Medical investigations have highlighted a biological link between reduced brain glucose metabolism and Alzheimer’s disease (AD). by promoting the development of tau neuropathology and synaptic dysfunction. Since restoring brain glucose levels and metabolism could afford the opportunity to positively influence the entire AD phenotype this approach should be considered as a novel and viable therapy for preventing and/or halting the disease progression. Introduction Alzheimer’s disease (AD) and related tauopathies are neurodegenerative disorders pathologically defined by the presence of abundant and highly phosphorylated forms of the microtubule-associated tau protein which later aggregates into fibrils and finally forms the neurofibrillary tangles (NFTs).1 Although it is known that the presence and abundance of NFTs correlates with the severity of dementia and neuronal loss 2 3 the mechanisms leading to the abnormal high phosphorylation of tau in the brain of these patients remain TAK-285 unclear. Consistent evidence has provided support for the notion that that exposure to physiological and psychological stressors can trigger tau phosphorylation in rodents. Among the different type of stress in recent years a lot of attention has been devoted to the relationship between metabolic stress and brain function.4 5 Despite the fact that the brain can use ketone bodies in order to maintain its basal functions glucose is the main source of energy for the organ and its depletion has been shown to induce endoplasmic reticulum (ER) stress.5 Glucose deprivation can occur in a variety of conditions including cerebral ischemia aging and neurodegenerative diseases.6 7 Interestingly positron emission tomography imaging studies have shown that glucose utilization is lower in AD than in age-matched healthy control Rabbit Polyclonal to p70 S6 Kinase beta. brains.8 In support to this observation previous studies have demonstrated that in the transgenic mice Tg2576 (overexpressing the Swedish mutant of human APP) energy metabolism inhibition causes a post-transcriptional increase in BACE-1 levels which leads to elevated Aβ formation and deposition.9 On the other hand we have previously reported that in response to glucose deprivation neuronal cells manifest an increase in tau phosphorylation via the activation of the P38 MAPK pathway.10 This observation supported the novel hypothesis that energy deprivation may also have a role in the development of tau neuropathology the second most important hallmark lesion of the AD brain. However to the best of our knowledge so far no data are available supporting these findings and their functional significance by demonstrating that indeed TAK-285 a condition of glucose deprivation by increasing tau phosphorylation will result in memory deficit and synaptic dysfunction evidence that this metabolic stressor by influencing tau metabolism is a pleiotropic and active modulator of the pathogenesis of AD and related tauopathies. Materials and methods Animals and treatment All animal procedures were approved by the Institutional TAK-285 Animal Care and Usage Committee in accordance with the US National Institutes of Health guidelines. The h-tau mouse model implemented TAK-285 in this study was previously described.11 Briefly the mouse line designed TAK-285 to express only human tau was generated by crossing of 8c tau mice which express all human tau isoforms and tau knock-out TAK-285 mice. Animals were kept in a pathogen-free environment on a 12-h light/dark cycle and fed a normal chow and water data we observed a significant increase in the levels of the phosphorylated form of P38 MAPK kinase but no changes in its total un-phosphorylated form (i.e. P38) (Figure 7). Figure 7 Glucose deprivation modulates tau phosphorylation via P38 MAPK kinase. (a) Representative western blots of total tau (HT7) and phosphorylated tau at residues S202/T205 (AT8) and S396/S404 (PHF-1) in primary cortical neuronal cells from h-tau mice incubated … Discussion In recent years growing experimental evidence has suggested a direct association between altered glucose metabolism brain function and neurodegeneration.18 19 Consistent data have indeed established a link between systemic metabolic dysfunction such as diabetes and dementing disorders suggesting that their recently observed significant increase in incidence could be in part justified by the worldwide dramatic rise in insulin resistance obesity and diabetes.20 The complexity of this relationship has been more.