PNAS News Archive: June 16 - 20, 2003

  Selected articles appearing in PNAS the week of June 16. . .

Nicotine Byproduct Reduces Alzheimer's Plaques

A metabolic byproduct of nicotine appears to prevent formation of the protein plaques associated with Alzheimer's disease, according to new research in PNAS. Although it is unclear whether aggregation of amyloid beta proteins into plaques causes Alzheimer's disease, these plaques are a definitive marker of the devastating condition. Previous research suggested that cigarette smoking may delay the onset of Alzheimer's disease, but the mechanism of this neuroprotective effect is unclear. Kim Janda and Tobin Dickerson of The Scripps Research Institute suspected that nornicotine, a breakdown product of nicotine, may contribute to the neuroprotection. Nornicotine participates in a reaction between sugars and proteins called glycation, a process that resembles what happens to protein in food when it's cooked. Nornicotine-based glycation is generally considered to be detrimental to the body. The researchers incubated nornicotine and glucose with amyloid beta proteins and observed reduced protein plaque formation. The authors note that, although nornicotine may provide a potentially useful treatment for Alzheimer's disease, the substance is toxic. Therefore, further research into nontoxic compounds that mimic the action of nornicotine is warranted.

"Glycation of the amyloid beta-protein by a nicotine metabolite: A potentially fortuitous chemical dynamic between smoking and
Alzheimer's disease" by Tobin J. Dickerson and Kim D. Janda

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Diabetes Autoimmune Target Identified

Scientists have identified a protein that is targeted by immune cells during the early stages of type 1 diabetes. The result, according to new research in PNAS, may lead the way to new therapies for treating and preventing this autoimmune disease. In type 1 diabetes, which is usually diagnosed during childhood or adolescence, immune cells called CD8+ T cells attack and destroy insulin-producing pancreatic beta cells. However, the specific beta-cell proteins targeted by the CD8+ T cells are largely unknown. By studying a strain of mice that readily develops diabetes, Teresa DiLorenzo of the Albert Einstein College of Medicine and colleagues identified a protein called IGRP, found only in pancreatic islet cells, as one of the proteins targeted by CD8+ T cells. The researchers detected IGRP-reactive T cells in the bloodstream and in the pancreatic islets of the mice. Intriguingly, the gene for human IGRP is located on a segment of chromosome 2 previously associated with diabetes susceptibility. The authors propose that an immune attack targeting IGRP and the resulting inflammation of the islets may be the very first destructive stage of diabetes. IGRP could therefore be a potential new target for diagnosis and treatment.

"Identification of the beta cell antigen targeted by a prevalent population of pathogenic CD8+ T cells in autoimmune diabetes" by Scott M. Lieberman, Anne M. Evans, Bingye Han, Toshiyuki Takaki, Yuliya Vinnitskaya, Jennifer A. Caldwell, David V. Serreze, Jeffrey Shabanowitz, Donald F. Hunt, Stanley G. Nathenson, Pere Santamaria, and Teresa P. DiLorenzo

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Aspirin plus Genes Equals Reduced Cancer Risk

Aspirin and a specific gene variant appear to work via different mechanisms to affect the same metabolic pathway, acting synergistically to reduce the risk of recurring colon adenomas. Maria Elena Martinez of the University of Arizona and colleagues analyzed blood samples from nearly 700 men and women to determine the contribution of a gene called ODC to the risk of developing adenomas, the precursor lesions to colon cancer. According to new research in PNAS, individuals with two copies of the rare ODC A-allele were less likely to experience adenoma recurrence, compared to individuals with other variants of the gene. The likelihood of recurrence was even lower in individuals with the A-alleles who also reported aspirin use. Subsequent cell culture studies indicated that both the ODC A-allele and aspirin cause a reduction in cellular polyamines-small, nitrogen-rich molecules that are necessary for cell proliferation and are often overproduced by cancer cells. The ODC variant appears to lower polyamine production, whereas aspirin appears to speed polyamine destruction. These results suggest that aspirin combined with drugs that target the ODC enzyme may be a promising strategy for colon cancer prevention.

"Pronounced reduction in adenoma recurrence associated with aspirin use and a polymorphism in the ornithine decarboxylase gene" by Maria Elena Martinez, Thomas G. O'Brien, Kimberly E. Fultz, Naveen Babbar, Hagit Yerushalmi, Ning Qu, Yonqjun Guo, David Boorman, Janine Einsphar, David S. Alberts, and Eugene W. Gerner

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Controversial RU486 Also Protects Nerve Cells

Rat cerebellum samples cultured in the absence (left) or presence (right) of RU486.

RU486, the same chemical used to terminate pregnancies, may also help protect brain cells from the effects of nerve damage, according to research published in PNAS this week. Abdel Ghoumari of INSERM and colleagues found that RU486, also known as mifepristone, appears to extend the life of certain brain cells. Mifepristone is well known for its use in ending pregnancies, but research had suggested that it also protects nerve cells during traumatic brain injury and improves symptoms in patients with psychotic depression. The drug binds strongly to steroid receptors, suggesting a mechanism by which it may prevent cell death. To determine mifepristone's mode of action, the researchers tried to mimic or prevent the drug's action. They used cerebellar Purkinje cells as a model. Isolated from newborn mice, these brain cells undergo automatic, programmed cell death in tissue culture. Mifepristone alone can extend the life of these cells, but the researchers found that adding other chemicals that also bind to the steroid receptors mifepristone targets did not prevent the cells from dying. In addition, brain cells isolated from mice with an inactive mutant version of either the progesterone or glucocortisoid steroid receptor were still rescued by the addition of mifepristone. Additional experiments showed that mifepristone's effects were not due to antioxidant activity either, suggesting that the drug acts through a novel pathway to prevent the death of brain cells. This protective effect of mifepristone may offer a future treatment for selected neurodegenerative diseases.

"Mifepristone (RU486) protects Purkinje cells from cell death in organotypic slice cultures of postnatal rat and mouse cerebellum" by A. M. Ghoumari, I. Dusart, M. El-Etr, F. Tronche, C. Sotelo, M. Schumacher, and E. E. Baulieu

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Climate Change Alters Grassland Diversity

Global climate change may rapidly alter grassland diversity, according to new research in PNAS. Erika Zavaleta of Stanford University and colleagues studied the effects of four major factors associated with anthropogenic climate change--increased carbon dioxide, nitrogen deposition, precipitation, and temperature--at a biological preserve near San Francisco. The researchers divided a large field containing 43 different plant species into small parcels. Over 3 years, various parcels were gassed with CO2, fertilized with nitrogen, watered, or heated. The treatments were applied singly or in various combinations. Additional CO2 or nitrogen rapidly decreased species diversity, whereas additional water increased diversity. A 1°C temperature increase had no effect. Most of the diversity gains and losses occurred in forb species, which include all the wildflowers in a grassland, from native morning glories to dandelions. The effects of combined treatments were additive. For example, parcels that received both CO2 and nitrogen exhibited twice the decrease in diversity, compared to parcels that received just one of the treatments. These results demonstrate the importance of considering many climate change factors simultaneously, because the effects are additive.

"Additive effects of simulated climate changes, elevated CO2, and nitrogen deposition on grassland diversity" by Erika S. Zavaleta, M. Rebecca Shaw, Nona R. Chiariello, Harold A. Mooney, and Christopher B. Field

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