Maintaining Brain Sugar Levels May Be Key to Alzheimer’s Prevention

Preventing or slowing the development of Alzheimer’s disease (AD), a fatal brain disorder expected to impact one in 85 people worldwide by 2050, may be as easy as making sure a brain protein’s sugar levels are maintained.

This is the conclusion of seven researchers, including Dr. David Vocadlo, a Simon Fraser University (SFU; Burnaby, BC, Canada) chemistry professor and Canada research chair in chemical glycobiology, make in the March 2012 issue of Nature Chemical Biology. The journal has published the researchers’ latest paper Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation.

Dr. Vocadlo and his coworkers described how they have employed an inhibitor they have chemically created--Thiamet-G--to block O-GlcNAcase, a naturally occurring enzyme, from depleting the protein Tau of sugar molecules. “The general thinking in science,” said Dr. Vocadlo, “is that Tau stabilizes structures in the brain called microtubules. They are kind of like highways inside cells that allow cells to move things around.”

Previous research has demonstrated that the linkage of these sugar molecules to proteins, such as Tau, in cells is vital. In fact, according to Dr. Vocadlo, researchers have tried but failed to rear mice that do not have these sugar molecules attached to proteins.

Dr. Vocadlo, an accomplished chess player, is having great success checkmating problematic enzymes with inhibitors he and his students are creating in the SFU chemistry department’s laboratory of chemical glycobiology.

Earlier research to Dr. Vocadlo’s has revealed that clumps of Tau from an AD brain have nearly none of this sugar attached to them, and O-GlcNAcase is the enzyme that is robbing them. Such clumping is an early event in the development of AD and the amount of clumps correlate with the disease’s severity.

Scott Yuzwa and Xiaoyang Shan, grad students in Dr. Vocadlo’s lab, discovered that Thiamet-G blocks O-GlcNAcase from removing sugars off Tau in mice that drank water with a daily dose of the inhibitor. The researchers found that mice given the inhibitor had fewer clumps of Tau and maintained healthier brains.

“This work shows targeting the enzyme O-GlcNAcase with inhibitors is a new potential approach to treating Alzheimer’s,” said Dr. Vocadlo. “This is vital since to date there are no treatments to slow its progression. A lot of effort is needed to tackle this disease and different approaches should be pursued to maximize the chance of successfully fighting it. In the short term, we need to develop better inhibitors of the enzyme and test them in mice. Once we have better inhibitors, they can be clinically tested.”

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