Transmissible spongiform encephalopathies (TSEs), such as bovine spongiform encephalopathy (BSE) in cattle, scrapie in sheep, and Creutzfeldt-Jakob disease (CJD) in humans, are all fatal neurological disorders resulting from the deposition of a misfolded form of the prion protein (designated PrPSc) in the central nervous system. Accumulation of PrPSc can also be found in other tissues the organism. Of greatest concern to public health is the potential presence of the aberrant form of PrPSc in muscle tissue of infected cattle. Recently PrPSc studies on experimentally infected rodents showed that PrPSc was present in the muscle tissue. To assess the relative risk associated with this finding, Michael Beekes and colleagues investigated the time course of PrPSc accumulation in the muscle tissue of infected rodents both and find the defective form of the prion protein is present prior to clinical symptoms. The accumulation of PrPSc is seen close to the onset of symptoms but is greatest after clinical symptoms are well established. Deposition appears to occur through the spinal motor neurons into the myofibers of the muscle tissue. This animal model provides an excellent source for investigation of the timing and mechanisms for PrPSc spread in an infected animal, but should not be extrapolated to an indication that cattle with BSE likewise will have PrPSc build-up in muscle tissue prior to clinical symptoms as this rodent model has much higher levels of infectivity and PrPSc production than do other non-experimental produced TSEs.
TITLE: Preclinical deposition of pathological prion protein PrPSc in muscles of hamsters orally exposed to scrapie
AUTHOR CONTACT:
Michael Beekes
Robert Koch-Institut, Berlin, Germany.
Phone: 49-30-4547-2396; Fax: 49-30-4547-2267; E-mail: BeekesM@rki.de
View the PDF of this article at: https://www.the-jci.org/press/21083.pdf
**********************************************
ADAM: Good Enzyme for Alzheimer Disease
Alzheimer Disease (AD), a progressive neurological disorder, is characterized by the presence of amyloid plaques in the brain. These plaques are comprised of aggregates of amyloid beta-peptides (AB peptides), which are believed to play a central role in disease development. Most strategies to prevent AD have been aimed at reducing the generation of amyloid beta-peptides. This is done by targeting specific enzymes, beta- and gamma-secretase, in the amyloid precursor protein (APP) degradation pathway, which sequentially cleave APP to form the AB peptide. Falk Fahrenholz and colleagues at the University of Mainz, Germany, now provide evidence that targeting and alternative enzyme, a-secretase, might be a useful alternative strategy for reducing AB peptide. In the APP processing pathway, alpha-secretase cleavage of APP generates an alternative breakdown product of the protein that cannot generate AB peptide. Here the researchers use a mouse model deficient in or over expressing the gene ADAM10, which codes for alpha-secretase. In these studies, they find that moderate increased expression of ADAM10 in mice reduced AB peptide formation, prevented plaque formation, and, from a functional standpoint provided improvement in both long-term potentiation and cognitive impairment. On the other hand, mice lacking ADAM10 had increased number and size of amyloid plaques. The data here provide evidence that alpha-secretase might be a useful therapeutic target for AD, and also suggest that impairment of this enzyme might underlie some forms of the disease.
An accompanying commentary by Christian Haas and Stefan F. Lichtenthaler provides details on the APP degradation pathway and places this work and AD in this context.
TITLE: A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model
AUTHOR CONTACT:
Falk Fahrenholz
University of Mainz, Mainz, Germany.
Phone: 49-6131-392-5833; Fax: 49-6131-392-5348; E-mail: bio.chemie@uni-mainz.de
View the PDF of this article at: https://www.the-jci.org/press/20864.pdf
ACCOMPANYING COMMENTARY: Amyloid at the cutting edge: activation of alpha-secretase prevents amyloidogenesis in an Alzheimer disease mouse model
AUTHOR CONTACT:
Christian Haass
Ludwig-Maximilians-Universitat, Munich, Germany.
Phone: 49-89-5996-471; Fax: 49- 5996-415; E-mail: chaass@pbm.med.uni-muenchen.de
View the PDF of this commentary at: https://www.the-jci.org/press/21746.pdf
**********************************************
Toll-free Road from Sepsis
Immune system failure to limit the spread of a bacterial infection results in sepsis: a loss of control on the normal inflammatory response, leading to tissue damage, increased vascular permeability, and finally multi-organ failure and shock. The death rate for sepsis patients is in the range of 70%, and the health-care sticker price for such runaway infections is around $15 billion annually in the US alone. Strategies for treating septic shock are aimed at limiting the inflammatory response, as treatments to directly reduce the bacterial infection, such as the use of antibiotics, can result in furthering the already out-of-control inflammatory response. Now, Cartson Kirschning and colleagues, from the Technical University of Munich, have tested a new therapeutic possibility by creating antibodies directed against the receptor to which bacteria bind in order to infect the cell. The strategy here, therefore, is to interrupt the initial step of septic inflammation. They showed that use of antibodies against the toll-like receptor 2 (TLR2) in lipopeptide-challenged mice blocked the release of markers of the inflammatory response, such as TNFa, and protected the mice from a lethal shock-like syndrome. The results here indicate the potential suitability for antibody-directed therapy in treating septic shock.
An accompanying commentary by Thomas Decker, of the University of Vienna, provides an overview of Toll-like receptors, their role in bacterial infection, and a discussion of the potential strengths and weaknesses of targeting these receptors for combating sepsis.
TITLE: Antagonistic antibody prevents toll-like receptor 2–driven lethal shock-like syndromes
AUTHOR CONTACT:
Carsten J. Kirschning
Technical University of Munich, Munich, Germany.
Phone: 49-89-4140-4132; Fax: 49-89-4140-4139; E-mail: carsten.kirschning@lrz.tum.de
View the PDF of this article at: https://www.the-jci.org/press/20762.pdf
ACCOMPANYING COMMENTARY: Sepsis: avoiding its deadly toll
AUTHOR CONTACT:
Thomas Decker
University of Vienna, Vienna, Austria.
Phone: 43-1-4277-54605; Fax: 43-1-4277-9546; E-mail: thomas.decker@univie.ac.at
View the PDF of this commentary at: https://www.the-jci.org/press/21819.pdf
**********************************************
Bile Keeps Triglycerides Down
Elevated triglyceride (TG) levels have been shown to be a cardiovascular disease risk factor. TG production is controlled largely at the transcriptional level by the transcription factor SREBP-1c, which governs fatty acid synthesis. TG levels are also inversely affected by bile acids, although the mechanism underlying this relationship is unknown. Johan Auwerx and collaborators, from Institut de Genetique et Biologie Moleculaire et Cellulaire, traced this elusive pathway through experiments with a diet-inducible hypertriglyceridemic mouse model and showed that bile acid–related TG level reduction occurs through transcriptional regulation. TG levels were significantly lowered in mice receiving either a natural or a synthetic agonist for the bile acid receptor FXR. Mice treated with cholic acid, a type of bile acid, also had increased SHP expression levels. SHP, an FXR target, represses the nuclear receptor LXR. LXR is essential for a basal transcription level of SREBP-1c. The authors analyzed the SREBP-1c promoter using luciferase assays to show that SREBP-1c expression was attenuated via the FXR/SHP cascade. Finally, SHP–/– mice as well as LXR_/_–/– mice showed no decrease in TG levels upon cholic acid treatment, further supporting this transcription pathway as the link between bile acid presence and TG levels.
TITLE: Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c
AUTHOR CONTACT:
Johan Auwerx
Institut de Genetique et Biologie Moleculaire et Cellulaire, Illkirch, France.
Phone: 33-38-865-3425; Fax: 33-3-8865-3201; E-mail: auwerx@igbmc.u-strasbg.fr
View the PDF of this article at: https://www.the-jci.org/press/21025.pdf
**********************************************
Pancreatic Maturity Lost with E2F Loss
The E2F transcription factor family is known to be important in regulating cell growth and differentiation. Phenotypes of single- and double-mutant mice of the six gene family members display varied defects in systemic and cellular function. Ana Zubiaga and colleagues, from the University of the Basque Country, previously characterized E2F1 and E2F2 single-knockout mice and concluded that these two members have distinct roles in T lymphocyte homeostasis. They now show that E2F1 an E2F2 are critical for proper pancreatic development and function, as mice deficient in both these genes develop diabetes and exocrine gland dysfunction. Loss of both these factors results in gross abnormalities in pancreatic function as the mice age, and disease manifests as diabetes due to lack of insulin. Cell cycle assays showed increased proliferation and apoptosis in the double-knockout mouse cells. These results suggest the involvement of E2F1 and E2F2 in the maintenance of differentiated cells in the pancreas and support their distinct role as transcriptional repressors that cannot be compensated for by other members of the gene family.
TITLE: Diabetes and exocrine pancreatic insufficiency in E2F1/E2F2 double-mutant mice
AUTHOR CONTACT:
Ana Zubiaga
University of the Basque Country, Bilbao, Spain.
Phone: 34-94-601-2603; Fax: 34-94-464-8500; E-mail: ggpzuela@lg.ehu.es
View the PDF of this article at: https://www.the-jci.org/press/18879.pdf
**********************************************
CD39 Thins Out Thrombosis
Vascular thrombosis results from platelet recruitment and aggregation at a site of vascular injury. CD39 converts ATP and ADP to AMP, which can be further degraded to adenosine, an antithrombotic mediator. Anthony d'Apice and colleagues, from St. Vincent's Hospital, Melbourne, pursued CD39 as a potential antithrombosis agent in disease and in transplantation using mice transgenic for human CD39. hCD39-transgenic mice had increased bleeding times and were also protected from collagen-induced thrombosis. Moreover, the study showed that hCD39 expression in either endothelial cells alone or blood components alone was sufficient to increase bleeding times. To test CD39's potential in improving xenotransplantation, the researchers performed cardiac grafts from the transgenic mice and promoted transplant rejection by immune system induction. Transgenic hearts were protected from rejection that is manifested as widespread intravascular thrombosis and platelet infiltration in small blood vessels of wild-type mice. Thus, CD39-transgenic cells may aid in improving xenotransplantation protocols as well as other clinical problems involving vascular injury and thrombosis.
TITLE: Thromboregulatory manifestations in human CD39 transgenic mice and the implications for thrombotic disease and transplantation
AUTHOR CONTACT:
Anthony J.F. d'Aspice
St. Vincent's Hospital- Melbourne, Fitzroy, Victoria, Australia.
Phone: 61-3-9288-3140; Fax: 61-3-9288-3151; E-mail: Anthony.DAPICE@svhm.org.au
View the PDF of this article at: https://www.the-jci.org/press/19560.pdf
**********************************************
B7-1 Beyond the Immune System
Proteinuria is a hallmark of nephrotic disease and results from dysfunction in the podocyte structure of kidney glomeruli. While a great deal has been discovered in the last several years about the molecular underpinnings of proteinuria, Peter Mundel and colleagues, from Albert Einstein College of Medicine, have identified an unexpected player in the development of this disease: B7-1, a transmembrane protein primarily known for its role in the immune system. B7-1 is expressed on antigen-presenting cells, where it acts as a T cell costimulatory molecule. In this study, using an RNA differential display screen, the authors found increased expression of B7-1 in podocytes from a3-integrin–deficient mice, which have abnormal podocyte structures. They further observed induction of podocyte B7-1 expression in other models of nephrotic syndrome and found a correlation between podocyte B7-1 levels and the clinical severity of human lupus nephritis. Additionally, the absence of B7-1 protected mice from LPS-induced proteinuria. These results point to a novel role for B7-1 in the kidney in response to damage in this organ and offer new insights into the mechanism of kidney dysfunction.
TITLE: Induction of B7-1 in podocytes is associated with nephrotic syndrome
AUTHOR CONTACT:
Peter Mundel
Albert Einstein College of Medicine, New York, New York, USA.
Phone: 718-430-3219; Fax: 718-430-8963; E-mail: mundel@aecom.yu.edu
View the PDF of this article at: https://www.the-jci.org/press/20402.pdf
**********************************************
Other Papers in this Issue:
*Giving Yourself a Heart Attack*
TITLE: Direct evidence for a beta1-adrenergic receptor-directed autoimmune attack as a cause of idiopathic dilated cardiomyopathy
AUTHOR CONTACT:
Roland Jahns, University of Wuerzburg, Wuerzburg, Germany.
Phone: 49-931-201-70460; Fax: 49-931-201-70730; E-mail: jahns@wpxx.02.toxi.uni-wuerzburg.de
View the PDF of this article at: https://www.the-jci.org/press/20149.pdf
ACCOMPANYING COMMENTARY: Anti–beta1-adrenergic receptor antibodies and heart failure: causation, not just correlation
AUTHOR CONTACT:
Robert J. Lefkowicz, Duke University Medical Center, Durham, North Carolina, USA.
Phone: 919-684-2974; Fax: 919-684-8875; E-mail: lefko001@receptor-biol.duke.edu
View the PDF of this commentary at: https://www.the-jci.org/press/21748.pdf
*The Many Moods of Ca2+ Channels*
TITLE: Isoform-specific regulation of mood behavior and pancreatic beta cell and cardiovascular function by L-type Ca2+ channels
AUTHOR CONTACT:
Joerg Striessnig, Universitat Innsburck, Inssbruck, Austria.
Phone: 43-512-507-5600; Fax: 43-512-507-2931; E-mail: joerg.striessnig@uibk.ac.at
View the PDF of this article at: https://www.the-jci.org/press/20208.pdf
ACCOMPANYING COMMENTARY: Dissecting the functional role of different isoforms of the L-type Ca2+ channel
AUTHOR CONTACT:
Emmanuel Bourinet, Laboratoire de Genomique Fonctionnelle, Montpellier, France.
Phone: 33-499-61-99-36; Fax: 33-499-61-99-01; E-mail: Emmanuel.Bourinet@igh.cnrs.fr
View the PDF of this commentary at: https://www.the-jci.org/press/21815.pdf
*From the Bowels of Ulcerative Colitis*
TITLE: Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis
AUTHOR CONTACT:
Ivan J. Fuss, National Institutes of Health, Bethesda, Maryland, USA.
Phone: 301-496-6810; Fax: 301-402-2240; E-mail: ifuss@niaid.nih.gov
View the PDF of this article at: https://www.the-jci.org/press/19836.pdf
*Idiosyncrasies in Epitope Recognition*
TITLE: Autologous lymphoma vaccines induce human T cell responses against multiple, unique epitopes
AUTHOR CONTACT:
Sivasubramanian Baskar, National Cancer Institute at Fredrick, Fredrick, Maryland, USA.
Phone: 301-846-5147; Fax: 301-846-6107; E-mail: baskar@ncifcrf.gov
View the PDF of this article at: https://www.the-jci.org/press/20312.pdf
*Breaking Barriers with MMP-9*
TITLE: Cortical spreading depression activates and upregulates MMP-9
AUTHOR CONTACT:
Michael A. Moskowitz, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
Phone: 617-726-8440; Fax: 617-726-2547; E-mail: moskowitz@helix.mgh.harvard.edu
View the PDF of this article at: https://www.the-jci.org/press/21227.pdf
**********************************************
Warning: This document and the Journal of Clinical Investigation papers to which it refers, may contain information that is price sensitive with respect to publicly quoted companies. Anyone dealing in securities using information contained within this document or within advance copies of the JCI, may be guilty of insider trading under the US Securities Exchange Act of 1934.
Journal
Journal of Clinical Investigation