Glucose modification and oxidation of macrophage migration inhibitory factor in Alzheimer’s disease

Abstract

Objectives: Increasingly, scientists are looking toward Alzheimer’s disease (AD) risk factors such as oxidative stress, impaired immune response and hyperglycaemia/diabetes to identify preventative and therapeutic strategies. However, a link between these risk factors has yet to be identified. This study set out to define the protein glycation profile of human brain with the aim to identify AD-specific glucose modifications. Methodology: We developed an electrophoresis-based method that enables the visualisation of early glycation adducts by exploiting the reversible covalent interaction between fluorescent boronic acid and the cis-diol of the fructosamine-protein adduct in glycated proteins [1-4]. Results: By applying this FluPAGE technology we have been able to: 1) identify a profile of hitherto undetectable early glycation adducts in human brains that precede the formation of the advanced glycation end-products associated with AD pathology. 2) identify an oxidised variant of glucose-modified macrophage migration inhibitory factor (MIF) in both early and late stage AD brains. 3) show that these modifications can develop within a matter of days in vitro and affect MIF activity and degradation. Conclusion: Our findings implicate glucose-modified and oxidised MIF as a molecular link between hyperglycaemia, oxidative stress and dysregulation of the innate immune system in AD.