JCI table of contents: December 8, 2005

December 08, 2005


Alzheimer's disease prevention may be easier than cure

Current hypotheses suggest that it is the accumulation over time of amyloid beta peptide 1-42 (Abeta42) that triggers changes in the brain that lead to cognitive dysfunction in Alzheimer's disease. The reduction of amyloid levels is therefore a major therapeutic objective. Todd Golde and colleagues from the Mayo Clinic Jacksonville report evidence to suggest that prevention of amyloid deposition may be easier than curing established Alzheimer's disease. Their results will appear online on December 8 in advance of print publication in the January 2006 issue of the Journal of Clinical Investigation.

The authors use transgenic mice genetically predisposed to accumulate amyloid deposits in their brain to show that an immunization strategy targeting Abeta42, or a second form of Abeta known as Abeta40, prevents the onset of amyloid deposition in these mice at a young age. In contrast, the anti-Abeta42 or anti-Abeta40 monoclonal antibodies were not effective in altering Abeta deposition in mice with modest levels of preexisting Abeta deposits, nor were they capable of clearing existing deposits. The results suggest that it may be easier to prevent Abeta deposition than to alter Abeta once deposited. This method may be an effective strategy to prevent amyloid deposition prior to the onset of Alzheimer's disease, but may have limited benefit in a therapeutic setting where amyloid deposits are already well established within the brain.

TITLE: Anti-Abeta42 and Anti-Abeta40-specific monoclonal antibodies attenuate amyloid deposition in an Alzheimer disease mouse model


Todd E. Golde
Mayo Clinic Jacksonville, Florida, USA.
Phone: 904-953-2538; Fax: 904-953-7370; E-mail: tgolde@mayo.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=25410


New therapy for asthma is a breath of fresh air

Glucocorticoids, the treatment of choice for many people with asthma, boost production of the molecule IL-10, which helps decrease airway inflammation. However, some asthmatic patients are resistant to glucocorticoid therapy because their T cells do not produce IL-10 in response to these steroids. In a study appearing online on December 8 in advance of print publication in the January 2006 issue of the Journal of Clinical Investigation, Catherine Hawrylowicz and colleagues from King's College London investigate IL-10-producing T cells in the context of human allergic and asthmatic disease.

The authors show that pre-treatment of patient T cells with IL-10 and vitamin D3 can overcome this defect and greatly enhance glucocorticoid-induced IL-10 synthesis by T cells from asthmatic patients who were resistant to glucocorticoid therapy. These manipulations increase IL-10 production to levels comparable to those observed in patients who do respond well to therapy. IL-10 increases glucocorticoid receptor expression, and the authors propose that this is the mechanism by which IL-10 overcomes the glucocorticoid-resistant patient defect in IL-10 synthesis. Therefore, this population of IL-10-producing T cells may help treat human allergic diseases and reverse glucocorticoid resistance in asthma.

TITLE: Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients


Catherine Hawrylowicz
King's College London, London, United Kingdom
Phone: 44-0207-188-0599; Fax: 44-0207-403-8640; E-mail: catherine.hawrylowicz@kcl.ac.uk

View the PDF of this article at: https://www.the-jci.org/article.php?id=21759


Inhibiting kidney protein USAG-1 may help decrease dialysis dependency

Dialysis has become a necessary form of treatment for the removal of waste products from the blood of patients with end-stage renal disease, a condition that cannot be reversed or repaired by currently available therapies. Motoko Yanagita and colleagues from Kyoto University report that mice lacking the kidney protein USAG-1 are resistant to kidney injury. The authors show that USAG-1 inhibits the activity of the protective kidney protein BMP-7, therefore the absence of USAG-1 increases the protective actions of BMP-7 following renal injury. These results, which appear online on December 8 in advance of print publication in the January 2006 issue of the Journal of Clinical Investigation, suggest that inhibition of USAG-1 is a promising avenue of development for new treatments of renal disease, which would ultimately alleviate patient dependency of dialysis.

TITLE: Uterine sensitization-associated gene-1 (USAG-1), a novel BMP antagonist expressed in the kidney, accelerates tubular injury


Motoko Yanagita
Kyoto University, Kyoto, Japan
Phone: 81-75-751-3465; Fax: 81-75-751-3574; E-mail: motoy@kuhp.kyoto-u.ac.jp

View the PDF of this article at: https://www.the-jci.org/article.php?id=25445


Inflamed about obesity: CCR2 keeps fat cells in a state of inflammation

Obesity is associated with a state of chronic, low-level inflammation in fatty tissue (adipose tissue), which contains an increased number of macrophages. These cells normally function to remove pathogens and stimulate cells of the immune system into action, but they also produce proinflammatory molecules that help maintain adipose tissue inflammation during obesity. In a study appearing online on December 8 in advance of print publication in the January 2006 issue of the Journal of Clinical Investigation, Anthony Ferrante Jr. and colleagues from the Naomi Berrie Diabetes Center at Columbia University show the importance of C-C chemokine receptor 2 (CCR2) in the recruitment of macrophages to adipose tissue and the development of obesity and its complications.

The authors found that mice lacking CCR2 did not eat as much as normal mice, nor did they develop obesity when fed a high-fat diet. Macrophage accumulation, adipose tissue inflammation, and insulin resistance in these animals were also reduced. The authors went on to show that even in mice with pre-existing obesity, administration of a drug that blocks binding to the CCR2 receptor reduced macrophage accumulation and led to an improvement in insulin sensitivity. The study provides new and important evidence that CCR2 participates in the process of macrophage recruitment into adipose tissue. Treatments that prevent macrophage infiltration into obese adipose tissue are expected to have beneficial effects on the metabolic and inflammatory effects caused by a high-fat diet.

TITLE: CCR2 modulates inflammatory and metabolic effects of high-fat feeding


Anthony Ferrante Jr.
Naomi Berrie Diabetes Center, New York, New York, USA
Phone: 212-851-5322; Fax: 212-851-5331; E-mail: awf7@columbia.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=24335


Preventing atherosclerosis is all about going with the flow

Despite the presence of risk factors such as high cholesterol, some regions of blood vessels remain relatively resistant to the development of atherosclerotic lesions that can block blood flow to essential organs. In a study appearing online on December 8 in advance of print publication in the January 2006 issue of the Journal of Clinical Investigation, Guillermo Garcia-Cardeña and colleagues from Harvard Medical School show that this resistance is based in part on the induction of the transcription factor KLF2 by distinct blood flow patterns in these regions.

Previous studies have shown that blood flow-induced shear stress on the vessel wall is transduced into a biochemical signal that can cause changes in the vessel wall that may protect against or make a vessel prone to atherosclerosis. Garcia-Cardeña et al. show that the transcription factor KLF2 (Kruppel-like factor 2) is selectively induced in endothelial cells lining the vessel wall by arterial blood flow patterns that mimic the hemodynamic environment in the atheroprotected regions of the human carotid artery. This flow-mediated increase in KLF2 expression occurs via a MEK5/ERK5/MEF2 signaling pathway. Increased KLF2 activity helps regulate inflammation, clot formation, and new vessel growth. These data suggest that KLF2 acts as a mechanically-activated transcription factor that is important for integrating multiple functions of cells of the vessel wall in regions of the blood vessel network that are relatively resistant to the development of atherosclerosis.

TITLE: Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2


Guillermo Garcia-Cardeña
Harvard Medical School, Boston, Massachusetts, USA
Phone: 617-525-4302; Fax: 617-525-4329; E-mail: guillermo-_garcia-cardena@hms.harvard.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=24787

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