Alzhemier disease (AD) is characterized by the progressive accumulation of amyloid beta protein (Abeta) in areas of the brain serving cognitive functions such as memory and language. In 2001, Todd Golde and colleagues demonstrated that three commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) were capable of selectively lowering the levels of Abeta42 (an isoform of the Abeta protein) in mice. In the August 1 issue of the Journal of Clinical Investigation, Golde and colleagues from the Mayo Clinic in Jacksonville, Florida, extend their previous studies and report that of 20 commonly used NSAIDs, 8 FDA-approved drugs successfully lowered Abeta42 levels in mice at doses achievable in humans.
Multiple forms of Abeta42 are generated from the Abeta42 protein precursor (APP) following cleavage with enzymes known as beta- and gamma-secretases. Abeta40 is the most abundant, however Abeta42 is deposited earlier and more consistently than Abeta40 and is therefore more toxic.
Of the NSAIDs tested, meclofenamic acid and flurbiprofen were the most effective at decreasing Abeta42 levels. The authors found that flurbiprofen, currently in clinical trials for the treatment of prostate and colon cancer, directly targets gamma-secretase and the conversion of APP to Abeta42 without inducing toxic gastrointestinal or renal side-effects associated with some NSAIDs.
In their accompanying commentary, Drs. John Cirrito and David Holtzman from Washington University in St. Louis, Missouri comment that "these studies provide exciting new insights and avenues for AD treatment by furthering our understanding of how NSAIDs alter Abeta42 production. While it is not going to be easy, there remains much hope that the amyloid hypothesis of AD will be tested and that truly effective therapies for AD can be developed".
TITLE: NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta42 in vivo
AUTHOR CONTACT:
Todd Golde
Mayo Clinic, Jacksonville, Florida, USA.
Phone: 904-953-2538
Fax: 904-953-7370
Email: tgolde@mayo.edu
View the PDF of this article at: https://www.the-jci.org/press/18162.pdf
ACCOMPANYING COMMENTARY:
Amyloid-beta and Alzheimer disease therapeutics: The devil may be in the details
AUTHOR CONTACT:
David M. Holtzman
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: 314-747-0286
Fax: 314-362-2826
Email: holtzman@neuro.wustl.edu
View the PDF of this commentary at: https://www.the-jci.org/press/19420.pdf
Immune response to Alzheimer disease–related protein changes as we age
Alzhemier disease (AD) is characterized by the progressive accumulation of amyloid beta protein (Abeta) in areas of the brain serving cognitive functions such as memory and language. Active immunization with Abeta peptides has been shown to decrease Abeta-related lesions in the brain in mouse models of AD. Unfortunately, the first clinical trials for Abeta vaccination in humans were halted due to side-effects experienced by a small subset of subjects. However, these immunization strategies remain a viable concept in developing treatments for AD.
In the August 1 issue of the Journal of Clinical Investigation Howard Weiner and colleagues from Harvard Medical School and Brigham and Women's Hospital in Boston, Massachusetts, have further characterized the immune response to Abeta in humans, and revealed intriguing reactions of the elderly human body to Abeta. The authors found that some healthy, elderly individuals, as well as those with AD, contained elevated levels of T cells reactive towards Abeta, when compared to healthy middle-aged adults. While the general trend is for a diminished immune response with age, this finding demonstrates a very selective increase in the Abeta-reactivity of T cells with age in both healthy and AD-affected individuals. The authors went on to characterize the particular regions of the Abeta protein and T cells that react. This reactivity has implications for the design of Abeta vaccines and may itself be linked to susceptibility and course of disease, and appears to be linked with the aging process.
In their accompanying commentary Drs. John Cirrito and David Holtzman from Washington University in St. Louis, Missouri discuss the implications of this study with regard to the development of Abeta vaccines.
TITLE: Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer disease
AUTHOR CONTACT:
Howard L. Weiner
Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.
Phone: 617-525-5300
Fax: 617-525-5252
Email: hweiner@rics.bwh.harvard.edu
View the PDF of this article at: https://www.the-jci.org/press/18104.pdf
ACCOMPANYING COMMENTARY:
Amyloid-beta and Alzheimer disease therapeutics: The devil may be in the details
AUTHOR CONTACT:
David M. Holtzman
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: 314-747-0286
Fax: 314-362-2826
Email: holtzman@neuro.wustl.edu
View the PDF of this commentary at: https://www.the-jci.org/press/19420.pdf
Endocannabinoids influence whether we are what we eat
A study by Uberto Pagotta and colleagues at the Max-Planck Institute of Psychiatry in Munich, Germany, demonstrates that CB1, the receptor that binds endocannabinoids (intrinsic molecules in both animals and humans that are similar to the active component in marijuana) is present on selective neurons in the brain that most likely mediate endocannabinoid-induced changes in appetite and energy balance.
A complex combination of mechanisms modulates our desire to eat and the ability to efficiently utilize consumed calories as energy in order to maintain our body composition. Diseases such as obesity are characterized by impaired energy balance and there exists an urgent need to develop new treatment options.
Pagotto and colleagues found that mice lacking cannabinoid receptor type 1 (CB1) exhibited decreased appetite and a more lean body type. They also found that CB1 is present on neurons that express peptides known to regulate food intake, suggesting that endocannabinoids may directly alter appetite-regulating signaling pathways in the brain. They also demonstrate that the CB1 receptor is also present in fat cells and may affect the breakdown of fat.
The report suggests that drugs designed to block the CB1 receptor should be able to modulate food intake and the deposition and/or breakdown of fat.
"These studies, in conjunction with the fact that cannabinoid receptor antagonist compounds are currently in clinical trials as antiobesity drugs in Europe, raise the hope that single-drug therapies could be successful in the treatment of obesity" states Dr. Tamas Horvath from Yale University in his accompanying commentary.
TITLE: The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis
AUTHOR CONTACT:
Uberto Pagatto
Orsola-Malpighi Hospital, Bologna, Italy.
Phone: 39-051-6363009
Fax: 39-051-6363080
E-mail: pagube@med.unibo.it
View the PDF of this article at: https://www.the-jci.org/press/17725.pdf
ACCOMPANYING COMMENTARY:
Endocannabinoids and the regulation of body fat: the smoke is clearing
AUTHOR CONTACT:
Tamas Horvath
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: 203-785-4597
Fax: 203-785-4747
Email: tamas.horvath@yale.edu
View the PDF of this commentary at: https://www.the-jci.org/press/19376.pdf
Enzyme that breaks down fat has unforeseen dual role in atherosclerosis
Silvia Santamarina-Fojo and colleagues from the Heart, Lung, and Blood Institute at the National Institutes of Health in Bethesda, Maryland, have now identified an alternative pathway by which the enzyme hepatic lipase (HL) modulates the risk of developing atherosclerosis, the condition where blood vessels narrow and harden due to high levels of fat deposits.
Cholesterol and other fats cannot dissolve in the blood and instead are ferried by lipoproteins (such as LDL and HDL; "bad" and "good" cholesterol, respectively) from the outer areas of the body back to the liver. Enzymes such as HL break down these lipoproteins and the fat is either used by the body or excreted. The role of HL in atherosclerosis has remained controversial. Some studies have demonstrated that HL contributes to atherogenesis, while others have demonstrated that it protects against the disease.
The authors demonstrate that in addition to HL production in the liver, HL is also produced locally by macrophage cells within the vessel wall and the atherosclerotic lesion itself, thereby contributing to lesion formation. The findings indicate that localized expression of HL by macrophages in the vessel wall may significantly enhance early lesion formation, and provide evidence that in addition to the role of HL in lipoprotein metabolism, there exists a novel mechanism whereby HL modulates the risk of atherosclerosis.
TITLE: Hepatic lipase expression in macrophages contributes to atherosclerosis in apoE-deficient and LCAT-transgenic mice
AUTHOR CONTACT:
Silvia Santamarina-Fojo
National Institutes of Health, Bethesda, Maryland, USA.
Phone: 301-496-5095
Fax: 301-402-0190
E-mail: silvia@mdb.nhlbi.nih.gov
View the PDF of this article at: https://www.the-jci.org/press/16484.pdf
Protein inhibits harmful soft-tissue calcification
Natural mineralization occurs in our bones and teeth, however pathological mineralization of organs, known as ectopic calcification, is a frequent complication of degenerative diseases. Willi Jahnen-Dechent and colleagues from IZKF BIOMAT in Aachen, Germany, have now identified the serum protein alpha2–Heremans-Schmid glycoprotein (Ahsg, also known as fetuin-A) as the first inhibitor of ectopic calcification. The authors investigate Ahsg-deficient mice, which develop severe calcification of various organs on a mineral-rich diet. This condition is not caused by changes in calcium and phosphate homeostasis, but by the decreased inhibitory activity of the remaining serum proteins on mineral formation. These findings demonstrate a critical role of Ahsg as an inhibitor of unwanted mineralization and provide novel therapeutic targets for preventing ectopic calcification in degenerative diseases.
TITLE: The serum protein alpha2–Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification
AUTHOR CONTACT:
Willi Jahnen-Dechent
University Clinics, Aachen, Germany.
Phone: 49-241-80-80163
Fax: 49-0-241-80-82573
E-mail: willi.jahnen@rwth-aachen.de
View the PDF of this article at: https://www.the-jci.org/press/17202.pdf
Key to blocking assembly of hepatitis delta virus highlights potential new treatment
Jeffrey Glenn and colleagues at Stanford University in California have developed a small animal model for hepatitis delta virus (HDV) which confirms that inhibitors of prenylation – a vital step in virus assembly within host cells – are capable of blocking this assembly and facilitating viral clearance. The study highlights their potential relevance for the treatment of chronic delta hepatitis.
In the accompanying commentary, Drs. Theo Heller and Jay Hoofnagle from the National Institutes of Health in Bethesda, Maryland, discuss the different stages of HDV replication within host cells and how this most recent finding can be used to develop suitable therapies for HDV.
TITLE: In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus
AUTHOR CONTACT:
Jeffrey Glenn
Stanford University School of Medicine, Palo Alto, California, USA.
Phone: 650-725-3373
Fax: 650-723-5488
E-mail: jeffrey.glenn@stanford.edu
View the PDF of this article at: https://www.the-jci.org/press/17704.pdf
ACCOMPANYING COMMENTARY:
Denying the wolf access to sheep's clothing
AUTHOR CONTACT:
Jay H. Hoofnagle
National Institutes of Health, Bethesda, Maryland, USA.
Phone: 301-496-1333
Fax: 301-480-7926
Email: hoofnaglej@extra.niddk.nih.gov
View the PDF of this commentary at: https://www.the-jci.org/press/19417.pdf
IL-13 and adenosine: partners in the molecular dance we call asthma
Inflammation and airway remodeling are two responses readily apparent in asthma and other inflammatory disorders of the airway and lungs. Both adenosine and IL-13 play critical roles in contributing pathways. A study by Jack A. Elias and colleagues at Yale University reveals a previously unrecognized interaction between adenosine and IL-13 that indicates a mutual stimulation that may contribute to the nature and severity of airway inflammation and fibrosis.
"The authors hypothesize that IL-13–induced adenosine and adenosine-induced IL-13 production stimulate proinflammatory receptors or mediators that may play important roles in the pathogenesis of asthma and chronic obstructive pulmonary disease" states Dr. Gabriele Grünig from St. Luke's Roosevelt Hospital in New York. Therapies designed to target enzymes or specific steps crucial to these pathways may be of significant therapeutic use in the treatment of other IL-13-–-mediated inflammatory diseases.
TITLE: Adenosine mediates IL-13–induced inflammation and remodeling in the lung and interacts in an IL-13–adenosine amplification pathway
AUTHOR CONTACT:
Jack A. Elias
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: 203-785-4163
Fax: 203-785-3826
E-mail: jack.elias@yale.edu
View the PDF of this article at: https://www.the-jci.org/press/16815.pdf
ACCOMPANYING COMMENTARY:
IL-13 and adenosine: partners in a molecular dance?
AUTHOR CONTACT:
Gabriele Grünig
St. Luke's-Roosevelt Hospital, New York, New York, USA.
Phone: 212-523-4765
Fax: 212-523-8005
Email: gg398@columbia.edu
View the PDF of the commentary at: https://www.the-jci.org/press/19392.pdf
Treating renal fibrosis: not just PAI-1 in the sky
Nancy Noble and colleagues from the Fibrosis Research Laboratory in Salt Lake City, Utah, report that therapy with a mutant form of the protein PAI-1 is capable of reducing the severity of fibrotic renal disease.
The extracellular matrix (ECM) is comprised of material produced by cells and secreted into the surrounding medium. The composition and amount of matrix depends on a delicate balance between pathways of matrix synthesis and degradation. Fibrotic renal disease results when this balance is disrupted, resulting in an accumulation of ECM.
The protein plasminogen activator inhibitor-1 (PAI-1) inhibits ECM breakdown. Noble and colleagues demonstrate that administration of a mutant form of PAI-1, known as PAI-1R, which does not inhibit ECM breakdown, resulted in increased matrix turnover and reduced glomerulosclerosis in rats.
"The studies of Noble and her colleagues show us that modulating fibrosis is a goal within reach, and inhibition of these mechanisms could confer benefits beyond existing therapies in the treatment of chronic kidney diseases" stated Dr. Agnes Fogo from Vanderbilt University in Nashville, Tennessee, in her accompanying commentary.
TITLE: A mutant, noninhibitory plasminogen activator inhibitor type 1 decreases matrix accumulation in experimental glomerulonephritis
AUTHOR CONTACT:
Nancy Noble
University of Utah, Salt Lake City, Utah, USA.
Phone: 801-581-4615
Fax: 801-585-0579
E-mail: Nancy.Noble@hsc.utah.edu
View the PDF of this article at: https://www.the-jci.org/press/18038.pdf
ACCOMPANYING COMMENTARY:
Renal fibrosis: not just PAI-1 in the sky
AUTHOR CONTACT:
Agnes B. Fogo
Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Phone: 615-322-3114
Fax: 615-343-7023
Email: agnes.fogo@vanderbilt.edu
View the PDF of this commentary at: https://www.the-jci.org/press/19375.pdf
Blocking receptor relieves obstructed arteries
Platelets exist in the bloodstream and upon injury bind to fibrinogen, thereby creating a thrombus, and initiate the blood clotting process. However, in narrowed or hardened arteries platelets can block the flow of blood, resulting in stroke or heart attack. A recently identified drug designed to block platelet aggregation and thrombosis targets the receptor P2Y12. However, drugs designed to block P2Y12 are administered to patients at levels that only block half of the P2Y12 on platelets and aspirin cotherapy is required for optimal efficacy. Pamela Conley and colleagues at Millenium Pharmaceuticals Inc. in San Francisco, and the University of North Carolina, have now defined the role of P2Y12 in platelet thrombosis. In a mouse model of arterial injury, the appearance of thrombi was delayed in mice lacking P2Y12. When thrombi did appear, they were highly unstable and never reached sizes large enough to cause complete arterial bloackage, even in the absence of aspirin. P2Y12 was found to be a critical player in platelet adhesion and activation and in thrombus growth and stability. These findings have important implications for the potential of P2Y12 antagonists as well as for the continued development of this class of drugs.
TITLE: P2Y12 regulates platelet adhesion/activation, thrombus growth, and thrombus stability in injured arteries
AUTHOR CONTACT:
Pamela B. Conley
Millennium Pharmaceuticals, Inc., South San Francisco, California, USA.
Phone: 650-244-6839
Fax: 650-244-9208
Email: pconley@mpi.com
View the PDF of this article at: https://www.the-jci.org/press/17864.pdf
Increasing tolerance to contact allergens
Common contact allergies are triggered by allergens that affect the skin such as poison oak, poisin ivy, latex, dyes, fragrances, and metals. Researchers at the University of Mainz, Germany, have now shown that IL-10, a critical mediator of the immune response, is required in order to build-up tolerance to such allergens. The authors achieve what is known as low zone tolerance (LZT), in which repeated applications of low doses of contact allergens hinders the development of the allergic reaction. They demonstrate that mice lacking IL-10 cannot achieve LZT to allergens, suggesting that this IL-10–driven response may be utilized in allergic therapies.
TITLE: Critical role of IL-10 in the induction of low zone tolerance to contact allergens
AUTHOR CONTACT:
Kerstin Steinbrink
University of Mainz, Mainz, Germany.
Phone: 49-6131-17-2297
Fax: 49-6131-17-6614
E-mail: steinbrink@hautklinik.klinik.uni-mainz.de
View the PDF of this article at: https://www.the-jci.org/press/18106.pdf
OutFoxing obesity
Obesity results from a massive expansion of fat cells. This expansion involves the differentiation of early precursor fat cells, known as preadipocytes, into mature fat cells. Researchers at Rockefeller University in New York have revealed that preadipocytes stably expressing the Foxa-2 protein do not differentiate into mature fat cells. Furthermore, in multiple rodent models of obesity they observed that Foxa-2 production is increased, in what may be an important counterregulatory mechanism to prevent the expansion of fat cell numbers. While the stimuli that induce Foxa-2 expression in mature fat cells is unknown, the authors propose that the pathways involved may serve as a new target for pharmaceutical interventions of both obesity and diabetes.
TITLE: Role of Foxa-2 in adipocyte metabolism and differentiation
AUTHOR CONTACT:
Markus Stoffel
Rockefeller University, New York, New York, USA.
Phone: 212-327-8797
Fax: 212-327-7997
E-mail: stoffel@rockvax.rockefeller.edu
View the PDF of this article at: https://www.the-jci.org/press/18698.pdf
A new form of Griscelli syndrome
Griscelli syndrome (GS) is a rare autosomal recessive disorder, with patients presenting partial albinism and either a primary neurological impairment or a severe deficit in immune function. Two different genetic forms, GS1 and GS2, account for the mutually exclusive neurological and immunological phenotypes. Mutations in the gene encoding the molecular motor protein Myosin5A cause GS1, whereas mutations in the gene encoding the small GTPase Rab27a are responsible for GS2. Geneviève de Saint Basile and colleagues from Hôpital Necker-Enfants Malades in Paris, France, now present genetic and functional evidence that a third form of GS, restricted to the characteristic partial albinism expression of this syndrome, results from mutation in the gene that encodes melanophilin. This spectrum of GS conditions pinpoints the distinct molecular pathways used by melanocytes, neurons, and immune cells in secretory granule exocytosis.
TITLE: Griscelli syndrome restricted to hypopigmentation results from a melanophilin defect (GS3) or a MYO5A F-exon deletion (GS1)
AUTHOR CONTACT:
Geneviève de Saint Basile
Hôpital Necker-Enfants-Malades, Paris, France.
Phone: 33-1-44-49-50-80
Fax: 33-1-42-73-06-40
E-mail: sbasile@necker.fr
View the PDF of this article at: https://www.the-jci.org/press/18264.pdf
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