Administrative Supplement: Role of Hypothalamic MC4R in Glucose Homeostasis via a Novel Neuroendocrine Circuit Involving the Kidneys and Adrenal Glands

Recurrent hypoglycemia - because of hypothalamic dysfunction in type 1 and late-stage type 2 diabetes - dramatically increases the risk of old age dementia and Alzheimer’s disease. How does the chronic recurrent glucose deficit mediate cognitive decline and Alzheimer’s disease? During our investigation of recurring hypoglycemia in different ages of melanocortin receptor 4 (Mc4r) knockout mice (which is the focus of the primary project), we observed that the Mc4r knockout mice exhibit cognitive decline and features of Alzheimer’s disease. After this observation, we measured Mc4r expression in the hypothalamus and hippocampus in traditional mouse models of Alzheimer’s disease such as 3xTg-AD mice. The expression of Mc4r was dramatically reduced in both the tissues. Thus, our preliminary findings show that hypothalamic and hippocampal MC4R could be a possible link between defective counterregulatory response to hypoglycemia, recurrent hypoglycemia, and Alzheimer’s disease. Encouraged by these results, we propose to establish the contribution of Mc4r to causing features of Alzheimer’s disease following recurrent hypoglycemia (which is currently not the focus of this study). We hypothesize that recurrent hypoglycemia (because of downregulated hypothalamic Mc4r in diabetes) reduces hippocampal Mc4r to mediate features of Alzheimer’s disease / cognitive dysfunction. Aim of the study: we will establish the contribution of Mc4r to mediating features of Alzheimer’s disease following recurrent hypoglycemia using traditional mouse models of Alzheimer’s disease such as 3xTg-AD mice and our Mc4r knockout mouse model. We will also determine whether restoring hypothalamic or hippocampal Mc4r in 3xTg-AD mice can prevent or reverse cognitive dysfunction including the neuropathological features of Alzheimer’s disease. Overall, this work will likely establish the contribution of hypothalamic and hippocampal MC4R to mediating the pathogenesis of Alzheimer’s disease following recurrent hypoglycemia. Project Summary/Abstract Page 6