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Fat goes cerebral

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Little things-from the dozens of Beanie Babies that line her office shelves to the lipoproteins under her microscope-make U of C physiologist Mary Jo LaDu light up. She beams when she talks about the latest findings of her research team, assembled two years ago to investigate how cholesterol is transported in the brain. The team ended up finding tiny particles that may have big implications for people at risk for Alzheimerís disease.
LaDu, who had studied the movement of cholesterol in the body, became interested in its activity in the brain when Duke researchers established a genetic link between Alzheimerís and a variant of a fat-carrying particle called apolipoprotein E, or apoE. Found in 15 percent of the population, the variant apoE4 was shown to increase the risk of developing Alzheimerís by threefold if inherited from one parent and by eightfold if inherited from both.
When LaDu, an assistant professor in pathology, went looking for more information about the biological function of apoE in the brain, she was surprised by the lack of research on the topic. Scientists had well documented how protein components, known as lipoproteins, transport fats and cholesterol in the body. They also knew that a blood-brain barrier prevents these lipoproteins from entering the brain. But they had done little to back up the widely held assumption that the brain produces its own supply of lipoproteins.
The U of C team decided to test this hypothesis. Building on the work of the Duke geneticists, they began investigating just how the brain does metabolize and transport its fats, or lipids, and how apoE-containing particles might assist in this process.
"The odds were that the particles that carried fats in the brain were going to be made as an auxiliary function of a brain cell," says the 39-year-old LaDu, who holds a B.A. from Grinnell and a Ph.D. from the University of Illinois at Chicago. "The particles were bound to be very different from those in the rest of the body."
Sure enough, the team found that astrocytes, brain cells that nourish nerve cells, also produce lipoproteins. Comparing the lipoproteins found in the fluid that bathes the rest of the nervous system to those secreted by astrocytes, the team concluded that lipoproteins produced by the astrocytes perform the dual function of carrying "good" cholesterol to, and removing "bad" cholesterol from, nerve cells.
The team also found that the brainís apoE-containing lipoproteins are oval-shaped, smaller, and less dense than the circular ones in the rest of the body. The findings, reported at the annual meeting of the Society for Neuroscience, will help researchers get to the next rung of inquiry.
"Figuring out what brain lipoproteins look like helps us understand what they are doing in the brain," says LaDu. "We think this is an early but fundamental study that opens the field of brain research to the analysis of lipoproteins, which are clearly crucial to normal function."
LaDu's team includes pathology chair Godfrey S. Getz; researchers Catherine Reardon, Vi Cabana, Sean Gilligan, and John Lukens at the U of C; Linda Van Eldik of Northwestern; and David Holtzman of Washington University.
LaDu says they are now working to characterize the differences in the physical structure of apoE4 compared with other apoE variants. Next, they will compare the behavior of the apoE variants as they deliver and remove cholesterol. The results, she says, should help determine what apoE4 is doing or not doing to affect Alzheimerís and other neurological problems, such as Parkinsonís disease, boxerís dementia, and damage from stroke.
"We've solved one piece of the puzzle," says LaDu. "Alzheimer's is what triggered interest in this area, but lipid transport in the brain is a fundamental biological function that hasnít received the study it deserves. A proper lipid balance in the brain is as important as having a proper balance in the body. In the far future, we will be talking about good and bad cholesterol in the brain, and understanding the ramifications."-C.S.

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