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BrightFocus-Supported Researchers Discover How ApoE4 Contributes To Alzheimer’s Plaques

Malfunctioning protein slows the brain’s ability to “clear out” toxic beta-amyloid

June 30, 2011

Mice that make different forms of the APOE protein have different levels of Alzheimer's plaques, a hallmark of the devastating illness. Source: David Holtzman, M.D.
Mice that make different forms of the APOE protein have different levels of Alzheimer's plaques, a hallmark of this devastating illness.

Photo courtesy of David Holtzman, M.D., Washington University School of Medicine in St. Louis and Science Translational Medicine

“More and more, breaking news reflects BrightFocus’ significant effort to end Alzheimer's disease,” says BrightFocus President and CEO Stacy Pagos Haller.  “Our tradition of funding early-stage, innovative projects results in important discoveries like the one announced in this latest Alzheimer's disease news update.  See how our grants are making a difference.”

People with a particular variation of the apolipoprotein E (ApoE) gene, called ApoE4, have a strong risk of developing late-onset Alzheimer's disease. ApoE4 protein helps to metabolize cholesterol, but how it causes an increased risk for Alzheimer's is unknown.

In the June 29 issue of the journal Science Translational Medicine, BrightFocus-supported researchers reported that brains expressing ApoE4 versus other forms of ApoE aren't as good in clearing the toxic beta-amyloid peptide. This build-up leads to increased plaque deposits, a hallmark of Alzheimer's disease.

This ground-breaking discovery offers a new path for researchers to discover novel prevention and treatment approaches for Alzheimer's disease. In the future, a drug could be designed to speed up the beta-amyloid clearance and prevent the plaques from forming in the brain.

On behalf of our donors, Alzheimer's Disease Research—a program of the BrightFocus Foundation—salutes co-authors and grantees Drs. Jungsu Kim and David Holtzman (co-investigator on an award shared with Drs. Bradley Hyman and Ben Barres), for this important work.

For more information, see the press release below or the original publication.

Scientists have found that a protein made by a key Alzheimer's gene slows the brain's ability to get rid of amyloid beta, the main ingredient of the amyloid plaques that characterize the devastating illness.

The research, in humans and mice, links slow amyloid beta clearance rates to one form of the apolipoprotein E (APOE) gene.

The finding moves researchers closer to understanding a major risk factor for Alzheimer's disease and may point to natural pathways for clearing amyloid beta that can be enhanced pharmaceutically. Scientists at Washington University School of Medicine in St. Louis report the results this week in Science Translational Medicine.

APOE comes in three forms: E2, E3 and E4. Neurologists have been interested because of genetic studies showing that APOE E4 substantially increases Alzheimer's risk and lowers age of onset by 10 to 15 years.

“We knew that APOE was linked with amyloid beta accumulation and suspected that APOE E4 might slow amyloid-beta clearance. This study directly shows that this is particularly true for APOE E4,” says David Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology at Washington University. “The next step is to find out how APOE affects amyloid beta clearance and how APOE E4 disrupts that process, with the eventual goal of developing ways to enhance clearance.”

To begin the study, scientists analyzed the APOE genes in nearly 300 healthy human volunteers and used scans and cerebrospinal fluid to determine approximately how much amyloid plaque deposition the volunteers had in their brains. Those with one or two copies of the E4 form of the APOE gene were much more likely to have plaque deposition compared to individuals with other versions of APOE. Although all of the volunteers were healthy, amyloid plaque deposition and other brain changes associated with Alzheimer's disease begin as much as 10 to 15 years or more before clinical symptoms become apparent.

APOE's normal roles in the brain are still somewhat unclear. In the rest of the body, it circulates in the blood and plays an important role in controlling cholesterol levels.

Some causes of Alzheimer's disease increase the brain's production of amyloid beta, but scientists did not know whether APOE E4 caused more amyloid beta production or slowed its removal. To answer that question, Joseph Castellano, a doctoral student in Holtzman's laboratory, worked with mice genetically altered to develop brain changes similar to Alzheimer's and to exclusively make one of the three human forms of APOE.

Castellano used a technique called in vivo microdialysis to monitor amyloid beta levels in the brains of mice. He found that young adult mice that made APOE E4 had significantly higher levels of amyloid beta in their brains, and they cleared amyloid beta much more slowly than mice producing APOE E2 or E3. When he assessed amyloid plaque deposition in older mice, those that produced APOE E4 had many more plaques than mice that made APOE E2 or APOE E3.

To determine whether the different forms of APOE had any effect on amyloid beta production rates, Castellano applied another technique called stable isotope labeling kinetics in collaboration with the laboratory of Randall Bateman, MD, assistant professor of neurology at Washington University. The experiment showed no significant difference in production rates in mice with each of the three forms of human APOE.

“These experiments show that APOE E4 is impairing amyloid beta clearance compared to other forms of APOE,” Castellano says. “One very significant question is whether APOE and amyloid beta interact directly or indirectly. If they do bind to each other, does this binding differ according to the form of APOE, causing the differences in clearance we observed?”

Holtzman's laboratory has already identified a receptor in the brain that removes APOE and amyloid beta.

“We would like to find out whether that receptor clears amyloid beta and APOE together, or if the two are removed from the brain through distinct mechanisms,” Holtzman says. “Answering these questions could be very important for new therapies.”

View the original press release.

Adapted from Washington University in St. Louis School of Medicine

View all news updates for Alzheimer's disease


Disclaimer: The information provided in this section is a public service of the BrightFocus Foundation, and should not in any way substitute for the advice of a qualified healthcare professional, and is not intended to constitute medical advice. Although we take efforts to keep the medical information on our website updated, we cannot guarantee that the information on our website reflects the most up-to-date research. Please consult your physician for personalized medical advice; all medications and supplements should only be taken under medical supervision. BrightFocus Foundation does not endorse any medical product or therapy.

Some of the content in this section is adapted from other sources, which are clearly identified within each individual item of information.

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