AlzDiabetes · Insulin resistance and Tauopathy : Insights from Drosophila models and human brain samples

Insulin resistance and Tauopathy : Insights from Drosophila models and human brain samples

Problem being addressed Presently 850,000 individuals in UK suffer from Dementia the most prevalent of which is Alzheimer's disease. Currently there is no cure for AD so it is important to look for risk factors that would allow early detection of this disease. Although age is the most important risk factor for AD, current studies have shown that cerebrovascular diseases and metabolic disorders such as obesity and Type 2 Diabetes (T2DM) greatly increase the risk of AD. Presently, 3.9 million people in UK are suffering from diabetes of which 90% suffer from T2DM which is characterized by insulin resistance. Epidemiological studies suggest that individuals with Type 2 Diabetes (T2DM) are at 1.5 to 2.5 fold higher risk of dementia especially Alzheimer’s Disease (AD). A vast body of scientific evidence suggests a shared pathophysiology between these two diseases, but the mechanisms that link AD and T2DM are not well defined.The purpose of this investigation is to decipher the underlying mechanistic pathways connecting insulin resistance to AD and explore the possibility of developing combinatorial therapies to reduce the risk of dementia in diabetic individuals. Why is it important for society ? The World Health Organization (WHO) estimates that over 50 million people worldwide including 850,000 individuals in the UK have AD. The WHO reports further state that dementia costs in the UK surpass the cost incurred by cancer or cardiac failures. Moreover, the susceptibility of diabetic patients to AD, greatly threatens the increased prevalence of this devastating disease in the elderly, thus escalating the healthcare costs. Consequently The obtained results will have an impact in the development of new diagnostic tools and benefit the society overall. Overall objectives For these studies I have exploited the genetic tractability of the fruit fly, Drosophila melanogaster, and utilized a well-established model of tauopathy that I made in my Post_doc tenure. (1) to decipher the connection between tau pathology and impaired autophagic clearance in Drosophila tauopathy models in the context of insulin sensitivity and insulin resistance and test antidiabetic/pro-autophagy drugs in fly models (2) To analyse if these markers of tau pathology are altered in Control human brains as well as in AD brains at different Braak stages with and without T2DM. Conclusion: I have been able to conclude that the tau pathology of hyperphosphorylation and aggregation is exacerbated in Drosophila tauopathy models in an insulin resistant state due to the hyperactivation of GSK-3beta as well as due to an imbalance of the mTOR/autophagy pathway. I have also concluded that these effects are ameliorated in an insulin-sensitive environment and in the presence of insulin-sensitizing drug Metformin. Brain analysis from normal control post-mortem brains display a decrease of total tau levels with an increase of autophagy. Age-matched brain experiments from AD patients with and without T2DM are in progress.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз