Alzheimer's disease (AD) is the most common form of neurodegenerative disease. The vast majority cases of AD are sporadic, without clear cause, and a combination of environmental and genetic factors ...has been implicated. The hypothesis that homocysteine (Hcy) is a risk factor for AD was initially prompted by the observation that patients with histologically confirmed AD had higher plasma levels of Hcy, termed hyperhomocysteinemia (HHcy), than age-matched controls. Most evidence accumulated so far implicates HHcy as a risk factor for AD onset, but there are also conflicting results. In this review we summarize reports on the relationship between HHcy and AD from epidemiological investigations, including observational studies and randomized controlled clinical trials. We also examine recent in vivo and in vitro studies of potential mechanisms whereby HHcy could influence AD development. Finally, we discuss possible reasons for the existing conflicting data and provide suggestions for future studies.
Cell type-specific expression of optogenetic molecules allows temporally precise manipulation of targeted neuronal activity. Here we present a toolbox of four knock-in mouse lines engineered for ...strong, Cre-dependent expression of channelrhodopsins ChR2-tdTomato and ChR2-EYFP, halorhodopsin eNpHR3.0 and archaerhodopsin Arch-ER2. All four transgenes mediated Cre-dependent, robust activation or silencing of cortical pyramidal neurons in vitro and in vivo upon light stimulation, with ChR2-EYFP and Arch-ER2 demonstrating light sensitivity approaching that of in utero or virally transduced neurons. We further show specific photoactivation of parvalbumin-positive interneurons in behaving ChR2-EYFP reporter mice. The robust, consistent and inducible nature of our ChR2 mice represents a significant advance over previous lines, and the Arch-ER2 and eNpHR3.0 mice are to our knowledge the first demonstration of successful conditional transgenic optogenetic silencing. When combined with the hundreds of available Cre driver lines, this optimized toolbox of reporter mice will enable widespread investigations of neural circuit function with unprecedented reliability and accuracy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The substituted benzene derivatives are essential to organic synthesis, medicinal chemistry, and material science. However, the 1,3-di- and 1,3,5-trisubstituted benzenes are far less prevalent in ...small-molecule drugs than other substitution patterns, likely due to the lack of robust, efficient, and convenient synthetic methods. Here, we report a Mo-catalyzed intermolecular deoxygenative benzene-forming reaction of readily available ynones and allylic amines. A wide range of unsymmetric and unfunctionalized 1,3-di- and 1,3,5-trisubstituted benzenes were obtained in up to 88% yield by using a commercially available molybdenum catalyst. The synthetic potential of the method was further illustrated by synthetic transformations, a scale-up synthesis, and derivatization of bioactive molecules. Preliminary mechanistic studies suggested that this benzene-forming process might proceed through a Mo-catalyzed aza-Michael addition/1,5-hydride shift/cyclization/aromatization cascade. This strategy not only provided a facile, robust, and modular approach to various meta-substituted benzene derivatives but also demonstrated the potential of molybdenum catalysis in the challenging intermolecular deoxygenative cross-coupling reactions.
The catalytic asymmetric cyclopropanation reaction of alkenes with diazo compounds is a direct and powerful method to construct chiral cyclopropanes that are essential to drug discovery. However, ...diazo compounds are potentially explosive and often require hazardous reagents for their preparation. Here, we report on the use of 1,2-dicarbonyl compounds as safe and readily available surrogates for diazo compounds in the direct catalytic asymmetric deoxygenative cyclopropanation reaction. Enabled by a class of simple and readily accessible chiral salen-Mo catalysts, the reaction proceeded with generally good enantioselectivities and yields toward a wide range of substrates (80 examples). Preliminary mechanistic studies suggested that the proposed μ-oxo bridged dinuclear Mo(III)-species was the catalytically active species. This strategy not only provides a promising route for the synthesis of chiral cyclopropanes but also opens a new window for the potential applications of chiral salen-Mo complexes in asymmetric catalysis.
A practical electrophilic aminoselenation of O-homoallyl benzimidate with diselenides promoted by PhICl2/Cu2O has been developed. The easily available and stable diselenides were used as selenium ...sources. Various selenyl 1,3-oxazines, which are important frameworks in medicinal and biological chemistry, were easily obtained in moderate to good yields for the first time. Easy scaleup and scalability make this method attractive for the preparation of other valuable organoselenides.
Epidemiological and clinical studies indicate that elevated circulating level of homocysteine (Hcy) is a risk factor for developing Alzheimer’s disease (AD). Dietary deficiency of folate, vitamin B6 ...and B12 results in a significant increase of Hcy levels, a condition also known as hyperhomocysteinemia (HHcy).
In the present study we tested the hypothesis that a diet deficient for these three important factors when administered to a mouse model of AD, i.e. Tg2576, will result in HHcy and in an acceleration of their amylodotic phenotype.
Compared with Tg2576 mice on regular chow, the ones receiving the diet deficient for folate, B6 and B12 developed HHcy. This condition was associated with a significant increase in Aβ levels in the cortex and hippocampus, and an elevation of Aβ deposits in the same regions. No significant changes were observed for steady-state levels of total APP, BACE-1, ADAM-10, PS1 and nicastrin in the brains of mice with HHcy. No differences were observed for the main Aβ catabolic pathways, i.e. IDE and neprilysin proteins, or the Aβ chaperone apolipoprotein E.
Our findings demonstrate that a dietary condition which leads to HHcy may also result in increased Aβ levels and deposition in a transgenic mouse model of AD-like amylodosis. They further support the concept that dietary factors can contribute to the development of AD neuropathology.
Solid polymer electrolytes with relatively low ionic conductivity at room temperature and poor mechanical strength greatly restrict their practical applications. Herein, we design ...semi‐interpenetrating network polymer (SNP) electrolyte composed of an ultraviolet‐crosslinked polymer network (ethoxylated trimethylolpropane triacrylate), linear polymer chains (polyvinylidene fluoride‐co‐hexafluoropropylene) and lithium salt solution to satisfy the demand of high ionic conductivity, good mechanical flexibility, and electrochemical stability for lithium metal batteries. The semi‐interpenetrating network has a pivotal effect in improving chain relaxation, facilitating the local segmental motion of polymer chains and reducing the polymer crystallinity. Thanks to these advantages, the SNP electrolyte shows a high ionic conductivity (1.12 mS cm−1 at 30 °C), wide electrochemical stability window (4.6 V vs. Li+/Li), good bendability and shape versatility. The promoted ion transport combined with suppressed impedance growth during cycling contribute to good cell performance. The assembled quasi‐solid‐state lithium metal batteries (LiFePO4/SNP/Li) exhibit good cycling stability and rate capability at room temperature.
Semi‐interpenetrating network polymer (SNP) electrolyte composed of an UV‐crosslinked polymer network (ETPTA), linear polymer chains (PVDF‐HFP) and lithium salt solution are designed to satisfy the demands of high ionic conductivity, good mechanical flexibility and electrochemical stability. LiFePO4/Li battery based on the SNP electrolyte delivers a high specific capacity, good rate capability and cycling stability at room temperature.
Mitophagy is a degradative pathway that mediates the degradation of the entire mitochondria, and defects in this process are implicated in many diseases including cancer. In mammals, mitophagy is ...mediated by BNIP3L (also known as NIX) that is a dual regulator of mitochondrial turnover and programmed cell death pathways. Acute myeloid leukemia (AML) cells with deficiency of BNIP3L are more sensitive to mitochondria-targeting drugs. But small molecular inhibitors for BNIP3L are currently not available. Some immunomodulatory drugs (IMiDs) have been proved by FDA for hematologic malignancies, however, the underlining molecular mechanisms are still elusive, which hindered the applications of BNIP3L inhibition for AML treatment. In this study we carried out MS-based quantitative proteomics analysis to identify the potential neosubstrates of a novel thalidomide derivative CC-885 in A549 cells. In total, we quantified 5029 proteins with 36 downregulated in CRBN
cell after CC-885 administration. Bioinformatic analysis showed that macromitophagy pathway was enriched in the negative pathway after CC-885 treatment. We further found that CC-885 caused both dose- and time-dependent degradation of BNIP3L in CRBN
, but not CRBN
cell. Thus, our data uncover a novel role of CC-885 in the regulation of mitophagy by targeting BNIP3L for CRL4CRBN E3 ligase-dependent ubiquitination and degradation, suggesting that CC-885 could be used as a selective BNIP3L degradator for the further investigation. Furthermore, we demonstrated that CC-885 could enhance AML cell sensitivity to the mitochondria-targeting drug rotenone, suggesting that combining CC-885 and mitochondria-targeting drugs may be a therapeutic strategy for AML patients.
Adult neurogenesis supports performance in many hippocampal dependent tasks. Considering the small number of adult-born neurons generated at any given time, it is surprising that this sparse ...population of cells can substantially influence behavior. Recent studies have demonstrated that heightened excitability and plasticity may be critical for the contribution of young adult-born cells for certain tasks. What is not well understood is how these unique biophysical and synaptic properties may translate to networks that support behavioral function. Here we employed a location discrimination task in mice while using optogenetics to transiently silence adult-born neurons at different ages. We discovered that adult-born neurons promote location discrimination during early stages of development but only if they undergo maturation during task acquisition. Silencing of young adult-born neurons also produced changes extending to the contralateral hippocampus, detectable by both electrophysiology and fMRI measurements, suggesting young neurons may modulate location discrimination through influences on bilateral hippocampal networks.
Objective:
12/15‐Lipoxygenase (12/15‐LO) is an enzyme widely distributed in the central nervous system, and it has been involved in the neurobiology of Alzheimer disease (AD). However, the mechanism ...involved remains elusive.
Methods:
We investigated the molecular mechanism by which 12/15‐LO regulates amyloid β (Aβ)/Aβ precursor protein (APP) metabolism in vivo and in vitro by genetic and pharmacologic approaches.
Results:
Here we show that overexpression of 12/15‐LO leads to increased levels of β‐secretase‐1 (BACE1) mRNA and protein, a significant elevation in Aβ levels and deposition, and a worsening of memory deficits in AD transgenic mice. In vitro and in vivo studies demonstrate that 12/15‐LO regulates BACE1 mRNA expression levels via the activation of the transcription factor Sp1. Thus, 12/15‐LO–overexpressing mice had elevated levels of Sp1 and BACE1, whereas 12/15‐LO–deficient mice had reduced levels of both. Preventing Sp1 activation by pharmacologic inhibition or dominant‐negative mutant blocks the 12/15‐LO–dependent elevation of Aβ and BACE1 levels.
Interpretation:
Our findings demonstrate a novel pathway by which 12/15‐LO increases the amyloidogenic processing of APP through a Sp1‐mediated transcriptional control of BACE1 levels that could have implications for AD pathogenesis and therapy. ANN NEUROL 2012;71:57–67
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