Increasing age is associated with lower levels of cognitive performance; concomitant with this is a decrease in brain glucose metabolism. This decrease is accelerated in Alzheimer’s disease (AD) where reduced brain glucose metabolism is evident prior to the clinical manifestation of dementia suggesting that decreased brain glucose metabolism contributes to the molecular cascade that results in cognitive decline and dementia. We hypothesise that age-dependent alteration in glucose metabolism impact negatively on neuronal function through dysregulation of protein O-GlcNAcylation, a glucose dependent glycosylation. The project will investigate alterations in brain protein O-GlcNAcylation and its regulatory enzymes that occur as we age and which alter as AD progresses using a multidisciplinary approach utilising Western blotting and proteomics methodologies.
Techniques and Methodology Proteomic analysis, protein purification, mass spectrometry, SDS-PAGE.
Impact on Alzheimer’s research How brain protein O-GlcNAcylation changes as we age has yet to be determined and there is no consensus about what alterations occur in AD. Protein O-GlcNAcylation is a poorly understood protein post-translational modification although its dysregulation has been identified in a number of other diseases. This research will identify the spectrum of changes in brain protein O-GlcNAcylation that occurs as we age and as AD progresses. It will identify key proteins that distinguish between ageing and Alzheimer’s disease and providing a basis for accelerating new therapeutic agents to combat Alzheimer’s.