Synthesis of Azuleno[2,1-]quinolones and Quinolines via Brønsted Acid-Catalyzed Cyclization of 2-Arylaminoazulenes.

Quinolone and quinoline derivatives are frequently found as substructures in pharmaceutically active compounds. In this paper, we describe a procedure for the synthesis of azuleno[2,1-]quinolones and quinolines from 2-arylaminoazulene derivatives, which are readily prepared via the aromatic nucleophilic substitution reaction of a 2-chloroazulene derivative with several arylamines. The synthesis of azuleno[2,1-]quinolones was established by the Brønsted acid-catalyzed intramolecular cyclization of 2-arylaminoazulene derivatives bearing two ester groups at the five-membered ring.

Construction of a 2,2'-biazulene framework Brønsted acid-promoted annulation of 2,3-di(1-azulenyl)benzofurans.

Dibenzofurans featuring a 2,2'-biazulene framework were prepared in good yields by Brønsted acid-promoted annulation of 2,3-di(1-azulenyl)benzofurans in 100% HPO. NMR, UV-Vis, and fluorescence spectroscopies were used to investigate the structural and optical properties of the products prepared. Remarkably, the annulated products exhibited fluorescence, with the longest wavelength of azulene derivatives reported to date, which extended into the near-infrared region under acidic conditions.

Peripheral apoE4 enhances Alzheimer's pathology and impairs cognition by compromising cerebrovascular function.

The ε4 allele of the apolipoprotein E (APOE) gene, a genetic risk factor for Alzheimer's disease, is abundantly expressed in both the brain and periphery. Here, we present evidence that peripheral apoE isoforms, separated from those in the brain by the blood-brain barrier, differentially impact Alzheimer's disease pathogenesis and cognition. To evaluate the function of peripheral apoE, we developed conditional mouse models expressing human APOE3 or APOE4 in the liver with no detectable apoE in the brain.

Synthesis, Reactivity, and Properties of Benz[]azulenes the [8 + 2] Cycloaddition of 2-Cyclohepta[]furan-2-ones with an Enamine.

Starting with the reaction of 2-cyclohepta[]furan-2-ones with an enamine, which was prepared from 4--butylcyclohexanone and pyrrolidine, benz[]azulenes having both formyl and -butyl groups were obtained in the three-step sequence. Subsequently, both the formyl and -butyl groups were eliminated by heating the benz[]azulene derivatives in 100% HPO to give benz[]azulenes without these substituents in high yields. In terms of product yield, this method is the best one ever reported for the synthesis of the parent benz[]azulene so far.

Preparation of single cell suspensions enriched in mouse brain vascular cells for single-cell RNA sequencing.

Cerebral blood vessels supply oxygen and nutrients, remove metabolic waste, and play a critical role in maintaining brain homeostasis. Cerebrovasculature is composed of heterogeneous populations of brain vascular cells (BVCs). A major challenge in effective cerebrovascular transcriptional profiling is high-quality BVC procurement, permitting high sequencing depth.

Azulene-Substituted Donor-Acceptor Polymethines and 1,6'-Bi-, 1,6';3,6''-Ter-, and Quinqueazulenes via Zincke Salts: Synthesis, and Structural, Optical, and Electrochemical Properties.

Azulene-substituted donor-acceptor polymethines, bi-, ter-, and quinqueazulenes composed of the 1,6'-biazulene unit have been successfully prepared from corresponding Zincke salts. The synthesis of polymethines through the reaction of Zincke salts with several amines, followed by a Knoevenagel reaction with malononitrile, was accomplished in moderate to high yields (40-92 %). Meanwhile, the reaction of Zincke salts with secondary amines and the subsequent sequential condensation-cyclization with cyclopentadienide ions, so-called Ziegler-Hafner method, produced the corresponding 1,6'-biazulenes, 1,6';3,6''-terazulenes, and quinqueazulene, respectively.

Vascular ApoE4 Impairs Behavior by Modulating Gliovascular Function.

The ε4 allele of the apolipoprotein E gene (APOE4) is a strong genetic risk factor for Alzheimer's disease (AD) and multiple vascular conditions. ApoE is abundantly expressed in multiple brain cell types, including astrocytes, microglia, and vascular mural cells (VMCs). Here, we show that VMC-specific expression of apoE4 in mice impairs behavior and cerebrovascular function.

Tau and apolipoprotein E modulate cerebrovascular tight junction integrity independent of cerebral amyloid angiopathy in Alzheimer's disease.

Introduction: Cerebrovascular pathologies including cerebral amyloid angiopathy (CAA) and blood-brain barrier (BBB) dysregulation are prominent features in the majority of Alzheimer's disease (AD) cases.

Methods: We performed neuropathologic and biochemical studies on a large, neuropathologically confirmed human AD cohort (N = 469). Amounts of endothelial tight junction proteins claudin-5 (CLDN5) and occludin (OCLN), and major AD-related molecules (amyloid beta [Aβ40], Aβ42, tau, p-tau, and apolipoprotein E) in the temporal cortex were assessed by ELISA.

Synthesis of thiophene-fused heptalenes by cycloaddition of azulenothiophenes with dimethyl acetylenedicarboxylate.

Heptalene has a fused structure of two cycloheptatrienes which is one of the non-aromatic bicyclic molecules with a 12π-electronic structure. We report herein the synthesis of thiophene-fused heptalene derivatives from the corresponding azulenothiophenes via cycloaddition reaction with dimethyl acetylenedicarboxylate. Their structure was clarified by single-crystal X-ray structural analysis.

Alzheimer's Risk Factors Age, APOE Genotype, and Sex Drive Distinct Molecular Pathways.

Evidence suggests interplay among the three major risk factors for Alzheimer's disease (AD): age, APOE genotype, and sex. Here, we present comprehensive datasets and analyses of brain transcriptomes and blood metabolomes from human apoE2-, apoE3-, and apoE4-targeted replacement mice across young, middle, and old ages with both sexes. We found that age had the greatest impact on brain transcriptomes highlighted by an immune module led by Trem2 and Tyrobp, whereas APOE4 was associated with upregulation of multiple Serpina3 genes.

Synthesis of phthalimides cross-conjugated with an azulene ring, and their structural, optical and electrochemical properties.

The preparation of phthalimides cross-conjugated with an azulene ring was established by a one-pot Diels-Alder reaction of the corresponding 2-aminofuran derivatives with several maleimides, without the isolation of the intermediately formed [4 + 2] cycloadducts. The structure, optical and electrochemical properties of the novel phthalimide derivatives were clarified by single-crystal X-ray analysis, UV/Vis and fluorescence spectra, spectroelectrochemistry and voltammetry experiments, and theoretical calculations. These results indicated that the substituents on the azulene ring greatly affect the optical and electrochemical properties of the molecules.

Direct synthesis of 2-arylazulenes by [8+2] cycloaddition of 2H-cyclohepta[b]furan-2-ones with silyl enol ethers.

We developed a procedure for the direct synthesis of 2-arylazulenes, which were obtained in moderate to excellent yields, by [8+2] cycloaddition of 2H-cyclohepta[b]furan-2-ones with aryl-substituted silyl enol ethers. The structures of some 2-arylazulenes were clarified by single-crystal X-ray analysis. The 2-phenylazulene derivatives obtained by this study showed noticeable fluorescence in acidic media.

Molecular Transformation to Pyrroles, Pentafulvenes, and Pyrrolopyridines by [2+2] Cycloaddition of Propargylamines with Tetracyanoethylene.

In this paper, we describe an efficient and atom-economical synthesis of highly functionalized pyrroles, pentafulvenes, and pyrrolopyridines by [2+2] cycloaddition-retroelectrocyclization of N-substituted propargylamines with tetracyanoethylene, followed by the treatment of the resulting tetracyanobutadiene derivatives with silica gel. In this reaction, silica gel plays an important role to promote the intramolecular cyclization to afford the heterocyclic products from the tetracyanobutadiene intermediates. The products were obtained selectively depending on the substituent on the nitrogen atom of the starting propargylamines.

ApoE (Apolipoprotein E) in Brain Pericytes Regulates Endothelial Function in an Isoform-Dependent Manner by Modulating Basement Membrane Components.

Objective: The ε4 allele of the gene () is the strongest genetic risk factor for Alzheimer disease when compared with the common ε3 allele. Although there has been significant progress in understanding how apoE4 (apolipoprotein E4) drives amyloid pathology, its effects on amyloid-independent pathways, in particular cerebrovascular integrity and function, are less clear. Approach and Results: Here, we show that brain pericytes, the mural cells of the capillary walls, differentially modulate endothelial cell phenotype in an apoE isoform-dependent manner.

Selective loss of cortical endothelial tight junction proteins during Alzheimer's disease progression.

While the accumulation and aggregation of amyloid-β and tau are central events in the pathogenesis of Alzheimer's disease, there is increasing evidence that cerebrovascular pathology is also abundant in Alzheimer's disease brains. In brain capillaries, endothelial cells are connected closely with one another through transmembrane tight junction proteins forming the blood-brain barrier. Because the blood-brain barrier tightly regulates the exchange of molecules between brain and blood and maintains brain homeostasis, its impairment is increasingly recognized as a critical factor contributing to Alzheimer's disease pathogenesis.