ARTICLE IN BRIEF
In a study with transgenic Alzheimer disease mice, investigators found that doubling the level of low-density lipoprotein receptor decreased apolipoprotein E (APOE) levels by up to 50 percent, suggesting that the extra receptors were binding to many of the available APOE molecules. The effect was even stronger in mice with higher levels of expression.
There's a surprising new target in site for Alzheimer disease (AD): the low-density lipoprotein (LDL) receptor. The receptor helps clear extracellular amyloid-beta (Abeta) accumulation in the brain, a function that also involves apolipoprotein E (APOE), according to a Dec. 10, 2009, study in Neuron. The work strengthens the case that a principal function of APOE in the brain is regulating Abeta, and suggests that elevating LDL receptor levels may be therapeutic in AD.
Much has been learned about the function of the LDL receptor in the periphery since it was described in the mid-1970s, a finding that led to the 1985 Nobel Prize in Physiology and Medicine for its discoverers, Michael S. Brown, MD, and Joseph L. Goldstein, MD. Its role is to shuttle cholesterol into the cell, which it does by binding to a cholesterol-carrying low-density lipoprotein (the so-called “bad cholesterol”). One such lipoprotein is APOE. There are also several other types of lipoprotein receptors in the periphery, including one for high-density lipoprotein (“good cholesterol”).
“The same exact receptor is found in the brain,” according to David M. Holtzman, MD, professor and chair of neurology at the Washington University School of Medicine in Saint Louis, MO, who led the study. In fact, it is the only central receptor for LDL, “but we don't know much about its biological function there,” Dr. Holtzman said.
There is also only one type of lipoprotein in the brain, namely APOE. Genetic variations in APOE are the principal risk factor for late-onset AD, but the mechanism through which APOE influences disease risk is unknown. But evidence has accumulated that altering APOE levels in the brain changes accumulation of Abeta, the peptide that forms amyloid plaques. “It looks like the reason that APOE is a risk factor is somehow its interaction with Abeta,” Dr. Holtzman said.
“If we know that APOE levels regulate disease pathology, then what are the things that regulate APOE levels in the brain?” That is the question he set out to answer. He and his team, led by Junsu Kim, PhD, overexpressed the gene for the LDL receptor in transgenic AD mice, which normally develop extensive Abeta pathology throughout the cortex.
Doubling the level of LDL receptor in these mice decreased APOE levels by up to 50 percent, suggesting that the extra receptors were binding to many of the available APOE molecules. The effect was even stronger in mice with higher levels of expression. The reduction in APOE was accompanied by significant reductions in extracellular Abeta plaque deposition. Receptor overexpression also reduced neuroinflammatory responses in the brains of treated mice.
“Together, these results suggest that one of the normal functions of APOE is to bind to Abeta and bring it into the cell to clear it,” Dr. Holtzman said. “The big take-home message is that the LDL receptor plays an important role in regulating APOE levels in the brain, and when you increase its levels, it helps clear APOE and Abeta, and that results in less Alzheimer pathology.”
It is not yet clear whether the treated mice perform better on cognitive tests, but that research is underway.
One finding needing fuller explanation was a strong sex difference in the effect. Overexpression of the LDL receptor reduced pathology by about 50 percent in females, and about 70 percent in males. In females, though not in males, even a low level of receptor overexpression prevented Abeta accumulation. In both mice and humans, females usually show more extensive amyloid pathology than males, for reasons that are not yet clear.
“I think this is an excellent study,” said Rudolph E. Tanzi, MD, PhD, professor of neurology at Harvard Medical School and director of the Genetics and Aging Research Unit at the Massachusetts General Hospital Institute for Neurodegenerative Disease in Charlestown, MA, who was not involved in the study.
“One big piece of the puzzle that hasn't been explained before is how APOE affects the risk for Alzheimer disease. I think this study does more than any previous study to provide a hypothesis for how APOE works.”
“There is still a lot to work out in the mechanism, but this paper opens a new window” into those questions, he said. “It means you have to pay attention.”
One important unanswered question concerns cholesterol. The better-known function of the LDL receptor, of course, is cholesterol transport, but it is not known whether any part of the effect seen in this study was due to altered cholesterol trafficking. The cholesterol connection is especially intriguing to Dr. Tanzi. “I have to think this might be somehow related to cholesterol,” he said. He noted that humans with two APOE epsilon-4 alleles, the high-risk alleles for AD, also develop hypercholesterolemia.
“It is very highly discussed whether cholesterol plays a role in Alzheimer disease,” Dr. Holtzman said. “It's a tough question to answer,” because there is so much cholesterol in the brain, mainly in myelin. Teasing out the relatively small changes that might occur with LDL receptor overexpression is challenging. “It probably is linked, but how it is linked is unclear,” he said.
Another important conclusion from the study, Dr. Holtzman said, is “if you could figure out a way to target the receptor, it might be a good target for therapy development.”
Dr. Tanzi agrees. “One of the exciting things is that the LDL receptor is a good target for getting amyloid out of brain,” he said.
There are currently drugs in development that target the peripheral version of the receptor, including a monoclonal antibody that inhibits a peptide that normally downregulates LDL receptor expression in the liver, the control site for most of the body's cholesterol metabolism. “We don't know yet whether liver drugs are candidates” for use in the brain, Dr. Holtzman said.
Timing is another critical issue. “When one attacks [Abeta] is probably critical,” he added. “Abeta definitely contributes to disease, there is no question about it, and it is probably the instigating factor in disease, and you probably can't get disease without it.” But the billions being spent on drugs to attack it are primarily focused on people who have already developed clinical dementia. “That may be too late,” Dr. Holtzman said. “It may be you need to attack it in the preclinical period. That's the main caveat. Whether it turns out to be a target in people who already have dementia is not clear. I think it will more likely be a better target as a prevention of clinical disease.”