T2D is a chronic metabolic disorder that increases the risk for dementia (including AD). Both aging-related T2D and AD belong to protein amyloidosis diseases, of which currently there are no known cures. Our long-term goal is to understand the molecular mechanisms that link T2D and its complication of neurological deficits and to develop new chemical biology strategies to prevent and treat amylin amyloidosis based diabetic complications. T2D patients have increased blood concentrations of amylin, a peptide hormone that is co-secreted with insulin from pancreatic beta-cells. This hyperamylinemic state makes highly amyloidogenic amylin hormone more prone to amyloid formation and deposition in the pancreas in T2D patients. Recent clinical and animal model studies provide strong evidence that amylin amyloid contributes to neurological symptoms mimicking AD. Therefore neutralizing the toxic amylin amyloid (without affecting the physiological roles of the monomeric hormone) could be an effective strategy to prevent and treat amylin amyloidosis. We discovered rosmarinic acid (RA) from library screening and we further engineered a unique RA analog (RA-amide) that is more potent than RA in inhibited amylin amyloid formation and reduced amylin amyloid-induced cytotoxicity against pancreatic beta-cells and neuronal cells. We provide evidence that RA- amide significantly reduces human amylin oligomers with sera samples taken from HIP rats and from diabetic patients. We hypothesize that RA-amide will potently inhibits amylin amyloid/oligomers in the circulation in vivo. To test this hypothesis, we will pursue two Specific Aims: (1) Determine RA-amide effects on neutralizing amylin amyloid-induced cytotoxicity in primary neurons and in rat islets. (2) Determine in vivo efficacy of RA-amide in alleviating human amylin plaque depositions and related pathology including neurobehavioral deficits. This pilot study serves as proof-of-concept in vivo efficacy tests of RA-amide to collect necessary data from a humanized rat model for a future R01 project.
Type 2 diabetes (T2D) and its complication, neurodegeneration are major and growing public health problems in the US. Specific molecular links between these diseases are poorly understood. Inhibiting toxic amylin amyloid/oligomer deposition in the pancreas and the brain with a potent synthetic rosmarinic acid analogue may be not only an attractive strategy to validate the link, but also lead to new therapeutic strategies for ameliorating and preventing T2D and related complications.
