood-brain barrier (BBB) may facilitate the onset and progression of Alzheimer's disease (AD). Additionally, experimental evidence suggests a central role for cellular cholesterol in amyloid-β protein precursor (AβPP) processing. The present study investigated whether brain capillary endothelial cells (BCEC; the anatomical basis of the BBB) are capable of endogenous AβPP synthesis and whether and to what extent AβPP synthesis and processing is under control of cellular cholesterol homeostasis. Intracellular cholesterol metabolism was pharmacologically manipulated by using natural and synthetic liver-X receptor (LXR) agonists. Using an in vitro model of the BBB consisting of primary porcine BCEC (pBCEC), we demonstrate that endogenous full-length AβPP synthesis by pBCEC is significantly increased while the amount of cell-associated, amyloidogenic Aβ oligomers is decreased in response to 24(S)-hydroxycholesterol (24OH-C) or 27OH-C, TO901317, cholesterol, or simvastatin treatment. Oxysterols, as well as simvastatin, enhanced the secretion of non-amyloidogenic sAβPPα up to 2.5-fold. In parallel, LXR agonists reduced cholesterol biosynthesis by 30-80% while stimulating esterification (up to 2.5-fold) and efflux (up to 2.5-fold) of cellular cholesterol by modifying hydroxymethylglutaryl-CoA reductase (HMGCR), sterol regulatory element-binding protein (SREBP-2), acyl-CoA: cholesterol acyltransferase 2 (ACAT-2), and ATP binding cassette transporter A1 (ABCA1) expression levels. In a polarized in vitro model mimicking the BBB, pBCEC secreted sAβPPα preferentially to the basolateral compartment. In summary endothelial cells of the BBB actively synthesize AβPP, Aβ oligomers, and secrete AβPPα in a polarized manner. AβPP processing by pBCEC is regulated by LXR agonists, which have been proven beneficial in experimental AD models. [ABSTRACT FROM AUTHOR]

This report presents a selective synthetic approach towards borazine from ammonia borane using a dinuclear rhodium olefin homogeneous catalyst. The synthesis and spectroscopic characterization of a dirhodium ammonia borane complex as an intermediate provides insight into a possible mode of activation.

A carbon-rich molecule is synthesized, which mainly contains conjugated sp 2 and sp hybridized carbon centers. Alkenyl and alkynyl binding sites are arranged such that this compound serves as ligand to a binuclear metal unit with a Rh I ─Rh I bond. Furthermore, CH units are placed in proximity to the metal centers. The dicationic complex [Rh 2 (bipy) 2 {Ph 2 Ptrop (C≡CCy)2 }] 2+ (OTf - ) 2 allows to study possible responses of the carbon-framework to redox reactions as well as deprotonation reactions. All products are, whenever possible, characterized by X-ray diffraction (XRD) methods, NMR and EPR spectroscopy as well as electrochemical methods. It is shown that the carbon skeleton of the ligand framework undergoes C─C bond rearrangement reactions of remarkable diversity. In combination with DFT (density functional theory) studies, these results allow to gain insight into the electronic structure changes caused by metal sites in a carbon-rich environment, which may be of relevance for the properties of metal particles on carbon support materials when they are exposed to hydrogen, electrons, or protons., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Starting from C 6 H 4 (PCl 2 ) 2 and the TMS-substituted ylide (TMS) 2 C=PR 3 (TMS=trimethylsilyl, R=p-tolyl), the phosphonium-substituted diphosphaindenylide PPI was prepared in two steps. CASSCF calculations as well as the reactivity toward diphenyl acetylene suggest a notable biradical character in PPI. Reaction with [Cr(CO) 3 (MeCN) 3 ] affords the complex [Cr(CO) 3 (η 5 -PPI)] (5). This complex was employed to explore the ligand properties of PPI, which demonstrates considerable potential through the combination of strong metal-ligand interactions and the possibility of a pronounced indenyl effect., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Dehydrogenation of ammonia borane to well-defined products is an important but challenging reaction. A dinuclear ruthenium complex with a Ru-Ru bond bearing a diazadiene (dad) unit and olefins as non-innocent ligands catalyzes the highly selective formation of conjugated polycondensed borazine oligomers (B x N x H y ), predominantly B 21 N 21 H 18 , the BN analogue of superbenzene.

Main group systems capable of undergoing controlled redox events at extreme potentials are elusive yet highly desirable for a range of organic electronics applications including use as energy storage media. Herein we describe phosphine oxide-functionalized terthiophenes that exhibit two reversible 1e - reductions at potentials below -2 V vs Fc/Fc + (Fc=ferrocene) while retaining high degrees of stability. A phosphine oxide-functionalized terthiophene radical anion was synthesized in which the redox-responsive nature of the platform was established using combined structural, spectroscopic, and computational characterization. Straightforward structural modification led to the identification of a derivative that exhibits exceptional stability during bulk 2 e - galvanostatic charge-discharge cycling and enabled characterization of a 2 e - redox series. A new multi-electron redox system class is hence disclosed that expands the electrochemical cell potential range achievable with main group electrolytes without compromising stability., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Reaction of the imidazolium-stabilized diphosphete-diide IDP with trityl phosphaalkyne affords a mixture which contains the molecules 1 a and 1 b with a central C 3 P 3 core, which formally carries a two-fold negative charge. In order to avoid the formation of an antiaromatic 8π electron system within a conjugated dianionic six-membered [C 3 P 3 ] 2- ring, 1 a adopts a bicyclic [3.1.0] and 1 b a tricyclic [2.2.0.0] structure which are in a dynamic equilibrium. 1 a, b can be reversibly oxidized to a triphosphinine dication [5] 2+ with a central flat aromatic six-membered C 3 P 3 ring. This two-electron redox reaction occurs in two single-electron transfer steps via the 7π-radical cation [4]⋅ + , which could also be isolated and fully characterized. The profound reversible structural change observed for the two-electron redox couple [5] 2+ /1 a, b is in sharp contrast to the C 6 H 6 /[C 6 H 6 ] 2- couple, which undergoes only a modest structural deformation., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Reaction of the 6π-electron aromatic four-membered heterocycle (IPr) 2 C 2 P 2 (1) (IPr=1,3-bis(2,6-diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene) with [Fe 2 CO 9 ] gives the neutral iron tricarbonyl complex [Fe(CO) 3 -η 3 -{(IPr) 2 C 2 P 2 }] (2). Oxidation with two equivalents of the ferrocenium salt, [Fe(Cp) 2 ](BArF 24 ), affords the dicationic tricarbonyl complex [Fe(CO) 3 -η 4 -{(IPr) 2 C 2 P 2 }](BArF 24 ) 2 (4). The one-electron oxidation proceeds under concomitant loss of one CO ligand to give the paramagnetic dicarbonyl radical cation complex [Fe(CO) 2 -η 4 -{(IPr) 2 C 2 P 2 }](BArF 24 ) (5). Reduction of 5 allows the preparation of the neutral dicarbonyl complex [Fe(CO) 2 -η 4 -{(IPr) 2 C 2 P 2 }] (6). An analysis by various spectroscopic techniques ( 57 Fe Mössbauer, EPR) combined with DFT calculations gives insight into differences of the electronic structure within the members of this unique series of iron carbonyl complexes, which can be either described as electron precise or Wade-Mingos clusters., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Processing of the amyloid precursor protein (APP) and amyloid beta (Aβ) has been for decades in the center of Alzheimer's disease (AD) research. Beside many other variables, lipids, especially cholesterol and its derivatives, are discussed to contribute to AD pathogenesis. Several studies show that cholesterol affects APP metabolism. Also the converse mechanism, the direct influence of Aβ on cholesterol metabolism, has been described. To further investigate this crosstalk between cholesterol- and APP metabolism, a high-fat feeding study was conducted with animals overexpressing human APPSL and/or human ApoB-100. The impact of diet and genotype on cerebral cholesterol metabolism and content as well as spatial learning and memory was examined. While behavioral performance was not influenced by this high fat diet (HFD), reduction of cortical free cholesterol levels and mRNA expression patterns under normal diet and HFD conditions in human APPSL overexpressing mice argue for an important role of APP in cerebral lipid metabolism. From our results we conclude that increased APP metabolism in ApoBxAPP and APPSL mice induces mechanisms to reduce free cholesterol levels., (Copyright © 2016. Published by Elsevier Inc.)

Abstract: The new PSP pincer ligand 4,6-bis(diphenylphosphinomethyl)dibenzothiophene (PSP Ph ) was prepared in 89 % yield. With this ligand, a solvothermal synthesis of a Cr complex of the type [Cr(κ 3 P,S,P -PSP)(CO) 3 ] is described. The X-ray structure of this compound is presented. We demonstrate that the solvothermal synthesis technique provides a powerful, simple, and practical synthetic method resulting in a high isolated yield in a short reaction time.

Background: β-Synuclein (β-Syn) is a member of the highly homologous synuclein protein family. The most prominent family member, α-synuclein (α-Syn), abnormally accumulates in so-called Lewy bodies, one of the major pathological hallmarks of α-synucleinopathies. Notably, parts of the peptide backbone, called the nonamyloid component, are also found in amyloid plaques. However, β-Syn seems to have beneficial effects by reducing α-Syn aggregation, and amyloid antiaggregatory activity has been described., Objective: The aim of the study was to analyze if wild-type β-Syn can counteract functional and pathological changes in a murine Alzheimer model over different time periods., Methods: At the onset of pathology, lentiviral particles expressing human β-Syn were injected into the hippocampus of transgenic mice overexpressing human amyloid precursor protein with Swedish and London mutations (APPSL). An empty vector served as the control. Behavioral analyses were performed 1, 3 and 6 months after injection followed by biochemical and histological examinations of brain samples., Results: β-Syn expression was locally concentrated and rather modest, but nevertheless changed its effect on APP expression and plaque load in a time- and concentration-dependent manner. Interestingly, the phosphorylation of glycogen synthase kinase 3 beta was enhanced in APPSL mice expressing human β-Syn, but an inverse trend was observed in wild-type animals., Conclusion: The initially reported beneficial effects of β-Syn could be partially reproduced, but locally elevated levels of β-Syn might also cause neurodegeneration. To enlighten the controversial pathological mechanism of β-Syn, further examinations considering the relationship between concentration and exposure time of β-Syn are needed., (© 2015 S. Karger AG, Basel.)

Background: Beyond cognitive decline, Alzheimer's disease (AD) is characterized by numerous neuropathological changes in the brain. Although animal models generally do not fully reflect the broad spectrum of disease-specific alterations, the APPSL mouse model is well known to display early plaque formation and to exhibit spatial learning and memory deficits. However, important neuropathological features, such as neuroinflammation and lipid peroxidation, and their progression over age, have not yet been described in this AD mouse model., Methods: Hippocampal and neocortical tissues of APPSL mice at different ages were evaluated. One hemisphere from each mouse was examined for micro- and astrogliosis as well as concomitant plaque load. The other hemisphere was evaluated for lipid peroxidation (quantified by a thiobarbituric acid reactive substances (TBARS) assay), changes in Aβ abundance (Aβ38, Aβ40 and Aβ42 analyses), as well as determination of aggregated Aβ content (Amorfix A4 assay). Finally, correlation analyses were performed to illustrate the time-dependent correlation between neuroinflammation and Aβ load (soluble, insoluble, fibrils), or lipid peroxidation, respectively., Results: As is consistent with previous findings, neuroinflammation starts early and shows strong progression over age in the APPSL mouse model. An analyses of concomitant Aβ load and plaque deposition revealed a similar progression, and high correlations between neuroinflammation markers and soluble or insoluble Aβ or fibrillar amyloid plaque loads were observed. Lipid peroxidation, as measured by TBARS levels, correlates well with neuroinflammation in the neocortex but not the hippocampus. The hippocampal lipid peroxidation correlated strongly with the increase of LOC positive fiber load, whereas neocortical TBARS levels were unrelated to amyloidosis., Conclusions: These data illustrate for the first time the progression of major AD related neuropathological features other than plaque load in the APPSL mouse model. Specifically, we demonstrate that microgliosis and astrocytosis are prominent aspects of this AD mouse model. The strong correlation of neuroinflammation with amyloid burden and lipid peroxidation underlines the importance of these pathological factors for the development of AD. The new finding of a different relation of lipid peroxidation in the hippocampus and neocortical regions show that the model might contribute to the understanding of complex pathological mechanisms and their interplay in AD.

Niemann-Pick type C disease (NPC) is an inherited disorder mainly caused by loss-of-function mutations in the NPC1 gene, that lead to intracellular cholesterol accumulation and disturbed cholesterol homeostasis. Similarly to Alzheimer's disease (AD), NPC is associated with progressive neurodegeneration and altered metabolism of amyloid precursor protein (APP). Liver X receptors (LXRs), the key transcriptional regulators of cholesterol homeostasis, were reported to play neuroprotective roles in NPC mice. We investigated the impacts of LXRs on APP metabolism in mutant CHO cells lacking the NPC1 gene (-NPC1 cells). Pharmacological activation of LXRs in -NPC1 cells tended to reduce the ratio of total secreted APP (sAPP) to full length APP (flAPP) levels and sAPPβ levels as well as to increase the ratio of APP Cterminal fragments to flAPP levels, resulting in decreased levels of amyloid β (Aβ) peptides. -NPC1 cells treated with LXR agonist TO901317 (TO90) displayed a modest increase in cholesterol efflux to apolipoprotein A-I (apoA-I) but not to HDL3, or in the absence of extracellular cholesterol acceptors. The observed similar reduction of Aβ levels upon TO90 treatment in the presence or in the absence of extracellular apoA-I indicated a cholesterol-efflux independent effect of TO90 on Aβ levels. Furthermore, TO90 had no effect on the cholesterol synthesis rate in -NPC1 cells, while it reduced the rate of cholesterol esterification. The obtained results indicate that LXR activation may decrease Aβ levels in NPC1- deficient conditions. The underlying mechanism of this action does not appear to be related to effects on cholesterol efflux or synthesis rates.

Context: Phospholipid (PL) transfer protein (PLTP) plays a crucial role in high-density lipoprotein (HDL) metabolism. In the fetal circulation, HDL particles are the main cholesterol carriers and are involved in maternal-fetal cholesterol transfer across human placental endothelial cells (HPEC)., Objective: The aim was to investigate local function(s) of PLTP at the fetoplacental endothelium. Because HPEC display morphological and functional diversity when isolated from arteries or veins, we hypothesized that PLTP activity may differ between arterial and venous HPEC., Design: We determined PLTP mRNA and activity levels from isolated HPEC and investigated PLTP-mediated remodeling of fetal HDL particles and their capacity in mediating cholesterol efflux from HPEC., Results: Incubation of fetal HDL with active human plasma PLTP resulted in increased particle size (12.6 vs. 13.2 nm, P < 0.05), with a concomitant increase (3.5-fold) in pre-β-mobile HDL particles. Arterial HPEC showed higher Pltp expression levels and secreted PL transfer activity (1.8-fold, P < 0.001) than venous HPEC. In contrast to adult HDL(3), [(3)H]cholesterol efflux to fetal HDL was 21% higher (P < 0.05) from arterial than from venous HPEC. PLTP-facilitated particle conversion increased the cholesterol efflux capacity of fetal HDL to similar extents (55 and 48%, P < 0.001) from arterial and venous HPEC, respectively., Conclusion: PLTP mediates PL transfer and participates in reverse cholesterol transport pathways at the fetoplacental barrier. Enhanced cellular cholesterol efflux from HPEC to fetal HDL remodeled by PLTP supports the idea of a local atheroprotective role of PLTP in the placental vasculature.

Context: Gestational diabetes mellitus (GDM) causes alterations in fetal high-density lipoproteins (HDL). Because phospholipid transfer protein (PLTP) is important for HDL (re)assembly and is expressed in the human placenta, we hypothesized that circulating fetal and/or placental PLTP expression and activity are altered in GDM., Design: PLTP levels and activity were determined in maternal and fetal sera from GDM and controls. Placental PLTP was immunolocalized, and its expression was measured in placental tissue. PLTP regulation by glucose/insulin was studied in human endothelial cells isolated from placental vessels (HPEC)., Results: Placental Pltp expression was up-regulated in GDM (1.8-fold, P < 0.05). PLTP protein (5-fold, P < 0.01) and activity (1.4- to 2.5-fold) were higher in fetal than in maternal serum. The placental endothelium was identified as a major PLTP location. Insulin treatment of HPEC significantly increased secreted PLTP levels and activity. In GDM, fetal cholesterol, HDL-triglycerides and phospholipids were elevated compared with controls. Fetal PLTP activity was higher than maternal but unaltered in GDM., Conclusion: HPEC contribute to the release of active PLTP into the fetal circulation. Pltp expression is increased in GDM with hyperglycemia and/or hyperinsulinemia contributing. High PLTP activity in fetal serum may enhance conversion of HDL into cholesterol-accepting particles, thereby increasing maternal-fetal cholesterol transfer.

Currently, little is known about the role of intracellular triacylglycerol (TAG) lipases in the brain. Adipose triglyceride lipase (ATGL) is encoded by the PNPLA2 gene and catalyzes the rate-limiting step of lipolysis. In this study, we investigated the effects of ATGL deficiency on brain lipid metabolism in vivo using an established knock-out mouse model (ATGL-ko). A moderate decrease in TAG hydrolase activity detected in ATGL-ko versus wild-type brain tissue was accompanied by a 14-fold increase in TAG levels and an altered composition of TAG-associated fatty acids in ATGL-ko brains. Oil Red O staining revealed a severe accumulation of neutral lipids associated to cerebrovascular cells and in distinct brain regions namely the ependymal cell layer and the choroid plexus along the ventricular system. In situ hybridization histochemistry identified ATGL mRNA expression in ependymal cells, the choroid plexus, pyramidal cells of the hippocampus, and the dentate gyrus. Our findings imply that ATGL is involved in brain fatty acid metabolism, particularly in regions mediating transport and exchange processes: the brain-CSF interface, the blood-CSF barrier, and the blood-brain barrier., (© 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.)

Although maternal-fetal cholesterol transfer may serve to compensate for insufficient fetal cholesterol biosynthesis under pathological conditions, it may have detrimental consequences under conditions of maternal hypercholesterolemia leading to preatherosclerotic lesion development in fetal aortas. Maternal cholesterol may enter fetal circulation by traversing syncytiotrophoblast and endothelial layers of the placenta. We hypothesized that endothelial cells (ECs) of the fetoplacental vasculature display a high and tightly regulated capacity for cholesterol release. Using ECs isolated from human term placenta (HPECs), we investigated cholesterol release capacity and examined transporters involved in cholesterol efflux pathways controlled by liver-X-receptors (LXRs). HPECs demonstrated 2.5-fold higher cholesterol release to lipid-free apolipoprotein (apo)A-I than human umbilical vein ECs (HUVECs), whereas both cell types showed similar cholesterol efflux to high-density lipoproteins (HDLs). Interestingly, treatment of HPECs with LXR activators increased cholesterol efflux to both types of acceptors, whereas no such response could be observed for HUVECs. In line with enhanced cholesterol efflux, LXR activation in HPECs increased expression of ATP-binding cassette transporters ABCA1 and ABCG1, while not altering expression of ABCG4 and scavenger receptor class B type I (SR-BI). Inhibition of ABCA1 or silencing of ABCG1 decreased cholesterol efflux to apoA-I (-70%) and HDL(3) (-57%), respectively. Immunohistochemistry localized both transporters predominantly to the apical membranes of placental ECs in situ. Thus, ECs of human term placenta exhibit unique, efficient and LXR-regulated cholesterol efflux mechanisms. We propose a sequential pathway mediated by ABCA1 and ABCG1, respectively, by which HPECs participate in forming mature HDL in the fetal blood.