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

Periodic Reporting for period 1 - AlzDiabetes (Insulin resistance and Tauopathy : Insights from Drosophila models and human brain samples)

Berichtszeitraum: 2016-12-19 bis 2018-12-18

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.

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Tasks for Aim1 :

1. Scanning and light microscopy has been performed to study the amelioration or exacerbation of the tau-induced ""rough-eye"" phenotype in Tau-only, Tau+Chico and Tau+Chico-LOF transgenics
3. Western blot has been done with AT8, PHF1 and AT100 antibodies to study tau hyperphosphorylation in these genotypes
4. The level of the kinases GSK-3beta and ERK has been investigated in these genotypes to study the correlation between the dysregulation of the kinases and tau hyperphosphorylation

Tasks for Aim2:

1. The levels of sarcosyl soluble and insoluble tau, TOR and autophagy in the transgenics have been determined
2. Autophagic flux has been analysed

For Aim 3 : Effect of anti-diabetic drug Metformin and pro-autophagy drug Rapamycin on total tau and tau hyperphosphorylation have been tested

For Aim 4: Brains from AD patients with and without T2DM has been requested and availability confirmed from Brain Dementia Research, UK. Age matched control brains from non-demented, non-diabetic individuals have been obtained post-mortem and the tissues have been analyzed for optimization of total tau levels and autophagy markers.

Dissemination of my results:

I have disseminated my findings at the following meetings Alzheimer's Research UK, Autophagy Network Meeting , Embo Neurodegeneration Meeting. EuroTau meeting, Institute of Lifesciences and SONG meetings in Southampton . I have also presented my findings at the Pint of Science and Age-UK community for the lay audience.

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Potential impacts in research

My project will identify the crucial metabolic changes in brain cells that are influenced by insulin and serve as major risk factors for AD. This will help inform people about health and lifestyle choices that can help prevent diagnosis of AD as well as enable design of early treatment interventions that are urgently needed with the growing global dementia crisis. Specifically, my findings will facilitate the following:
(1) Developing new drugs against tau tangles. I have demonstrated in Drosophila Tauopathy models that abnormal tau is not cleared properly in an insulin-resistant condition. This
knowledge will pave the way for the development of new drugs that not only stop tau tangle formation but also tau propagation.
2) Repositioning of existing drugs. My results will shed light on the pathways that link AD and Type 2 diabetes. This could mean that drugs already used for treating Type 2 diabetes may in the future be considered for AD. There are studies which show that insulin inhalers used in treatment of Type 2 diabetes significantly improves memory problems in individuals with early stage AD. Other anti-diabetic drugs like liraglutide, which increase the availability of insulin, are also effective in reversing memory loss. Repurposing diabetic drugs for AD in this way will be highly cost effective and save a lot of time. Currently, it takes 10-15 years and billions of pounds to develop any new drug. A large number of these drugs fail in AD clinical trials due to ineffectiveness or side effects. The most important benefit from my research will be repositioning well established government-approved drugs used in diabetes for early intervention in AD; these drugs have already been proven to be safe and effective at boosting insulin in humans.

Socioeconomic impacts:

It is predicted that 1 million people will suffer from AD by 2025 if we are not able to treat this disease immediately. This research will increase awareness of AD risk amongst people with diabetes and the importance of making good health and lifestyle choices during adulthood to prevent this risk. This is important because early intervention is key to preventing dementia. Furthermore, the benefits of my research may have a long-term financial impact. Currently the cost of treating dementia in the UK is an exorbitant £26.3 billion. An estimated £14 billion a year is spent on treating diabetes and its many complications (including dementia) representing the significantly larger share. In designing treatment interventions that could halt the development of dementia in elderly individuals with insulin resistance, our study will potentially significantly reduce the number of people affected by these two conditions and alleviate the resulting socioeconomic burden.

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Periodic Reporting for period 1 - AlzDiabetes (Insulin resistance and Tauopathy : Insights from Drosophila models and human brain samples)

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