Scientists closing in on how increased Alzheimer's risk is linked to fat and cholesterol transport in the brain

October 25, 1997

Scientists studying the brain are learning how the removal of cholesterol and the proper delivery of fatty compounds are vital for the healthy function of the brain, in an effort to understand how these processes gone awry can lead to Alzheimer's disease.

Despite the fact that the brain is 70 percent fat, scientists have known little about how fats, or lipids, are metabolized and transported within it. The interest intensified several years ago with the surprising discovery that an increased risk of Alzheimer's disease was linked to a natural genetic variant of a key fat-transporter molecule called apolipoprotein E, or apoE.

Now a team of scientists, led by Mary Jo LaDu in the department of pathology at the University of Chicago Medical Center, has shown that the apoE-containing fat transporters found in brain cells are very different from the apoE particles found elsewhere in the body and contain most of their cholesterol in a different form. The study may give new insights into how one variant, apoE4, found in 15 percent of the population, can increase a person's risk of developing Alzheimer's.

People who inherited a copy of the apoE4 gene from one parent have been found to have a three-fold greater risk of the disease, while those who inherited a copy from both parents have eight times the risk.

The new findings were reported at the annual meeting of the Society for Neuroscience in New Orleans on October 27, 1997.

The brain is constantly moving around huge amounts of fat and cholesterol because these compounds are major components of cell membranes, which the nervous system must constantly rearrange as it makes and breaks links from cell to cell.

"If there's one organ in your body that needs to be plastic and adaptable, it's your brain," LaDu says. "It's constantly making new synaptic junctions that allow you to form a thought or hold a memory."

The brain must have a dependable source of cholesterol, LaDu says, because it is a vital component of membranes; however, the brain needs to be able to clear the excess because it is also very toxic to the sensitive nerve cells.

How the brain is able to maintain such exquisite balance has been perplexing. In the blood, fats and cholesterol are packaged, with key protein components, into particles called lipoproteins. But the brain is shielded from these particles by the so-called blood-brain barrier. Instead, the brain makes its own supply of lipoprotein particles using some of the same protein components, including apoE.

LaDu's team analyzed lipoproteins found in the cerebrospinal fluid (CSF) that bathes the entire nervous system. They also compared the CSF lipoproteins with those secreted by astrocytes, helper cells in the brain that nourish and support the firing nerve cells.

The differences between the lipoproteins secreted by astrocytes and those found in the CSF suggest that the astrocytes produce particles that help the brain rid itself of excess cholesterol in addition to helping deliver membrane components to the nerve cells.

"We think this is an early but landmark study that opens up the field of brain research to the analysis of lipoproteins, which are clearly crucial to normal function," LaDu said. "ApoE also gives us another tool to try to dissect the causes of Alzheimer's disease."

LaDu's team at the University of Chicago includes Catherine Reardon, PhD, Godfrey S. Getz, MD/PhD, Vi Cabana, PhD, Sean Gilligan, and John Lukens, as well as Linda Van Eldik, PhD, at Northwestern University Medical School and David Holtzman, MD, at Washington University School of Medicine.

The work was funded by the National Institutes of Health, American Health Assistance Foundation, and the Alzheimer's Association.

Summary:
In their effort to understand how one variation of a key fat-transporter molecule called apolipoprotein E can lead to Alzheimer's disease, University of Chicago researchers are beginning to unravel how fatty compounds are distributed within the brain, which is 70 percent fat.

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