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New Thinking About the Role of an Alzheimer's Risk Gene in Amyloid Clearance

Fitzgerald, Susan

doi: 10.1097/01.NT.0000431953.46503.86
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New findings from a research lab at Washington University in St. Louis propose that rather than binding with amyloid-beta (Abeta), apolipoprotein E — the risk gene for Alzheimer's disease (AD) — blocks a pathway involved in the degradation and clearance of Abeta from the brain.

What if a risk gene implicated in Alzheimer's disease (AD) did not have the role in the disease pathogenesis it was long theorized to play? That's what a new study by a prominent AD research group proposes, and according to experts not involved with the study, the findings could lead to new paradigms and models for therapeutic targets.

It's long been thought that the apolipoprotein (APOE) protein binds to the amyloid-beta (Abeta) peptide in cerebrospinal fluid, causing a deleterious buildup of amyloid plaque. But new findings from a research lab at Washington University in St. Louis propose a different mechanism: Rather than binding with Abeta, the investigators claim APOE blocks a pathway involved in the degradation and clearance of Abeta from the brain.

“Amyloid-beta and APOE are affecting each other, but not because they bind to each other,” David M. Holtzman, MD, told Neurology Today. His team's laboratory experiments demonstrated that APOE and Abeta compete at the cellular level for a receptor that acts as a pathway to clear the Abeta. With less opportunity to bind to the receptor, Abeta, the molecule in amyloid plaques, increases.

“APOE inhibits the cellular degradation of amyloid-beta by astrocytes,” said Dr. Holtzman, who is the Andrew B. and Gretchen P. Jones professor and chair of neurology at Washington University. His team reported its findings in the May 7 Proceedings of the National Academy of Sciences.

“These findings do not change the current thinking on the major role that APOE plays in Abeta metabolism,” Dr. Holtzman said. “But they do add new details about what APOE appears to be doing to affect Abeta.”

The findings are important because they point to a new avenue for pursuing AD drug therapies, said David Gill, MD, a behavioral neurologist at Unity Rehabilitation and Neurology in Rochester, NY, who was not involved with the study. Dr. Gill, who serves on the Neurology Today editorial advisory board, noted that the scientific evidence outlined in the paper was convincing. He said efforts to develop effective therapies to reduce amyloid plaque buildup have been frustrating to date, and identifying another mechanism to potentially remove Abeta might help remove more plaque from the brains of AD patients.

“This study gives us another potential pathway to get rid of amyloid-beta,” Dr. Gill said. “However, the true benefit of amyloid removal as a treatment for Alzheimer's disease has yet to be shown, so there may be more to the process of Alzheimer's disease than we currently understand.”

This latest research does not dispute the fact that the APOE gene, which encodes for the APOE protein involved in lipid metabolism, is a strong contributor to the risk for AD. People who have one copy of the APOE4 variant of the APOE gene are 3.7 times more at risk for Alzheimer's than those who do not carry an APOE4 allele. Individuals who have two copies of the APOE4 gene are 12 times more likely to get AD, Dr. Holtzman said.

Scientists have long thought that the APOE protein interacts directly with Abeta to influence its clearance from fluids circulating in the brain. Dr. Holtzman and his team tested that theory in a series of laboratory experiments. In test tube experiments using human cerebrospinal fluid and cell culture media, they demonstrated that the APOE protein does not bind to any significant degree to Abeta.



“We found that most of the APOE and most of the amyloid-beta peptide are not bound to each other in physiological fluids,” Dr. Holtzman said, a finding that suggested that another mechanism was at work.

They then conducted experiments using cell cultures to see what happened on the surface of astrocytes, brain cells that are thought to be involved in the clearance of Abeta. The researchers found that the APOE protein bound to the same receptor — lipoprotein receptor-related protein 1 (LRP1) — on the surface of astrocytes that Abeta did. With APOE vying for the receptor, there was less opportunity for uptake of Abeta into the clearance pathway.

The researchers did follow-up experiments using an AD mouse model that involved manipulating the level of circulating APOE in brain interstitial fluids. More protein of the APOE4 variety led to an increase in Abeta, while the same degree of buildup did not occur with APOE2, which is a form of APOE that is protective against Alzheimer's.

“We propose that the ability of APOE to influence [Abeta] clearance or aggregation probably is mediated not through direct binding…but rather through its actions with LRP1 and other interacting receptors/transporters,” the researchers concluded. “Evidence indicates that decreasing APOE in the (central nervous system) and modulating the level and activity of APOE receptors and transporters may provide opportunities for developing AD therapeutics.”

A drug that would cause an upregulation of the LRP1 receptor, for instance, could lead to more Abeta being cleared, Dr. Holtzman said.

He said these latest findings, which his team continues to explore, highlight the cellular complexity of Alzheimer's.

Mary Jo LaDu, PhD; Leon Tai, PhD; and a team of other Alzheimer's disease researchers at the University of Illinois at Chicago cautioned that people should not discount the importance of binding between APOE and Abeta peptide on this paper alone. They said it is not clear whether the in vitro results published in the paper are relevant in vivo. Using a new laboratory assay, the researchers recently demonstrated that APOE does bind to Abeta, suggesting that APOE/Abeta complex formation may influence Abeta clearance. Their findings were published in the Feb. 22 issue of the Journal of Biological Chemistry.

“Every technique and model has strengths and weaknesses, making conclusions that eliminate one hypothesis in favor of another premature at this point, as the story continues to unfold,” Dr. LaDu and Dr. Tai wrote in an e-mail.

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•. Verghese PB, Castellano JM, Holtzman DM ApoE influences amyloid-β(Aβ) clearance despite minimal apoE/Aβ association in physiological conditions. Proc Natl Acad Sci U S A. 2013;110(19):E1807-;16. E-pub 2013 Apr 25.
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      •. Neurology Today: “Increased LDL receptor lowers amyloid plaques via apolipoprotein E: Study offers new insight on how APOE works in Alzheimer disease”:
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