Title: Does Nrf2 provide neuroprotection against diabetes-associated vascular dysfunction?
Funder: The Academy of Medical Sciences

Abstract: Diabetes is a significant public health disorder with increasing prevalence worldwide. Improvements in healthcare have lengthened the life expectancy of those with diabetes, but diabetes-associated complications, including dementia, have also risen. Chronic hyperglycaemia increases the risk of dementia in Type 1 (T1D) and Type 2 (T2) diabetes. Conversely, hypoglycaemia, an almost unavoidable side-effect of insulin therapy and currently the only treatment for T1D, accelerates this decline. I have developed a mouse model of T1D, which exhibits cognitive impairments associated with increased oxidative stress and neuroinflammation. These defects are augmented following hypoglycaemia. Significantly, the cognitive defects were reversed following treatment with sulforaphane, a potent activator of Nrf2. Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor and master regulator of the endogenous antioxidant defence. Nrf2 activity decreases with age and in Alzheimer's Disease. I propose that impaired Nrf2 signalling and increased oxidative stress following hyperglycaemia damages the blood-brain barrier (BBB), causing it to become leaky and triggering microglial activation; this is further exacerbated by recurrent hypoglycaemia. In turn, activated microglia contribute to BBB permeability via the production of inflammatory mediators. To test this hypothesis, I will perform quantitative proteomics on isolated microglia from my mouse model of T1D in the presence and absence of Nrf2 activator, along with functional assays and immunohistochemistry to assess BBB integrity and function. These studies will determine a potential mechanism for diabetes-associated cognitive impairment, identify unique microglial proteins that are integral to its development, and explore the therapeutic potential of Nrf2 targeted therapy

Lay abstract: Improved health care in diabetes has increased life expectancy but at the cost of additional diabetic complications, including dementia. High blood glucose (hyperglycaemia) damages blood vessels. Low blood glucose (hypoglycaemia), an unwanted but common side effect of insulin therapy used to treat Type 1 (T1D) and Type 2 diabetes (T2D), is also damaging. High and low glucose cause damage to the body by stimulating the production of toxic free radicals (ROS) and inflammatory cells. The body has defence mechanisms to protect cells from ROS, including the Nrf2 system. Unfortunately, these are faulty in many diseases, e.g. Alzheimer's Disease and potentially diabetes. I have demonstrated in a mouse model of T1D that chronic hyperglycaemia leads to memory problems that are made even worse following recurrent hypoglycaemia. Treatment with sulforaphane, an Nrf2 activator, reversed the memory problems. I propose that in diabetes, impaired Nrf2 signalling and increased ROS damages the blood-brain barrier (BBB), making it 'leaky'. This is made worse by repeated hypoglycaemia. When the BBB is damaged, immune cells (microglia) become activated, causing damage to the brain and affecting memory. To test this hypothesis, I will use my mouse model of T1D and repeated hypoglycaemia to investigate whether activation of the Nrf2 pathway prevents damage to BBB. I will also study the microglia to identify new proteins and networks that are altered by diabetes and SFN. By doing this, I hope to identify new drug targets and improve our understanding of why diabetes and its treatment lead to accelerated brain ageing.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE