The paper, An NF-kB-sensitive micro RNA-146a-mediated inflammatory circuit in Alzheimer's disease and in stressed human brain cells, will be published in the November 14, 2008 issue of The Journal of Biological Chemistry.

Dr. Lukiw's lab at the LSU Health Sciences Center New Orleans Neuroscience Center of Excellence has shown that this tiny piece of RNA, or microRNA, called miRNA-146a is found in increased amounts in stressed human brain cells and in Alzheimer's disease, and that it plays a crucial role in the regulation of inflammation and disease-related neuropathology thought to be integral to the Alzheimer's disease process. Dr. Lukiw's research team, which also included LSUHSC's Jian Guo Cui, MD, PhD and Yuhai Zhao, a post doctoral student in the lab, demonstrated in human brain cells in primary culture that MiRNA-146a targets the messenger RNA of an important anti-inflammatory regulator called complement factor H (CFH). Testing both control cells and Alzheimer's disease-affected tissues, they found that miRNA-164a appears to reduce the amount and bioavailability of CFH, promoting the inflammation of brain cells and contributing to the development of Alzheimer's disease.

The most common form of dementia, Alzheimer's Disease is a fatal, age-related neurodegenerative disorder characterized clinically by the progressive erosion of cognition and memory, and neuropathologically by defective gene expression and increased inflammatory cell signaling. According to the Alzheimer's Foundation of America, it is estimated that Alzheimer's disease currently affects more than 5 million Americans and it is projected that the number could more than triple to 16 million by mid-century.

"The goal of these neuroscience research studies is to further our understanding of the molecular biology and genetic mechanisms associated with Alzheimer's Disease and to advance the design of therapeutic strategies to counteract this common and tragic neurological disorder," said Dr. Lukiw.

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"We were quite surprised because the ER didn't seem to have any connection with the misfolded proteins in the cytosol," Duennwald adds. "This study tells us to investigate cellular pathways beyond the usual suspects."

He went on to uncover the basis for this breakdown: The polyQ-expanded fragments glom onto the key VCP/Npl4/Ufd1 protein complex that aids in the transport and degradation of the proteins that flunk quality control in the ER. When Duennwald genetically modified cells to over-express two crucial proteins in the protein complex, the toxic effect dropped.

Additionally, his experiments showed that polyQ-expanded proteins avoid a main method by which cells deal with misfolded proteins. Generally, a class of proteins called "chaperone" or "heat shock" proteins move in and either help the misfolded proteins assume their normal shape or help to get rid of them. "Amazingly, polyQ-expanded proteins don't elicit the heat shock response, and that might contribute to their toxicity," Duennwald says.

Such findings may help in eventually treating the disease. The research suggests that activating the cell's protein quality control mechanisms may provide novel and effective strategies for combating Huntington's and other illnesses driven by polyQ-expanded proteins.

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