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Jianjia Fan, Rui Qi Zhao, Cameron Parro, Wenchen Zhao, Hsien-Ya Chou, Jerome Robert, Tarek Z Deeb, Carina Raynoschek, Samantha Barichievy, Ola Engvist, Marcello Maresca, Ryan Hicks, Johan Meuller, Stephen J Moss, Nicholas J Brandon, Michael W Wood, Iva Kulic, Cheryl L Wellington
Apolipoprotein E (apoE) is the primary lipid carrier within the central nervous system (CNS) and the strongest genetic risk factor for late onset Alzheimer's disease (AD). ApoE is primarily lipidated via the ATP-binding cassette transporter 1 (ABCA1), and both are under transcriptional regulation by the liver X nuclear receptor (LXR). Considerable evidence from genetic (using ABCA1 overexpression) and pharmacological (using synthetic LXR agonists) studies in AD mouse models suggests that increased levels of lipidated apoE can improve cognitive performance and, in some strains, can reduce amyloid burden...
March 21, 2018: Journal of Lipid Research
Heng Zhang, Bo Zhou, Su Qin, Jing Xu, Rachel Harding, Wolfram Tempel, Vinod Nayak, Yanjun Li, Peter Loppnau, Yali Dou, Jinrong Min
The mixed-lineage leukemia (MLL)-AF10 fusion oncoprotein recruits DOT1L to the homeobox A ( HOXA ) gene cluster through the octapeptide motif leucine zipper (OM-LZ), thereby inducing and maintaining the MLL-AF10-associated leukemogenesis. However, the recognition mechanism between DOT1L and MLL-AF10 is unclear. Here, we present the crystal structures of both apo AF10OM-LZ and its complex with the coiled-coil domain of DOT1L. Disruption of the DOT1L-AF10 interface abrogates MLL-AF10-associated leukemic transformation...
March 21, 2018: Genes & Development
Eleanor Drummond, Fernando Goñi, Shan Liu, Frances Prelli, Henrieta Scholtzova, Thomas Wisniewski
There is growing genetic and proteomic data highlighting the complexity of Alzheimer's disease (AD) pathogenesis. Greater use of unbiased "omics" approaches is being increasingly recognized as essential for the future development of effective AD research, that need to better reflect the multiple distinct pathway abnormalities that can drive AD pathology. The track record of success in AD clinical trials thus far has been very poor. In part, this high failure rate has been related to the premature translation of highly successful results in animal models that mirror only limited aspects of AD pathology to humans...
March 16, 2018: Journal of Alzheimer's Disease: JAD
Faissal Stipho, Robert Jackson, Marwan N Sabbagh
BACKGROUND: Homozygous APOEɛ4 status is a well-known risk factor in the development of Alzheimer's disease (AD). However, other genotypes of APOE have not yet been found to have equal clinical significance. There is a paucity of reports regarding clinically or pathologically described AD in APOEɛ2 homozygotes compared to the other alleles. OBJECTIVE: To notify clinicians that patients with homozygous APOEɛ2 are also at risk of developing AD based on results from the largest prospectively gathered registry of brain samples to date...
March 16, 2018: Journal of Alzheimer's Disease: JAD
Madeleine L Werhane, Kelsey R Thomas, Emily C Edmonds, Katherine J Bangen, My Tran, Alexandra L Clark, Daniel A Nation, Paul E Gilbert, Mark W Bondi, Lisa Delano-Wood
BACKGROUND/OBJECTIVE: The APOE ɛ4 allele and increased vascular risk have both been independently linked to cognitive impairment and dementia. Since few studies have characterized how these risk factors affect everyday functioning, we investigated the relationship between APOE ɛ4 genotype and elevated pulse pressure (PP) on functional change in cognitively normal participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). METHODS: 738 normally aging participants underwent APOE genotyping, and baseline PP was calculated from blood pressure indices...
March 16, 2018: Journal of Alzheimer's Disease: JAD
Ji She, Jiangtao Guo, Qingfeng Chen, Weizhong Zeng, Youxing Jiang, Xiao-Chen Bai
The organellar two-pore channel (TPC) functions as a homodimer, in which each subunit contains two homologous Shaker-like six-transmembrane (6-TM)-domain repeats. TPCs belong to the voltage-gated ion channel superfamily and are ubiquitously expressed in animals and plants. Mammalian TPC1 and TPC2 are localized at the endolysosomal membrane, and have critical roles in regulating the physiological functions of these acidic organelles. Here we present electron cryo-microscopy structures of mouse TPC1 (MmTPC1)-a voltage-dependent, phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2 )-activated Na+ -selective channel-in both the apo closed state and ligand-bound open state...
March 21, 2018: Nature
Tianzhe Liu, Rabia Mazmouz, Brett A Neilan
Phosphopantetheinyl transferases catalyze the post-translational modification of carrier proteins involved in both primary and secondary metabolism. The functional expression of polyketide synthases and non-ribosomal peptide synthetases requires the activation of all carrier protein domains by phosphopantetheinyl transferases. Here we describe the characterization of five bacterial phosphopantetheinyl transferases by their substrate specificity and catalytic efficiency of four bacterial carrier proteins. Comparative in vitro phosphopantetheinylation analysis showed Sfp possesses the highest catalytic efficiency over various carrier proteins...
March 21, 2018: ACS Synthetic Biology
Andrea De Lorenzo, Juliana Duarte Lopes da Silva, Cinthia E James, Alexandre C Pereira, Annie Seixas Bello Moreira
BACKGROUND: Familial hypercholesterolemia (FH) is a common autosomal dominant disorder, characterized by a high level of low-density lipoprotein cholesterol (LDL-C) and a high risk of premature cardiovascular disease. OBJECTIVE: To evaluate clinical and anthropometric characteristics of patients with the familiar hypercholesterolemia (FH) phenotype, with or without genetic confirmation of FH. METHODS: Forty-five patients with LDL-C > 190 mg/dl were genotyped for six FH-related genes: LDLR, APOB, PCSK9, LDLRAP1, LIPA and APOE...
February 2018: Arquivos Brasileiros de Cardiologia
Agnieszka Drozd, Dominika Wojewska, Manuel David Peris-Díaz, Piotr Jakimowicz, Artur Krężel
Metallothioneins (MTs), small cysteine-rich proteins, present in four major isoforms, are key proteins involved in zinc and copper homeostasis in mammals. To date, only one X-ray crystal structure of a MT has been solved. It demonstrates seven bivalent metal ions bound in two structurally independent domains with M4S11 (α) and M3S9 (β) clusters. Recent discoveries indicate that Zn(ii) ions are bound with MT2 with the range from nano- to picomolar affinity, which determines its cellular zinc buffering properties that are demonstrated by the presence of partially Zn(ii)-depleted MT2 species...
March 21, 2018: Metallomics: Integrated Biometal Science
Adel Schwertani, Hong Y Choi, Jacques Genest
PURPOSE OF REVIEW: Plasma levels of HDL cholesterol are a biomarker of cardiovascular health but not a therapeutic target, as demonstrated by the failure of pharmacological modulation of HDL cholesterol to prevent or treat atherosclerotic cardiovascular disease. In health, HDL particles exert pleiotropic effects against atherosclerosis, including cholesterol removal from foam cells, vasodilatory effects through vascular endothelial cell nitric oxide production, decreased vascular inflammation and oxidative damage, endothelial cell proliferation and antiapoptotic effects...
March 19, 2018: Current Opinion in Cardiology
V N Shishkova, T V Adasheva, A Yu Remenik, V N Valyaeva, V M Shklovsky
AIM: To study the relationship between clinical-anthropometric, biochemical, metabolic, vascular-inflammatory, molecular-genetic parameters and the development of the first ischemic stroke, and to develop a prognostic model for determining the probability of its occurrence. MATERIAL AND METHODS: The study included 196 first ischemic stroke patients and 119 healthy people matched for age, place of residence and nationality to the group of patients. The main anthropometric, clinical, biochemical, metabolic parameters and markers of vascular inflammation and endothelial dysfunction were assessed...
2018: Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova
Ena Xiao, Qiang Chen, Aaron L Goldman, Hao Yang Tan, Kaitlin Healy, Brad Zoltick, Saumitra Das, Bhaskar Kolachana, Joseph H Callicott, Dwight Dickinson, Karen F Berman, Daniel R Weinberger, Venkata S Mattay
BACKGROUND: We explored the cumulative effect of several late-onset Alzheimer's disease (LOAD) risk loci using a polygenic risk profile score (RPS) approach on measures of hippocampal function, cognition, and brain morphometry. METHODS: In a sample of 231 healthy control subjects (19-55 years of age), we used an RPS to study the effect of several LOAD risk loci reported in a recent meta-analysis on hippocampal function (determined by its engagement with blood oxygen level-dependent functional magnetic resonance imaging during episodic memory) and several cognitive metrics...
November 2017: Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
Xiaochen Huang, Shengqi Dong, Jie Zhen, Huiqiang Zhang, Tong Lin, Yuhong Zeng, Nicholas Van Halm-Lutterodt, Linhong Yuan
Background: Epidemiology studies have indicated an association of apolipoprotein E (ApoE) genetic polymorphism and circulating steroid hormone levels with the risk of Alzheimer's disease. The established physiologic relationship between apolipoproteins and steroid hormone indicate an important role of ApoE polymorphism in impacting the relationship between serum steroid hormones and cognition in the elderly. Study design: A total of 500 Chinese adults aged between 50 and 75 participated in this community-based cross-sectional study...
2018: Frontiers in Endocrinology
Jessica Alber, Kelly McGarry, Richard B Noto, Peter J Snyder
Background: Recent genome-wide association screening (GWAS) studies have linked Alzheimer's disease (AD) neuropathology to gene networks that regulate immune function. Kan et al. recently reported that Arg1 (an anti-inflammatory gene that codes for arginase-1) is expressed in parts of the brain associated with amyloidosis prior to the onset of neuronal loss, suggesting that chronic brain arginine deprivation promotes AD-related neuropathology. They blocked arginine catabolism in their mouse AD model by administration of eflornithine (DFMO) to juvenile animals, effectively blocking the expression of AD-related amyloid pathology as the mice aged...
2018: Frontiers in Aging Neuroscience
Steven A Harris, Elizabeth A Harris
This review focuses on research in the areas of epidemiology, neuropathology, molecular biology and genetics that implicates herpes simplex virus type 1 (HSV-1) as a causative agent in the pathogenesis of sporadic Alzheimer's disease (AD). Molecular mechanisms whereby HSV-1 induces AD-related pathophysiology and pathology, including neuronal production and accumulation of amyloid beta (Aβ), hyperphosphorylation of tau proteins, dysregulation of calcium homeostasis, and impaired autophagy, are discussed. HSV-1 causes additional AD pathologies through mechanisms that promote neuroinflammation, oxidative stress, mitochondrial damage, synaptic dysfunction, and neuronal apoptosis...
2018: Frontiers in Aging Neuroscience
Daniele Giuffrida, Mariosimone Zoccali, Adriana Arigò, Francesco Cacciola, Coralia Osorio Roa, Paola Dugo, Luigi Mondello
An on-line method based on the coupling of supercritical fluid extraction and supercritical fluid chromatography with triple quadrupole mass spectrometry detection (SFESFCQqQ/MS) for the native carotenoids characterization and apocarotenoids detection in yellow tamarillo was developed for the first time; this is the first work reporting the application of this methodology for the apocarotenoids analysis in any matrix. An off-line liquid extraction (LE) and analysis by LC-PDA-MS, using both a conventional C30 (3 μm I...
March 17, 2018: Archives of Biochemistry and Biophysics
Nabab Khan, Gaurav Datta, Jonathan D Geiger, Xuesong Chen
BACKGROUND: Apolipoprotein E (ApoE) is the major carrier protein that mediates the transport and delivery of cholesterol and other lipids in the brain. Three isoforms of ApoE (ApoE2, ApoE3, ApoE4) exist in humans, and their relative expression levels impact HIV-1 infection, HIV-1/AIDS disease progression, and cognitive decline associated with HIV-1-associated neurocognitive disorder. Because HIV-1 Tat, a viral protein essential for HIV-1 replication, can bind to low-density lipoprotein receptor-related protein 1 (LRP1) that controls ApoE uptake in the brain, we determined the extent to which different isoforms of ApoE affected Tat-mediated HIV-1 LTR transactivation...
March 20, 2018: Journal of Neuroinflammation
Maolin Gu, Jing Qiu, Daoxia Guo, Yunfang Xu, Xingxiang Liu, Chong Shen, Chen Dong
BACKGROUND: Recent GWAS-associated studies reported that single nucleotide polymorphisms (SNPs) in ABCB1, TGFβ1, XRCC1 genes were associated with hepatitis A virus (HAV) infection, and variants of APOA4 and APOE genes were associated with and hepatitis E virus (HEV) infection in US population. However, the associations of these loci with HAV or HEV infection in Chinese Han population remain unclear. METHODS: A total of 3082 Chinese Han persons were included in this study...
March 20, 2018: Virology Journal
Milagros Castellanos, Almudena Torres-Pardo, Rosa Rodríguez-Pérez, María Gasset
Acid proteins capable of nucleating Ca2+ and displaying aggregation capacity play key roles in the formation of calcium carbonate biominerals. The helix-loop helix EF-hands are the most common Ca2+ -binding motifs in proteins. Calcium is bound by the loop region. These motifs are found in many proteins that are regulated by calcium. Gad m 1, an Atlantic cod β-parvalbumin isoform, is a monomeric EF-hand protein that acts as a Ca2+ buffer in fish muscle; the neutral and acid apo-forms of this protein can form amyloids...
March 20, 2018: Biomolecules
Seyedmehdi Hossaini Nasr, Anne Tonson, Mohammad El-Dakdouki, David C Zhu, Dalen Agnew, Robert Wiseman, Chunqi Qian, Xuefei Huang
Atherosclerosis is an inflammatory disease of arterial walls and the rupturing of atherosclerotic plaques is a major cause of heart attack and stroke. Imaging techniques that can enable the detection of atherosclerosis plaques before clinical manifestation are urgently needed. Magnetic resonance imaging (MRI) is a powerful technique to image the morphology of atherosclerotic plaques. In order to better analyze molecular processes in plaques, contrast agents that can selectively bind to plaque receptors will prove invaluable...
March 20, 2018: ACS Applied Materials & Interfaces
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