Amylin Amyloid, A Link Between Pancreas and Brain Pathologies in Diabetes

Type-2 diabetes (T2D) is a chronic metabolic disorder that increases the risk for dementia linked to cerebrovascular disease and/or Alzheimerfs disease. Increased risk for these diseases develops years before the onset of clinically apparent T2D and is higher in people with obesity or insulin resistance. Amylin is an amyloidogenic peptide synthesized and co-secreted with insulin by pancreatic ƒÀ-cells, is elevated in obesity and pre-diabetic insulin resistance, and has binding sites in the brain regulating satiety and gastric emptying. With increased secretion, amylin forms oligomers in the secretory vesicles of pancreatic ƒÀ-cells and large amyloids extracellularly, in pancreatic islets. Accumulation of oligomerized amylin in pancreatic islets is an important source of oxidative and inflammatory stress leading to ƒÀ-cell apoptosis and development of T2D. Our preliminary data show that, in addition to plaques laden with ƒÀ-amyloid, the brain of demented T2D patients also contains large deposits of amylin. Hence, we hypothesize that hyperamylinemia contributes to the development of dementia in T2D by a steady infiltration of oligomerized amylin in cerebral vasculature and brain parenchyma. To test the association of cerebral deposition of amylin with dementia in T2D, we will now compare amylin pathology in the brain of cognitively normal T2D patients with that in cognitively impaired T2D patients and non-diabetic controls (aged .65 years) to determine how amylin concentration and distribution of amylin deposits differ from our initial findings in demented T2D patients. In a broader sample, including appropriate controls, we will assess the level of co-localization of amylin and AƒÀ in cerebral blood vessels and brain parenchyma of demented diabetics. This research proposal exploits our laboratoryfs expertise in molecular mechanisms linking hyperamylinemia with diabetic degenerative disease and the skill of UK ADC in employing human brain tissue to characterize brain responses to aging and pathological stress. If the hypothesis of toxic amylin accumulation in the cerebrovascular system and brain is proven, then hyperamylinemia could be a feasible therapeutic target to slow the neurodegenerative process in diabetic patients, which will be the goal of a future R01 application.