jueves, 20 de julio de 2017

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Neurodegenerative Markers are Increased in Postmortem BA21 Tissue from African Americans with Alzheimer’s Disease

NCTR scientists conducted a research study that identified significant differences in Alzheimer's disease (AD) brain proteins that are related to ethnicity or race. The research community has known that African Americans and Hispanics develop AD at an earlier age and that their symptoms are often more severe, but have not understood why. Although the prevalence of the characteristic plaques and tangles may not exhibit ethnicity-related differences, differences in levels of neurodegenerative proteins have not been described. Because the symptoms of AD are worse in African Americans, understanding the differences in the brain may help explain this. 
The NCTR scientists looked at levels of neurodegenerative proteins in the brain tissue of African American men and women, and Caucasian men and women with AD. Some proteins in the brain are associated with AD. For example, levels of the S100B protein are typically increased in the brains of people with AD and brain injuries. Five proteins associated with neurodegenerative diseases were measured (S100B, sRAGE, GDNF, Aβ40, Aβ42 and the Aβ42/Aβ40 ratio). The tissue samples came from the BA21 region (a ridge on the cerebral cortex of the brain) which is involved in language generation and processing and is known to be affected by AD. A multiplex assay was used to determine the levels of these proteins. There were no significant differences between men and women and no significant ethnicity with sex interactions on any protein. Effect size calculations indicated "medium" to "very large" effects. The statistically significant levels of the proteins studied include:    
  • S100B levels were increased 17% in African Americans. S100B is typically elevated in AD cases; however, the increased levels in African Americans here may be indicative of increased severity in specific populations.
  • Aβ42 levels were increased 121% in African Americans, leading to a 493% increase in the Aβ42/Aβ40 ratio. Increased Aβ42/Aβ40 ratios in this study are compatible with increased disease severity and might indicate increased AD pathogenesis in African Americans.
While many brain proteins are altered in AD patients, these NCTR study results indicate that some of those AD-associated proteins are different between African Americans and Caucasians. The results are compatible with the hypothesis of increased neuroinflammation in African Americans with AD. The next step in this series of studies is to understand what other differences occur in the brains of African Americans and Caucasians with AD, such as:
  1. different levels of neuroinflammation
  2. differences in chemokines and cytokines in the brain
  3. genetic differences that might explain the protein level changes.
This comprehensive study could potentially lead to targeted pharmacotherapies for specific populations which could better treat AD symptoms and perhaps slow the disease progression. A manuscript describing the study is available online at Journal of Alzheimer’s Disease.
For additional information, please contact Sherry Ferguson, Ph.D., Division of Neurotoxicology. This study was an NCTR collaboration with:
  • Dr. John Panos, *formerly in the Division of Neurotoxicology
  • Dr. Vijayalakshmi Varma, Division of Systems Biology
  • Daniel Sloper, Division of Systems Biology

Effects of Mucous-Penetrating Nanoparticles in a Cultured Vaginal Epithelial-Cell Model  

FDA scientists from NCTR, Center for Drug Evaluation and Research, and Office of Regulatory Affairs published a study to demonstrate that mucous-penetrating nanoparticles consisting of poly lactic acid-co-glycolic acid (PLGA)-polyethylene glycol (PEG) nanospheres and PEG-functionalized graphene-oxide sheets were cytotoxic (toxic to cells) and exacerbated the oxidative stress from Candida albicans (yeast) infection in human vaginal epithelial cells in vitro. The representative mucous-penetrating nanoparticles for intravaginal drug delivery had varying effects on autophagy and endoplasmic reticulum stress, and also induced:
  • cytotoxicity
  • cell death
  • DNA damage
These results suggest that drug-delivery nanoparticles may cause intracellular damage to vaginal epithelial cells by multiple mechanisms. Additional in vivostudies will be necessary to determine the potential effects of these nanoparticles in women with active vaginal yeast infections.
Biodegradable and non-toxic nanoparticles have attracted attention as potential carriers for drugs. This work was supported in part by FDA's Office of Women’s Health. A manuscript describing the study is available online at PLoS ONE.
For more information, please contact Robert D. Wagner, Ph.D., Division of Microbiology.

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