Scientists have identified an enzyme inhibitor in the brain that reduces the phosphorylation of a key protein known to be associated with Alzheimer’s disease. The research, published online this week in Nature Chemical Biology, could lead to a new strategy for developing therapeutic treatments for patients with Alzheimer’s disease.
Hyperphosphorylated tau proteins tend to collect into clusters called neurofibrillary tangles. The presence of these tangles in the brain is a major hallmark of Alzheimer’s disease and associated neurodegenerative diseases called ‘tauopathies’. Scientists think that tau phosphorylation may have a reciprocal relationship with tau O-GlcNAcylation, or addition of a particular type of sugar molecule to tau. This means that increasing the levels of the sugar O-GlcNAc should decrease tau phosphorylation.
One way to increase tau O-GlcNAc levels is to inhibit the enzyme that removes the sugar from tau. The O-GlcNAcase inhibitors created so far are unstable within the body, difficult to synthesize or unable to enter the brain from the bloodstream. David Vocadlo and colleagues have created an inhibitor that overcomes these problems and shown that it elevates O-GlcNAc and lowers tau phosphorylation within the body.
With this inhibitor it will now be possible to investigate O-GlcNAcase as a target for treating Alzheimer’s disease and also to explore the role of O-GlcNAc in the brain.