Key heart and Alzheimer's disease protein imaged for first time in native state

Researchers for the first time have created a three-dimensional image of apolipoprotein E, a protein long associated with cardiovascular disease and more recently with Alzheimer's disease, as it appears when it is bound to fat-like substances known as lipids.

Using the technique known as x-ray crystallography, scientists at the Gladstone Institute of Cardiovascular Disease (GICD) have created the highest-resolution x-ray structure of a lipoprotein particle to date.

The work focuses apoE4, one of three specific forms of apolipoprotein E, commonly known as apoE. The breakthrough has already answered long-standing questions about the configuration of apoE4 in its active, or native, state. A complete understanding of the protein's functioning will be a key factor for development of future therapeutic interventions, according to the researchers.

Details of the works are reported in the January 13 edition of the Journal of Biological Chemistry.

"This is the first successful use of x-ray crystallography to reveal the structure of a protein bound to lipids," explains senior author Karl Weisgraber, PhD, a senior investigator at both GICD and the Gladstone Institute of Neurological Disease (GIND). "It's crucial to understand this molecule, since it plays such a pivotal role in both cardiovascular and neurological disease.

X-ray crystallography is a technique for determining the three-dimensional structure of a molecule by analyzing the x-ray diffraction patterns of crystals that make up the molecule.

"The next step is higher resolution, going from the current 10 angstroms to 3.5 or better," adds Weisgraber, who is also a professor of pathology at the University of California, San Francisco.

Lipid-bound proteins change their shape once they've bound to a lipid and have begun their key functions. "Until now, we've only been able to model the lipid-free structures of these proteins, and now we can begin learning about their lipid-bound forms," says lead author Clare Peters-Libeu, a GICD and GIND research scientist. "It's a huge step forward for those of us involved in the field."

ApoE, and particularly apoE4, has long been studied for its role as a lipid transport protein and its involvement in cardiovascular disease. Much of the pioneering work on this molecule has been done at Gladstone since the institutes' founding in 1979, led by researchers, including Weisgraber, who had been studying the protein at the National Institutes of Health before transitioning to Gladstone.

In the late 1980s, apoE emerged as a major player in neurological disease, based in part on observations made at Gladstone. Next to one's age, the greatest known risk factor for Alzheimer's disease is the gene for apoE4. ApoE4 is associated with 40-60 percent of cases of sporadic and familial Alzheimer's.

Everyone inherits two copies, or alleles, of every gene, one from each parent, Weisgraber explains. As the number of apoE4 alleles increases from 0 to 2, the risk of AD increases from 20 to 90 percent, and the typical age of onset decreases from 84 years to 68 years. The presence of one apoE4 allele results in an estimated 45 percent chance of developing Alzheimer's by 85 years of age. With two apoE4 alleles, the risk increases to 50–90 percent.

"Insights into the basic biology of apoE--and particularly apoE4--gained by Gladstone scientists have been invaluable in the study of Alzheimer's disease," says Peters-Libeu. "Gaining a complete, three-dimensional understanding of its configuration in its native, lipid-bound state will inevitably lead to even more insights into its role in cardiovascular and neurological disease in the years to come."

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Other co-authors of the paper are Yvonne Newhouse and Danny M. Hatters, who are associated with both GICD and GIND.

This study has been funded by the NIH since 1999. From 1994 to 1999, it was funded by the J. David Gladstone Institutes, which has a long tradition of subsidizing start-up research efforts by its 20-plus investigators. Known as the Gladstone Model, this tradition is described at www.gladstone.ucsf.edu/gladstone/site/publicaffairs/section.php?id=1617 .

Along with the Gladstone Institute of Virology and Immunology, GICD and GIND are among three research institutes of The J. David Gladstone Institutes, a private, nonprofit biomedical research institution. Gladstone is affiliated with UCSF, a leading university that consistently defines health care worldwide by conducting advanced biomedical research, educating graduate students in the life sciences, and providing complex patient care. For further information, visit www.gladstone.ucsf.edu and www.ucsf.edu.


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