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New Genetic Clue to Alzheimer's Disease
Variations in a gene known as SORL1 may be a factor in the development of late-onset Alzheimer’s disease (AD), an international team of researchers has discovered. The genetic clue gives scientists insight into the different ways AD might develop.
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| The darker orange/brown area is a beta-amyloid plaque in the brain of someone who had Alzheimer’s disease. Image courtesy of Dr. William Markesbery, University of Kentucky. |
A hallmark of AD is the buildup of "plaques" outside and around nerve cells in the brain. Plaques are made mostly of a protein called beta-amyloid, which is snipped from a larger protein called amyloid precursor protein (APP). APP, like other proteins, needs to be sorted and moved around the cell for processing. A research team at 14 collaborating institutions in North America, Europe and Asia set out to look for variations in genes for proteins involved in sorting APP. With funding from NIH’s National Institute on Aging (NIA) and National Human Genome Research Institute (NHGRI), as well as 18 other international public and private organizations, the team combed large data sets of genetic information from families in which more than one person has AD. They described their work online in the journal Nature Genetics on January 14, 2007.
The researchers saw that many of the families with AD had variations in the SORL1 gene but not consistently in any of the other genes examined. They then expanded their search to genetic data sets from families of Northern European, Caribbean Hispanic, Caucasian, African American and Israeli Arab heritage. Again, they found an association between SORL1 variations and AD. Searching additional data sets further confirmed the link. In all, the team analyzed the genes of about 6,000 people who had donated blood.
The researchers were able to identify particular areas of the SORL1 gene where disease-causing changes could lie. However, they were unable to pinpoint specific genetic changes that could result in AD.
The researchers think that certain variations of SORL1 may lead to AD by reducing production of SORL1. Preliminary experiments with the blood cells of people with AD and variations in one region of SORL1 showed significantly less active SORL1 genes. In laboratory experiments, altering the levels of the protein changed the way APP was moved around in cells. Low expression of SORL1 resulted in increased production of beta-amyloid fragments, while high expression decreased production. Further research is needed, however, to determine how different versions of SORL1 might influence plaque formation.
"Scientists have previously identified three genes, variants of which can cause early-onset Alzheimer’s, and one that increases risk for the late-onset form,” NIA Director Dr. Richard J. Hodes said. "This discovery provides a completely new genetic clue about the late-onset forms of this very complex disease. We are eager to investigate the role of this gene further.”
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