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In these two sections of mouse brains, the red represents neurofibrillary tangles while the green represents the O-GlcNAc modification. Mice treated with a chemical that increases O-GlcNAC had fewer tangles and showed less neurodegeneration than a control group.
By Tyler Irving
Posted April 2012
One of the hallmarks of Alzheimer’s disease is the aggregation of a protein called tau, which in turn gives rise to neurofibrillary tangles (NFT) and impairs brain function. A team of researchers from Simon Fraser University has shown that a specific sugar molecule attached to tau might control its aggregation and could lead to new therapeutics for Alzheimer’s.
David Vocadlo and his lab have been studying the biological role of a sugar molecule called O-linked N-acetylglucosamine (O-GlcNAc), which is routinely added and removed from many proteins in the body, including tau. The team has developed small molecule inhibitors for the enzymes that add and remove O-GlcNAc from proteins and can thereby control its levels.
In their latest study, the team used the inhibitors to increase the levels of O-GlcNAc in the brains of
mice that are genetically predisposed to develop the symptoms of Alzheimer’s. They then compared tau protein
aggregates in the brains of these mice with a control group. Mice with higher O-GlcNAc levels contained
anywhere from 23 to 62 per cent fewer aggregated proteins, depending on the part of the brain examined. They
also had 1.4 times the number of motor neurons and showed fewer symptoms of neurodegeneration. “This study is
important because it validates the practice of using inhibitors to increase O-GlcNAc as an approach with the
potential to generate Alzheimer’s therapeutics,” says Vocadlo. Along with business partner Ernest McEachern,
Vocadlo has founded a spinoff company, Alectos Therapeutics, to help commercialize his inhibitors. If all
goes well, inhibitors that can increase the levels of the O-GlcNAc sugar modification could be in the clinic
within five years. The research is published in Nature Chemical Biology. 
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