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AD Risk Gene Clears Amyloid Beta in Mouse Model: ‘Landmark Finding’ Opens Up New Target for Therapy, Experts Say


doi: 10.1097/01.NT.0000333570.81361.8d

Almost 15 years after apolipoprotein E4 (ApoE4) was identified as the first gene associated with increased risk for late-onset Alzheimer disease (AD), a team of researchers at Case Western Reserve University have figured out how the rogue lipoprotein is tied to amyloid-beta (Abeta) peptide, which is implicated in the disease.

Gary Landreth, PhD, professor of neurosciences as Case Western, and his colleagues have spent six years trying to figure out the biology that explains why the 20 percent of the population that has at least one copy of the ApoE4 gene are at risk for AD. Having even one copy of ApoE4 triples the risk for the disease, but it's been a mystery why this protein, which shuttles lipids in the peripheral circulation and within the brain, is linked to AD pathology. The investigators found that the ApoE molecule stimulates degradation of the sticky Abeta protein.

The study, published in the June 12 Neuron, provides a new avenue for targeting drugs. The scientists gave transgenic AD mice a drug that regulates lipid metabolism in the brain as well as throughout the periphery; it degraded the clumpy Abeta plaques and completely stopped the disease. The plaques were gone and the animals showed none of the signs of memory impairment that untreated adult animals experienced.

“It's a beautiful study,” said Cheryl Wellington, PhD, an associate professor in the department of pathology and laboratory medicine at the University of British Columbia in Vancouver, who conducts research on cholesterol metabolism in the CNS. “It is a landmark finding in understanding the mechanism of how ApoE works in the brain.” Dr. Wellington was not involved in the study.



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Dr. Landreth was intrigued by the work of Peter Tontonoz, MD, PhD, a professor of pathology and laboratory medicine at the University of California-Los Angeles, who was working with liver X receptors and their role in atherosclerosis. Liver X receptors, or LXRs, are the body's cholesterol sensors and they also have strong anti-inflammatory properties. LXRs control genes that metabolize high-density lipoprotein (HDL), the “good cholesterol”. Two important LXR target genes are ApoE and another gene called ABCA1 (ATP-binding cassette transporter), which loads apolipoproteins with phospholipids and cholesterol, forming HDL. They speculated that if they could increase the levels of HDL particles in the brain it would be good for ApoE metabolism. Despite its name, liver X receptors are important in regulating lipid metabolism in the brain as well as throughout the periphery.

They gave 12-month-old mice — bred to develop classic AD — a drug called GW3965, an LXR activator that failed in clinical trials for atherosclerosis because it dangerously increased triglyceride levels. But it did boost HDL, and Dr. Landreth and his colleagues wanted to see whether raising HDL would boost ApoE that would in turn degrade the amyloid accumulating in the brains of these aging animals. They gave the drug every day for four months; at the end of the study, 60 percent of the plaques were gone. In addition, Abeta peptide levels dropped by 60 percent. They also gave the drug to younger animals and found that it reversed the behavioral deficits their littermates were experiencing. “It appeared that we were clearing Abeta out of the brain,” said Dr. Landreth, whose student Jin Win Jiang conducted much of the work. “He spent three years going after one hypothesis after another until he figured it out.”

The investigators found that ApoE, a lipid transport protein, was cutting Abeta into small bits and excreting it. In a test-tube, if they added human ApoE, the rate of amyloid degradation was increased dramatically. Most Abeta clearance was taking place in microglia. The whole process was unexpected, said Dr. Landreth.

In in vitro studies, all forms of ApoE bind to amyloid and facilitate its degradation. But E2 and E3 were much more efficient. The E4 form was about 50 percent less capable of carrying out this job.

“Our study shows that ApoE plays an important role in clearance of amyloid,” Dr. Landreth said. Therefore, therapies that increase ApoE, such as liver X receptor agonists, may be just what the doctor will order to clear plaque out of the brain and prevent or reverse Alzheimer diseases. The LXR's anti-inflammatory role may also come into play. If it works in patients, it would actually modify the disease process and not just relieve symptoms temporarily, Dr. Landreth said.

“We need a good LXR agonist,” he added. After Glaxo's LXR agonist failed clinical trials because of the side effects, scientists and pharmaceutical companies began designing the next generation of medicines that don't increase triglycerides. Such compounds would offer a one-two punch: Degrading Abeta peptide and providing the brain protection against inflammation. Glaxo's drug turns on a whole bunch of LXR-regulated genes that integrate lipid metabolism and inflammation.

The ABCA1 gene is also key to understanding ApoE4's role in AD. In the February 2008 Journal of Clinical Investigation, David Holtzman, MD, chair of the neurology department and professor of neurology and molecular biology and pharmacology at Washington University in St. Louis, and his colleague crossed a transgenic ABCA1 mouse with a mouse that makes amyloid precursor protein, and the offspring were spared of plaques. Now, Dr. Landreth's study helps explain why the amyloid didn't accumulate. The extra ABCA1 in Dr. Holtzman's mice led to more lipidated forms of ApoE that facilitate the degradation of a beta peptide by two enzymes, neprilysin and insulin-degrading enzyme. “The mechanism was nailed down by Dr. Landreth's study,” Dr. Wellington added. “If we could find a way to do this safely in humans, we could get rid of amyloid.”

There are many challenges, she added. These studies have all been conducted in mice and these animals only have one form of ApoE and it is structurally different than the human form. One critical next step will be to take human forms of ApoE into animals to see if these networks are still critical to the degradation of amyloid.

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When investigators gave transgenic Alzheimer disease mice a drug that regulates lipid metabolism in the brain as well as throughout the periphery, it degraded the clumpy amyloid-beta plaques and completely stopped the disease.

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• Jiang Q, Lee CY, Landreth GE, et al. ApoE promotes the proteolytic degradation of A'. Neuron 2008; 58:681–693.
    • Zelcer N, Khanlou N, Tontonoz P, et al. Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors. Proc Natl Acad Sci USA 2007;104(25):10601–10606.
      • Wahrle SE, Jiang H, Holtzman DM, et al. Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease. J Clin Invest 2008;118(2):671–682.
        ©2008 American Academy of Neurology