• The role of proinflammatory cytokines on taste function

      Kumarhia, Devaki; Institute of Molecular Medicine and Genetics (2015)
    • Role of the NR2 Subunit and its Molecular Motifs on Memory and Cognition and the Physiological Outcomes after Experimental Intracerebral Hemorrhage

      Jacobs, Stephanie A.; Institute of Molecular Medicine and Genetics (2013-10)
      The N-methyl-D-aspartate receptor is the main coincidence detector in the brain. It is known to be necessary for many forms of learning and memory. Interestingly, the NR2 subunit composition of the NMDA receptor is modulated endogenously according to the location in the brain and the age of the animal, with the NR1 subunit being ubiquitously expressed. In the forebrain regions, including the cortex, hippocampus, striatum, and amygdala, the NR2A and NR2B subunits are the primary subunits expressed. While it is known that a high NR2B:NR2A ratio enhances memory and cognition, it is not directly known, the effects of a low NR2B:NR2A ratio. In this project, the effects of modulating the NR2A:NR2B ratio on multiple forms of learning and memory are explored by the use of a NR2A transgenic mouse. Our transgenic mice overexpress the NR2A subunit in the forebrain regions, driving the NR2A:NR2B ratio toward the expression of the NR2A. As the NR2B subunit is known to favor learning and memory; we also further explore the role of the N-terminal and membrane domains and the Cterminal domain in the observed enhancements. Our data indicate that a high NR2A:NR2B ratio constrains multiple forms of long-term memory in our transgenic animals. Additionally, we have observed additional forms of enhanced learning and memory in the NR2B transgenic mice that were not tested previously. We were able to show that the NR2B C-terminal tail, and thus the intracellular signaling cascades, is responsible for the enhancements seen in the NR2B animals. Using the NR2A and NR2B transgenic mice, we also investigated the long-held hypothesis that a low NR2B:NR2A ratio would be beneficial to hemorrhagic stroke recovery. Until now this hypothesis has only been investigated by the use of pharmaceuticals, whereby the NR2B subunit is antagonized. We found that while several physiological factors, including neurological deficit and survival rate were unchanged, lesion size and percent edema were significantly less in the NR2A transgenic mice than the NR2B transgenic mice. This demonstrates that a low NR2B:NR2A ratio may be beneficial for some aspects of hemorrhagic stroke recovery.
    • A New Antifibrotic Target of Ac-SDKP: Inhibition of Myofibroblast Differentiation in Rat Lung with Silicosis

      Xu, Hong; Yang, Fang; Sun, Ying; Yuan, Yuan; Cheng, Hua; Wei, Zhongqiu; Li, Shuyu; Cheng, Tan; Brann, Darrell W; Wang, Ruimin; et al. (2012-07-3)
      Background: Myofibroblast differentiation, characterized by a-smooth muscle actin (a-SMA) expression, is a key process in organ fibrosis, and is induced by TGF-b. Here we examined whether an anti-fibrotic agent, N-acetyl-seryl-aspartyllysylproline (Ac-SDKP), can regulate induction of TGF-b signaling and myofibroblast differentiation as a potential key component of its anti-fibrotic mechanism in vivo and in vitro.
    • Design, Synthesis, and Initial Evaluation of D-Glyceraldehyde Crosslinked Gelatin-Hydroxyapatite as a Potential Bone Graft Substitute Material

      Florschutz, Anthony V; Institute of Molecular Medicine and Genetics (2012-07)
      Utilization of bone grafts for the treatment of skeletal pathology is a common practice in orthopaedic, craniomaxillofacial, dental, and plastic surgery. Autogenous bone graft is the established archetype but has disadvantages including donor site morbidity, limited supply, and prolonging operative time. In order to avoid these and other issues, bone graft substitute materials are becoming increasingly prevalent among surgeons for reconstructing skeletal defects and arthrodesis applications. Bone graft substitutes are biomaterials, biologies, and guided tissue/bone regenerative devices that can be used alone or in combinations as supplements or alternatives to autogenous bone graft. There is a growing interest and trend to specialize graft substitutes for specific indications and although there is good rationale for this indication-specific approach, the development and utility of a more universal bone graft substitute may provide a better answer for patients and surgeons. The aim of the present research focuses on the design, synthesis, and initial evaluation of D-glyceraldehyde crosslinked gelatin-hydroxyapatite composites for potential use as a bone graft substitutes. After initial establishment of rational material design, gelatinhydroxyapatite scaffolds were fabricated with different gelatin:hydroxyapatite ratios and crosslinking concentrations. The synthesized scaffolds were subsequently evaluated on the basis of their swelling behavior, porosity, density, percent composition, mechanical properties, and morphology and further assessed with respect to cell-biomaterial interaction and biomineralization in vitro. Although none of the materials achieved mechanical properties suitable for structural graft applications, a reproducible material design and synthesis was achieved with properties recognized to facilitate bone formation. Select scaffold formulations as well as a subset of scaffolds loaded with recombinant human bone morphogenetic protein-2 were implanted ectopically in a rodent animal model and histologically evaluated for biocompatibility, degradation, and bone formation in vivo. The gelatin-hydroxyapatite scaffolds retained dimensional structure over 28 days and did not elicit any undesirable systemic or local effects. Distinct areas of mineralization and osteoid/bone were noted in all the implanted scaffolds and quantitative differences were primarily dependent on the presence of hydroxyapatite.
    • An Improved Test for Detecting Multiplicative Homeostatic Synaptic Scaling

      Kim, Jimok; Tsien, Richard W.; Alger, Bradley E.; Institute of Molecular Medicine and Genetics; Graduate Program in Neuroscience; Department of Neurology (2012-05-17)
      Homeostatic scaling of synaptic strengths is essential for maintenance of network "gain", but also poses a risk of losing the distinctions among relative synaptic weights, which are possibly cellular correlates of memory storage. Multiplicative scaling of all synapses has been proposed as a mechanism that would preserve the relative weights among them, because they would all be proportionately adjusted. It is crucial for this hypothesis that all synapses be affected identically, but whether or not this actually occurs is difficult to determine directly. Mathematical tests for multiplicative synaptic scaling are presently carried out on distributions of miniature synaptic current amplitudes, but the accuracy of the test procedure has not been fully validated. We now show that the existence of an amplitude threshold for empirical detection of miniature synaptic currents limits the use of the most common method for detecting multiplicative changes. Our new method circumvents the problem by discarding the potentially distorting subthreshold values after computational scaling. This new method should be useful in assessing the underlying neurophysiological nature of a homeostatic synaptic scaling transformation, and therefore in evaluating its functional significance.
    • Glucocorticoid-Induced Leucine Zipper (GILZ) Antagonizes TNF-a Inhibition of Mesenchymal Stem Cell Osteogenic Differentiation

      He, Linlin; Yang, Nianlan; Isales, Carlos M.; Shi, Xing-Ming; Institute of Molecular Medicine and Genetics; Department of Orthopaedic Surgery; Department of Pathology (2012-03-2)
      Tumor necrosis factor-alpha (TNF-a) is a potent proinflammatory cytokine that inhibits osteoblast differentiation while stimulating osteoclast differentiation and bone resorption. TNF-a activates MAP kinase pathway leading to inhibition of osterix (Osx) expression. TNF-a also induces the expression of E3 ubiquitin ligase protein Smurf1 and Smurf2 and promotes degradation of Runx2, another key transcription factor regulating osteoblast differentiation and bone formation. We showed previously that overexpression of glucocorticoid (GC)-induced leucine zipper (GILZ) enhances osteogenic differentiation of bone marrow mesenchymal stem cells (MSCs). We and others also showed that GILZ is a GC effecter and mediates GC anti-inflammatory activity. In this study, we asked the question whether GILZ retains its osteogenic activity while functioning as an anti-inflammatory mediator. To address this question, we infected mouse bone marrow MSCs with retroviruses expressing GILZ and induced them for osteogenic differentiation in the presence or absence of TNF-a. Our results show that overexpression of GILZ antagonized the inhibitory effects of TNF-a on MSC osteogenic differentiation and the mRNA and protein expression of Osx and Runx2, two pivotal osteogenic regulators. Further studies show that these antagonistic actions occur via mechanisms involving GILZ inhibition of TNF-a-induced ERK MAP kinase activation and protein degradation. These results suggest that GILZ may have therapeutic potential as a novel anti-inflammation therapy.
    • Promotion of plasma membrane repair by vitamin E

      Howard, Amber Cyran; McNeil, Anna K.; McNeil, Paul L.; Institute of Molecular Medicine and Genetics; Department of Cellular Biology and Anatomy (2011-12-20)
      Severe vitamin E deficiency results in lethal myopathy in animal models. Membrane repair is an important myocyte response to plasma membrane disruption injury as when repair fails, myocytes die and muscular dystrophy ensues. Here we show that supplementation of cultured cells with α-tocopherol, the most common form of vitamin E, promotes plasma membrane repair. Conversely, in the absence of α-tocopherol supplementation, exposure of cultured cells to an oxidant challenge strikingly inhibits repair. Comparative measurements reveal that, to promote repair, an anti-oxidant must associate with membranes, as α-tocopherol does, or be capable of α-tocopherol regeneration. Finally, we show that myocytes in intact muscle cannot repair membranes when exposed to an oxidant challenge, but show enhanced repair when supplemented with vitamin E. Our work suggests a novel biological function for vitamin E in promoting myocyte plasma membrane repair. We propose that this function is essential for maintenance of skeletal muscle homeostasis.
    • IGF-1 Induction by Acylated Steryl β-Glucosides Found in a Pre-Germinated Brown Rice Diet Reduces Oxidative Stress in Streptozotocin-Induced Diabetes

      Usuki, Seigo; Tsai, Ying-Ying; Morikawa, Keiko; Nonaka, Shota; Okuhara, Yasuhide; Kise, Mitsuo; Yu, Robert K.; Institute of Molecular Medicine and Genetics (2011-12-14)
      Background: The pathology of diabetic neuropathy involves oxidative stress on pancreatic b-cells, and is related to decreased levels of Insulin-like growth factor 1 (IGF-1). Acylated steryl b-glucoside (PR-ASG) found in pre-germiated brown rice is a bioactive substance exhibiting properties that enhance activity of homocysteine-thiolactonase (HTase), reducing oxidative stress in diabetic neuropathy. The biological importance of PR-ASG in pancreatic b-cells remains unknown.
    • VPS35 haploinsufficiency increases Alzheimerâ s disease neuropathology

      Wen, Lei; Tang, Fu-Lei; Hong, Yan; Luo, Shi-Wen; Wang, Chun-Lei; He, Wanxia; Shen, Chengyong; Jung, Ji-Ung; Xiong, Fei; Lee, Dae-hoon; et al. (2011-11-28)
      VPS35, a major component of the retromer complex, is important for endosome-to-Golgi retrieval of membrane proteins. Although implicated in Alzheimerâ s disease (AD), how VPS35 regulates AD-associated pathology is unknown. In this paper, we show that hemizygous deletion of Vps35 in the Tg2576 mouse model of AD led to earlier-onset AD-like phenotypes, including cognitive memory deficits, defective long-term potentiation, and impaired postsynaptic glutamatergic neurotransmission in young adult age. These deficits correlated well with an increase of β-amyloid peptide (Aβ) level in the mutant hippocampus. We further demonstrate that VPS35 is predominantly expressed in pyramidal neurons of young adult hippocampus and interacts with BACE1, a protease responsible for Aβ production. Loss of VPS35 function in the mouse hippocampus increased BACE1 activity. Suppression of VPS35 expression in culture decreased BACE1 trans-Golgi localization but enriched it in endosomes. These results demonstrate an essential role for VPS35 in suppression of AD neuropathology and in inhibition of BACE1 activation and Aβ production by promoting BACE1 endosome-to-Golgi retrieval.
    • Comparison and Avoidance of Toxicity of Penetrating Cryoprotectants

      Szurek, Edyta A.; Eroglu, Ali; Institute of Molecular Medicine and Genetics; Department of Medicine; Department of Obstetrics and Gynecology; GHSU Cancer Center (2011-11-16)
      The objective of this study was to elucidate the toxicity of widely used penetrating cryoprotective agents (CPAs) to mammalian oocytes. To this end, mouse metaphase II (M II) oocytes were exposed to 1.5 M solutions of dimethylsulfoxide (DMSO), ethylene glycol (EG), or propanediol (PROH) prepared in phosphate buffered saline (PBS) containing 10% fetal bovine serum. To address the time- and temperature-dependence of the CPA toxicity, M II oocytes were exposed to the aforementioned CPAs at room temperature (RT, ,23uC) and 37uC for 15 or 30 minutes. Subsequently, the toxicity of each CPA was evaluated by examining post-exposure survival, fertilization, embryonic development, chromosomal abnormalities, and parthenogenetic activation of treated oocytes. Untreated oocytes served as controls. Exposure of MII oocytes to 1.5 M DMSO or 1.5 M EG at RT for 15 min did not adversely affect any of the evaluated criteria. In contrast, 1.5 M PROH induced a significant increase in oocyte degeneration (54.2%) and parthenogenetic activation (16%) under same conditions. When the CPA exposure was performed at 37uC, the toxic effect of PROH further increased, resulting in lower survival (15%) and no fertilization while the toxicity of DMSO and EG was still insignificant. Nevertheless, it was possible to completely avoid the toxicity of PROH by decreasing its concentration to 0.75 M and combining it with 0.75 M DMSO to bring the total CPA concentration to a cryoprotective level. Moreover, combining lower concentrations (i.e., 0.75 M) of PROH and DMSO significantly improved the cryosurvival of MII oocytes compared to the equivalent concentration of DMSO alone. Taken together, our results suggest that from the perspective of CPA toxicity, DMSO and EG are safer to use in slow cooling protocols while a lower concentration of PROH can be combined with another CPA to avoid its toxicity and to improve the cryosurvival as well.
    • Acetylation of the Pro-Apoptotic Factor, p53 in the Hippocampus following Cerebral Ischemia and Modulation by Estrogen

      Raz, Limor; Zhang, Quan-Guang; Han, Dong; Dong, Yan; De Sevilla, Liesl; Brann, Darrell W; Institute of Molecular Medicine and Genetics (2011-10-26)
      Background: Recent studies demonstrate that acetylation of the transcription factor, p53 on lysine373 leads to its enhanced stabilization/activity and increased susceptibility of cells to stress. However, it is not known whether acetylation of p53 is altered in the hippocampus following global cerebral ischemia (GCI) or is regulated by the hormone, 17b-estradiol (17b2E2), and thus, this study examined these issues.
    • Unique phenotype in a patient with CHARGE syndrome

      Jain, Shobhit; Kim, Hyung-Goo; Lacbawan, Felicitas; Meliciani, Irene; Wenzel, Wolfgang; Kurth, Ingo; Sharma, Josefina; Schoeneman, Morris; Ten, Svetlana; Layman, Lawrence C; et al. (2011-10-13)
      CHARGE is a phenotypically heterogeneous autosomal dominant disorder recognized as a cohesive syndrome since the identification of CHD7 as a genetic etiology. Classic features include: Coloboma, Heart defects, Atresia choanae, Retarded growth and development, Genitourinary abnormalities, and Ear anomalies and/or deafness. With greater accessibility to genetic analysis, a wider spectrum of features are emerging, and overlap with disorders such as DiGeorge syndrome, Kallmann syndrome, and Hypoparathyroidism Sensorineural Deafness and Renal Disease syndrome, is increasingly evident. We present a patient with a unique manifestation of CHARGE syndrome, including primary hypoparathyroidism and a limb anomaly; to our knowledge, he is also the first CHARGE subject reported with bilateral multicystic dysplastic kidneys. Furthermore, with structural modeling and murine expression studies, we characterize a putative CHD7 G744S missense mutation. Our report continues to expand the CHARGE phenotype and highlights that stringent fulfillment of conventional criteria should not strictly guide genetic analysis.
    • Novel Role of Heat Shock Protein (HSP) 90 in Regulating ATR-CHK1 DNA Damage Response Pathway in Cancer Cells

      Ha, Kyungsoo; Institute of Molecular Medicine and Genetics (2011-10)
      DNA damage caused by environmental mutagens or reactive metabolic byproducts induces DNA damage response (DDR), which regulates cell cycle transit, DNA repair and apoptosis. DDR involves the phosphorylation and activation of Ataxia Telangiectasia Mutated (ATM) and ATM and RAD3-related (ATR) proteins. ATR regulates the firing of the replication forks during S phase, and the repair of damaged replication forks to prevent premature onset of mitosis. ATR phosphorylates and activates CHK1 which phosphorylates and inactivates CDC25, thereby inhibiting CDK1 activation and cell cycle progression. In the present studies, we determined that treatment with an hsp90 inhibitor AUY922, without affecting the mRNA levels, dose-dependently depletes the protein levels of p-ATR (Ser 428), ATR and CHK1 in human breast and cervical cancer cells. Additionally, treatment with the pan-histone deacetylase inhibitor panobinostat (PS), which is known to induce hyperacetylation and inhibition of hsp90 function, also depleted ATR and CHK1 levels in cancer cells. Co-treatment with the proteasome inhibitor bortezomib (BZ) partially reversed AUY922- or PS-mediated depletion of ATR and CHK1 expression, indicating proteasome-mediated degradation of ATR and CHK1. Treatment with either AUY922 or PS markedly inhibited the binding of ATR with hsp90, induced polyubiquitylation of ATR, and decreased the half-life of both ATR and CHK1 proteins. Treatment with AUY922 also abrogated ionizing radiation (IR)-induced cell cycle arrest and increased the amount of DNA damage in the cancer cells following IR. Treatment with AUY922 also inhibited the recruitment of p-ATR, ATR and 53BP1 to the site of DNA damage. In addition, HDAC3 binds to and deacetylates hsp90 in the nucleus. Depletion of HDAC3 by either short hairpin RNA or genetic knockout induced hyperacetylation of nuclear hsp90, resulting in the inhibition of chaperone association of ATR with hsp90 and depletion of ATR. These findings demonstrate that 1) ATR is chaperoned by hsp90, 2) Inhibition of chaperone function of hsp90 results in proteasomal degradation of ATR and inhibition of DDR, 3) pan-HDAC inhibitors abrogate ATRCHK1 cell cycle checkpoint pathway by modulating chaperone activity of hsp90 and 4) HD AC3 plays a critical role in the regulation of DNA damage response by stabilizing the chaperone activity of nuclear hsp90.
    • The role of sulfoglucuronosyl glycosphingolipids in the pathogenesis of monoclonal IgM paraproteinemia and peripheral neuropathy

      Ariga, Toshio; Institute of Molecular Medicine and Genetics (2011-07-25)
      In IgM paraproteinemia and peripheral neuropathy, IgM M-protein secretion by B cells leads to a T helper cell response, suggesting that it is antibody-mediated autoimmune disease involving carbohydrate epitopes in myelin sheaths. An immune response against sulfoglucuronosyl glycosphingolipids (SGGLs) is presumed to participate in demyelination or axonal degeneration in the peripheral nervous system (PNS). SGGLs contain a 3-sulfoglucuronic acid residue that interacts with anti-myelin-associated glycoprotein (MAG) and the monoclonal antibody anti-HNK-1. Immunization of animals with sulfoglucuronosyl paragloboside (SGPG) induced anti-SGPG antibodies and sensory neuropathy, which closely resembles the human disease. These animal models might help to understand the disease mechanism and lead to more specific therapeutic strategies. In an in vitro study, destruction or malfunction of the blood-nerve barrier (BNB) was found, resulting in the leakage of circulating antibodies into the PNS parenchyma, which may be considered as the initial key step for development of disease.
    • Expression of GD2 and GD3 gangliosides in human embryonic neural stem cells

      Yanagisawa, Makoto; Yoshimura, Saori; Yu, Robert K.; Institute of Molecular Medicine and Genetics (2011-04-7)
      NSCs (neural stem cells) are undifferentiated neural cells endowed with a high potential for proliferation and a capacity for self-renewal with retention of multipotency to differentiate into neurons and glial cells. It has been recently reported that GD3, a b-series ganglioside, is a marker molecule for identifying and isolating mouse NSCs. However, the expression of gangliosides in human NSCs is largely unknown. In the present study, we analysed the expression of gangliosides, GD2 and GD3, in human NSCs that were isolated from human brains at gestational week 17 in the form of neurospheres, which are floating clonal aggregates formed by NSCs in vitro. Employing immunocytochemistry, we found that human NSCs were strongly reactive to anti-GD2 antibody and relatively weakly reactive to anti-GD3 antibody. Treatment of these cells with an organic solvent such as 100% methanol, which selectively removes glycolipids from plasma membrane, abolished the immunoreactivity with those antibodies, indicating that the reactivity was due to GD2 and GD3, but not to GD2-/GD3-like glycoproteins or proteoglycans. The immunoreactivity of human NSCs to antibody against SSEA-1 (stage-specific embryonic antigen-1), a well-known carbohydrate antigen of NSCs, was not decreased by the treatment with 100% methanol, indicating that SSEA-1 is mainly carried by glycoproteins and/or proteoglycans in human NSCs. Our study suggests that GD2 and GD3 can be marker gangliosides for identifying human NSCs.
    • Genome-wide target profiling of piggyBac and Tol2 in HEK 293: pros and cons for gene discovery and gene therapy

      Meir, Yaa-Jyuhn J; Weirauch, Matthew T; Yang, Herng-Shing; Chung, Pei-Cheng; Yu, Robert K.; Wu, Sareina C-Y; Institute of Molecular Medicine and Genetics; Institute of Neuroscience (2011-03-30)
      Background: DNA transposons have emerged as indispensible tools for manipulating vertebrate genomes with applications ranging from insertional mutagenesis and transgenesis to gene therapy. To fully explore the potential of two highly active DNA transposons, piggyBac and Tol2, as mammalian genetic tools, we have conducted a side-by-side comparison of the two transposon systems in the same setting to evaluate their advantages and disadvantages for use in gene therapy and gene discovery.
    • The Pathological Roles of Ganglioside Metabolism in Alzheimer's Disease: Effects of Gangliosides on Neurogenesis

      Ariga, Toshio; Wakade, Chandramohan; Yu, Robert K.; Institute of Molecular Medicine and Genetics; Institute of Neuroscience (2011-01-9)
      Conversion of the soluble, nontoxic amyloid β-protein (Aβ) into an aggregated, toxic form rich in β-sheets is a key step in the onset of Alzheimer’s disease (AD). It has been suggested that Aβ induces changes in neuronal membrane fluidity as a result of its interactions with membrane components such as cholesterol, phospholipids, and gangliosides. Gangliosides are known to bind Aβ. A complex of GM1 and Aβ, termed “GAβ”, has been identified in AD brains. Abnormal ganglioside metabolism also may occur in AD brains. We have reported an increase of Chol-1α antigens, GQ1bα and GT1aα, in the brain of transgenic mouse AD model. GQ1bα and GT1aα exhibit high affinities to Aβs. The presence of Chol-1α gangliosides represents evidence for genesis of cholinergic neurons in AD brains. We evaluated the effects of GM1 and Aβ1–40 on mouse neuroepithelial cells. Treatment of these cells simultaneously with GM1 and Aβ1–40 caused a significant reduction of cell number, suggesting that Aβ1–40 and GM1 cooperatively exert a cytotoxic effect on neuroepithelial cells. An understanding of the mechanism on the interaction of GM1 and Aβs in AD may contribute to the development of new neuroregenerative therapies for this disorder.
    • Ceramide in Stem Cell Differentiation and Embryo Development: Novel Functions of a Topological Cell-Signaling Lipid and the Concept of Ceramide Compartments

      Bieberich, Erhard; Institute of Molecular Medicine and Genetics (2010-12-29)
      In the last two decades, the view on the function of ceramide as a sole metabolic precursor for other sphingolipids has completely changed. A plethora of studies has shown that ceramide is an important lipid cell-signaling factor regulating apoptosis in a variety of cell types. With the advent of new stem cell technologies and knockout mice for specific steps in ceramide biosynthesis, this view is about to change again. Recent studies suggest that ceramide is a critical cell-signaling factor for stem cell differentiation and cell polarity, two processes at the core of embryo development. This paper discusses studies on ceramide using in vitro differentiated stem cells, embryo cultures, and knockout mice with the goal of linking specific developmental stages to exciting and novel functions of this lipid. Particular attention is devoted to the concept of ceramide as a topological cell-signaling lipid: a lipid that forms distinct structures (membrane domains and vesicles termed â sphingosomeâ ), which confines ceramide-induced cell signaling pathways to localized and even polarized compartments.
    • Ganglioside metabolism in a transgenic mouse model of Alzheimer's disease: expression of Chol-1a antigens in the brain

      Ariga, Toshio; Yanagisawa, Makoto; Wakade, Chandramohan; Ando, Susumu; Buccafusco, Jerry J; McDonald, Michael P; Yu, Robert K.; Institute of Molecular Medicine and Genetics; Department of Pharmacology and Toxicology (2010-10-4)
      The accumulation of Ab (amyloid b-protein) is one of the major pathological hallmarks in AD (Alzheimer’s disease). Gangliosides, sialic acid-containing glycosphingolipids enriched in the nervous system and frequently used as biomarkers associated with the biochemical pathology of neurological disorders, have been suggested to be involved in the initial aggregation of Ab. In the present study, we have examined ganglioside metabolism in the brain of a double- Tg (transgenic) mouse model of AD that co-expresses mouse/ human chimaeric APP (amyloid precursor protein) with the Swedish mutation and human presenilin-1 with a deletion of exon 9. Although accumulation of Ab was confirmed in the double-Tg mouse brains and sera, no statistically significant change was detected in the concentration and composition of major ganglio-N-tetraosyl-series gangliosides in the double-Tg brain. Most interestingly, Chol-1a antigens (cholinergic neuron-specific gangliosides), such as GT1aa and GQ1ba, which are minor species in the brain, were found to be increased in the double-Tg mouse brain. We interpret that the occurrence of these gangliosides may represent evidence for generation of cholinergic neurons in the AD brain, as a result of compensatory neurogenesis activated by the presence of Ab.
    • Quantifiable Biomarkers of Normal Aging in the Japanese Medaka Fish (Oryzias latipes)

      Ding, Lingling; Kuhne, Wendy W.; Hinton, David E.; Song, Jian; Dynan, William S.; Institute of Molecular Medicine and Genetics (2010-10-11)
      Background: Small laboratory fish share many anatomical and histological characteristics with other vertebrates, yet can be maintained in large numbers at low cost for lifetime studies. Here we characterize biomarkers associated with normal aging in the Japanese medaka (Oryzias latipes), a species that has been widely used in toxicology studies and has potential utility as a model organism for experimental aging research.