The role of insulin resistance and protein O-GlcNAcylation in Neurodegeneration

Metabolic syndrome including obesity and type 2 diabetes is increasing at an alarming rate worldwide. Similarly, there has been an increase in the cases of neurodegenerative diseases such as Alzheimer's disease (AD) possibility due to increase in elderly population in the past few decades. Both, metabolic diseases and AD have one common feature that is insulin resistance. Recent studies suggest a link between the regulatory functions of insulin in the brain and AD. Hypoglycemia, a characteristic feature of AD may be a result of impaired insulin signaling in the affected regions of the brain. O-GlcNAcylation is a post-translational protein modification, the levels of which are dependent on the availability of glucose inside the cells. Hyperphosphorylation of Tau is a major molecular feature, which leads to its aggregation and neurotoxicity in AD. In addition, impaired processing of Amyloid precursor protein (APP) leading to toxic amyloid β (Aβ) aggregation is also implicated in the pathogenesis of AD. Both APP and Tau are also found to be O-GlcNAcylated. Reduced O-GlcNAcylation of APP and Tau due to hypoglycemia is found to be associated with their pathological features in AD brain. Recent studies have also identified perturbed O-GlcNAcylation/phosphorylation of several other proteins important for normal neuronal function, which may be contributing to the neuropathological development in AD. Herein, we discuss about the uptake and distribution of insulin inside the brain, brain insulin signaling and insulin resistance as well as its relation to neurodegenerative diseases with a special focus on protein O-GlcNAcylation and its potential role in the treatment of AD.