Abstract:
S-nitrosylation, a redox mediated post translational modification, is one of the most important mechanisms involved in cellular regulation of several metabolic, apoptotic and structural proteins. Aberrant S-nitrosylation has been linked to several disorders including Diabetes Mellitus (DM) and Alzheimer’s disease (AD). Recent studies have identified a role of impaired glucose signaling and hyperglycemia in development of pathological hallmarks of AD thus making Diabetes Mellitus Type 2 (T2DM) a major risk factor for dementia. Evidence from epidemiological studies shows a 50% to 100% increase in the risk of development of AD in patients suffering from T2DM. However the mechanism through which aberrant functioning of insulin signaling molecules contributes to development of AD is yet to be explored. In the current study, we have employed behavioral tests, Proteome profiling, Western blotting, gene expression analysis and immunohistochemical studies to identify behavior alterations, neurodegeneration, aberrant neurogenesis and altered protein S-nitrosylation status in Streptozotocin (STZ) induced mice models of T2DM. Our findings show that T2DM causes a significant decline in spatial learning and reference memory. Our study also suggests that an increase in expression of APP 770 with a simultaneous decrease in neurogenesis (as suggested by the expression analysis of Ki67, DCX and NeuN) might be the reason of marked neurodegeneration in diabetic brains. We found that S-nitrosylated proteins are significantly upregulated in diabetic brain, possibly in response to inflammation and nitrosative stress, in diabetic brain implicating the significant role of aberrant nitrosylation in T2DM and AD. In conclusion, it can be suggested that the combined action of increased APP770, decreased neurogenesis and aberrant S-nitrosylation in central nervous system of diabetic patients may mark their brains to develop AD
