New research identifies key contributor to Alzheimer's disease process
November 14, 2008Walter J. Lukiw, PhD, Associate Professor of Neuroscience and Ophthalmology at LSU Health Sciences Center New Orleans, is the lead author of a paper identifying, for the first time, a specific function of a fragment of ribonucleic acid (RNA), once thought to be no more than a byproduct, in regulating inflammation and the development of Alzheimer's disease.
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.
Source: Louisiana State University Health Sciences Center
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Lies. They don't identify key contributor, they research one of the many differences between cells form healthy patients and from patients with with Alzheimer's disease. Patients with Alzheimer's disease have more of a specific molecule (miRNA). Authors of the paper test this molecule and find that it inhibits cells inflammatory pathway.
This molecule can be a contributor or it can be a consequence of the disease. Even if it is a contributor nothing is known about the reason for its upregulation.
Here is the abstract:
Human brains retain discrete populations of micro RNA (miRNA) species that support homeostatic brain gene expression functions; however, specific miRNA abundance is significantly altered in neurological disorders such as Alzheimer disease (AD) when compared with age-matched controls. Here we provide evidence in AD brains of a specific up-regulation of an NF-kappaB-sensitive miRNA-146a highly complementary to the 3'-untranslated region of complement factor H (CFH), an important repressor of the inflammatory response of the brain. Up-regulation of miRNA-146a coupled to down-regulation of CFH was observed in AD brain and in interleukin-1beta, Abeta42, and/or oxidatively stressed human neural (HN) cells in primary culture. Transfection of HN cells using an NF-kappaB-containing pre-miRNA-146a promoter-luciferase reporter construct in stressed HN cells showed significant up-regulation of luciferase activity that paralleled decreases in CFH gene expression. Treatment of stressed HN cells with the NF-kappaB inhibitor pyrollidine dithiocarbamate or the resveratrol analog CAY10512 abrogated this response. Incubation of an antisense oligonucleotide to miRNA-146a (anti-miRNA-146a; AM-146a) was found to restore CFH expression levels. These data indicate that NF-kappaB-sensitive miRNA-146a-mediated modulation of CFH gene expression may in part regulate an inflammatory response in AD brain and in stressed HN cell models of AD and illustrate the potential for anti-miRNAs as an effective therapeutic strategy against pathogenic inflammatory signaling.