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Advanced glycation end products (AGEs) accumulate in diabetic patients due to high blood glucose levels and cause multiple deleterious effects. In this study, we provide evidence that the AGE increased cell death, one such deleterious effect.

Advanced glycation end products (AGE) accumulate in diabetic patients and aged persons due to high amounts of 3- or 4-carbon derivatives of glucose. Understanding the mechanism of AGE-mediated signaling leading to these consequences, like oxidative stress, inflammation, apoptosis, etc. and its regulation would be a viable strategy to control diabetic complication and age-related diseases. We have detected the probable mechanism by which AGE increases lipogenesis, the cause of fatty liver in diabetic patients. AGE increased lipid accumulation in different cells as shown by Oil Red O staining. AGE-mediated regulation of several transcription factors was determined by gel shift assay. Antioxidants like NAC, PDTC, and vitamin C, except mangiferin, were unable to protect AGE-induced activation of SREBP and subsequent lipid accumulation. AGE increased the phosphorylation of ERK, and IKK and also DNA binding ability of SREBP, thereby its dependent gene transcription. AGE induces NF-κB which might suppress PPARγ activity, in turn reducing lipid breakdown and mobilization. Mangiferin not only inhibits AGE-mediated ROI generation that requires NF-κB activation, but also inhibits ERK and IKK activity, thereby suppression of SREBP activity and lipogenesis. Mangiferin has shown a double-edged sword effect to suppress AGE-mediated ailments by reducing ROI-mediated responses as antioxidant and inhibiting SREBP activation thereby lipogenesis, suggesting its potential efficacy against diabetes and obesity-related diseases.

Introduction: More than 50 mutations in the MAPT gene result in heterogeneous forms of frontotemporal lobar dementia with tau inclusions (FTLD-Tau). However, early pathogenic events that lead to disease and the degree to which they are common across MAPT mutations remain poorly understood. The goal of this study is to determine whether there is a common molecular signature of FTLD-Tau.Methods: We analyzed genes differentially expressed in induced pluripotent stem cell–derived neurons (iPSC-neurons) that represent the three major categories of MAPT mutations: splicing (IVS10 + 16), exon 10 (p.P301L), and C-terminal (p.R406W) compared with isogenic controls. The genes that were commonly differentially expressed in MAPT IVS10 + 16, p.P301L, and p.R406W neurons were enriched in trans-synaptic signaling, neuronal processes, and lysosomal function. Many of these pathways are sensitive to disruptions in calcium homeostasis. One gene, CALB1, was significantly reduced across the three MAPT mutant iPSC-neurons and in a mouse model of tau accumulation. We observed a significant reduction in calcium levels in MAPT mutant neurons compared with isogenic controls, pointing to a functional consequence of this disrupted gene expression. Finally, a subset of genes commonly differentially expressed across MAPT mutations were also dysregulated in brains from MAPT mutation carriers and to a lesser extent in brains from sporadic Alzheimer disease and progressive supranuclear palsy, suggesting that molecular signatures relevant to genetic and sporadic forms of tauopathy are captured in a dish. The results from this study demonstrate that iPSC-neurons capture molecular processes that occur in human brains and can be used to pinpoint common molecular pathways involving synaptic and lysosomal function and neuronal development, which may be regulated by disruptions in calcium homeostasis.

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