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Taking a LOAD off your mind
05-07-2013
by Kelsey Kaustinen  |  Email the author

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NEW YORK—A team of researchers from the Icahn School of Medicine at Mount Sinai, together with the Icelandic Heart Association, Sage Bionetworks and other institutions, has announced the discovery that a network of genes known to play a role in the brain's inflammatory response also exists as a key mechanism in the development of late-onset Alzheimer's disease (LOAD).  
 
The study focused on the TREM2-TYROBP pathway. TYROBP is an inflammatory gene involved in this pathway, but previously, it had not been linked to the disease. TYROBP is known to interact with TREM2, a gene recently discovered to be associated with Alzheimer's disease by Rita Guerreiro of University College London, Thorlakur Jonsson of deCODE Genetics and their colleagues.  
 
This work began with an integrated analysis performed on the DNA of 376 deceased patients with LOAD, as well as gene expression data, which revealed the relationships between a network of genes that drive central pathways of Alzheimer's. The researchers then created a biological network model, integrating the genes key to Alzheimer's disease and the biological pathways they control.  
 
"In the same way that sophisticated predictive mathematical models drive decision making in the global financial markets … the field of medical research has begun to rely on network models such as this to derive meaning from vast amounts of patient data, enabling better understanding and treatment of human disease," Dr. Christopher Gaiteri, a co-lead author of the study and senior scientist at Sage Bionetworks, commented in a press release.  
 
Dr. Eric Schadt, an author of the study and director of the Icahn Institute for Genomics and Multiscale Biology and chair of the Department of Genetics and Genomic Sciences at Mount Sinai, called the model "a landmark achievement, yielding valuable insights into the complex mechanism of the disease."  
 
LOAD is the most common form of Alzheimer's disease, and despite extensive research, the cause of the disease is unknown, though it is attributed to a combination of "genetic, environmental and lifestyle factors," according to the National Institute on Aging. What is known, however, is that having the E4 allele of the apolipoprotein gene—a gene found on chromosome 19 that carries instructions for the coding of a protein that transports cholesterol and fats in the bloodstream—is a genetic risk factor for the likelihood of developing LOAD. No effective preventative or disease-modifying therapies exist for the disease, and the incidence of LOAD is expected to double by 2050.  
 
One of the key points of interest with this discovery, says Schadt, is the fact that "the microglia in the brain drive immune/inflammation processes that are causally associated with LOAD." Prior to this work, inflammation was believed to be a result of Alzheimer's disease damaging the brain, but their work "demonstrates that it is a driver, not a consequence of LOAD."  
 
"Defining the precise steps of the inflammatory response crucial to causing Alzheimer's disease has been elusive. We are pleased to discover these novel insights into that process," Dr. Bin Zhang, a co-lead author of the study and an associate professor of genetics and genomic sciences at Mount Sinai, said in a press release. "As a next step, we will evaluate drugs that impact the TREM2-TYROBP pathway as potential therapies for the disease. This discovery enables us to design more specific compounds that target these key steps precisely, in contrast to existing anti-inflammatory drugs that may be less ideal for hitting this target. "
 
"Currently, we see a long lag time between appearance of amyloid on brain scans of patients and the appearance of clinical symptoms," added Dr. Valur Emilsson, head of systems medicine at Icelandic Heart Association and a senior author of the paper. "An individual's inflammatory response could well play a role in the disease progression, and an appropriate anti-inflammatory drug, given after amyloid is detected but before symptoms begin, could be an important part of dementia prevention."  
 
Schadt says their prediction is that if the TYROBP pathway is down-regulated, the progression of Alzheimer's disease should be slowed or stopped, with the possibility that if the pathway is suppressed early enough, it might prevent the disease. In terms of therapies that could affect the network, Schadt notes that there are several possibilities, "even drugs such as anti-inflammatories." This work has potential outside of Alzheimer's disease as well, as Schadt says they are applying this approach to autism, Huntington's disease and schizophrenia as well.  
 
Moving forward, Schadt says the team will continue to identify and validate therapeutics that can molecularly affect this network, adding that they are set up to test the candidates in animal models. The researchers will also "explore pharma partnership to develop novel therapeutics against this work."  
 
Authors for the study, "Integrated Systems Approach Identifies Genetic Nodes and Networks in Late-Onset Alzheimer's Disease," include researchers from Icelandic Heart Association; Sage Bionetworks, Merck Research Laboratories, University of Bonn, Fred Hutchinson Cancer Research Center, Massachusetts General Hospital, University of Miami, Rush University Medical Center and GNF Novartis. The study appeared in Cell in late April.
 
 

 
Code: E05081303

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