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Extramural Papers of the Month

By Jerry Phelps
May 2008

Is Exposure to Air Pollution a Risk Factor for Alzheimer's and Parkinson's Diseases?

New research findings from NIEHS-supported researchers at the University of Montana reveal that exposure to air pollution at a young age may predispose people to develop Alzheimer's or Parkinson's disease. The researchers studied the brains of young people who died suddenly from causes unrelated to neurological conditions. Study subjects came from heavily polluted Mexico City or from two relatively unpolluted cities in Mexico.

The primary purpose of the research was to investigate key inflammatory genes and receptors based on previous research findings demonstrating that neuroinflammatory processes lead to a chain of events that result in neurodegeneration. The highly air-pollution exposed subjects exhibited increased activity of cyclooxygenase-2, interleukin-1, and CD14 in several areas of the brain, disruption of the blood-brain barrier, oxidative stress and other evidence of inflammatory processes. The researchers also found evidence of particulate matter in the olfactory bulbs.

The researchers conclude that exposure to air pollution causes neuroinflammation and the accumulation of amyloid and synuclein proteins in brain tissue. Subjects with a genetic susceptibility for Alzheimer's disease (APOE carriers) might have a higher risk of developing Alzheimer's disease if they live in a highly polluted environment. Further research is needed to confirm these results, but they represent evidence that exposure to highly polluted air at young ages may pre-dispose people to debilitating neurodegenerative diseases.

Citation: Calderón-Garcidueñas L, Solt AC, Henríquez-RoldÁn C, Torres-Jardón R, Nuse B, Herritt L, Villarreal-Calderón R, Osnaya N, Stone I, García R, Brooks DM, GonzÁlez-Maciel A, Reynoso-Robles R, Delgado-ChÁvez R, Reed W.(http://www.ncbi.nlm.nih.gov/pubmed/18349428?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum) Exit NIEHS Website 2008. Long-Term Air Pollution Exposure Is Associated with Neuroinflammation, an Altered Innate Immune Response, Disruption of the Blood-Brain-Barrier, Ultrafine Particulate Deposition, and Accumulation of Amyloid {beta}-42 and{alpha}-Synuclein in Children and Young Adults. Toxicol Pathol Mar 18; Epub ahead of print. DOI: 10.1177/0192623307313011.

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C. elegans Protect Chromosomes in Unique Way

Salk Institute scientists along with an NIEHS grantee at the University of North Carolina report that the roundworm C. elegans has telomeres with strands of DNA rich in cytosine, which is different than telomeres from mammals that normally terminate with DNA strands rich in guanine.

Protection of the ends of chromosomes with telomeres is essential for any animal's survival. Telomeres are the object of intense investigation because these structures represent the physical link between cancer and aging research. Telomere loss can lead to chromosome fusion, to chromosome breakage, and further to genome instability, a major cause of cancer. The researchers also determined that two unique proteins are necessary parts of the machinery regulating the length of cytosine- or guanine-tailed telomeres.

The research team used the roundworm model instead of an animal model to streamline the analysis, which could be conducted in much less time. The researchers will now focus efforts on determining whether cytosine-rich telomeres are present in mammals as well. If they are found, they could play a role in telomere maintenance and in cancer. The scientists hope to exploit these findings to stop cells from becoming cancerous by blocking the enzyme that synthesizes telomeres.

Citation: Raices M, Verdun RE, Compton SA, Haggblom CI, Griffith JD, Dillin A, Karlseder J.(http://www.ncbi.nlm.nih.gov/pubmed/18329362?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum) Exit NIEHS Website 2008. C. elegans telomeres contain G-strand and C-strand overhangs that are bound by distinct proteins. Cell 7;132(5):745-57.

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Manganese Caused Neurodegeneration in Non-Human Primates

Although manganese is an essential trace element in the diets of mammals, high concentrations in the brain produce neurological disease. The source of these potentially toxic levels can be naturally occurring, occupational or other man-made sources, including some recreational drugs and possibly gasoline additive.

NIEHS-supported researchers investigated gene expression changes in response to manganese exposures in long-tailed macaques. Previous research has shown that these monkeys have slight cognitive and fine motor deficits in response to manganese exposure. The results show that 61 genes were up-regulated and four genes had lower activity relative to the controls out of a total of 6,766 genes examined.

The affected genes were associated with a variety of cellular activities including DNA repair, apoptosis, protein folding, and inflammation. The gene coding for a member of the amyloid precursor protein family, amyloid-beta precursor-like protein 1, was the most highly up-regulated gene. Amyloid proteins are responsible for the protein plaques seen in Alzheimer's patients. These changes were seen in the frontal cortex, a region of the brain not previously associated with manganese neurotoxicity.

These results provide new evidence about manganese-induced effects in the frontal cortex which accumulates much lower concentrations of manganese than other brain regions. These data suggest that manganese-induced neurodegeneration cannot be solely defined by the concentration of manganese in brain tissue, but also by the sensitivity of particular brain regions.

Citation: Guilarte TR, Burton NC, Verina T, Prabhu VV, Becker KG, Syversen T, Schneider JS.(http://www.ncbi.nlm.nih.gov/pubmed/18284614?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum) Exit NIEHS Website 2008. Increased APLP1 expression and neurodegeneration in the frontal cortex of manganese-exposed non-human primates. J Neurochem 17; Epub ahead of print.

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Notch: A Protein that Controls Bone Formation and Strength

Notch is a protein known to be involved in governing the determination of cell differentiation; however, recent NIEHS-supported research shows that the protein also plays a critical role in bone formation and strength later in life.

The research shows that if there is an increase in Notch activity in bone cells, more bone is produced. Notch stimulated early proliferation of bone building cells known as osteoblasts. However, Notch knock-out mice exhibited age-related osteoporosis similar to that seen in humans. These animals also lost the ability to suppress bone resorption. Future studies will investigate whether the loss of Notch interferes with the signaling between osteoblasts and bone resorbing cells, osteoclasts, necessary for proper homeostasis between the activities of the two cell types.

This line of research began in patients who suffer from a condition called spondylocostal dysplasia, which is characterized by multiple malformations of the vertebrae and ribs coupled with clinical manifestations such as short neck, scoliosis, short trunk and deformities of the rib cage. This research demonstrates the importance of integrative research - investigations that couple human diseases and conditions with basic laboratory studies. The researchers speculate that Notch and the cellular pathways that express and control it may be targets for drugs to treat debilitating and costly bone disorders such as osteopenia and osteoporosis.

Citation: Engin F, Yao Z, Yang T, Zhou G, Bertin T, Jiang MM, Chen Y, Wang L, Zheng H, Sutton RE, Boyce BF, Lee B.(http://www.ncbi.nlm.nih.gov/pubmed/18297084?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum) Exit NIEHS Website 2008. Dimorphic effects of Notch signaling in bone homeostasis. Nat Med 14(3):299-305.

(Jerry Phelps is a program analyst in the Program Analysis Branch of the NIEHS Division of Extramural Research and Training. Each month, he contributes summaries of extramural papers to the Environmental Factor.)



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