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2017 Grants - Cirrito
Role of Glucocorticoid Receptors in Sex-Related Differences in Alzheimer’s Disease
John R. Cirrito, Ph.D.
Washington University in St. Louis
St. Louis, Missouri
2017 Sex and Gender in Alzheimer’s (SAGA) Grant
Are there sex differences in the mechanisms that underlie stress and Alzheimer’s disease?
Women are disproportionately affected by Alzheimer’s disease and emerging evidence suggests there may be unique biological and lifestyle factors that underlie these differences. Scientists are actively working to address gaps in our understanding of how biological sex and related genetic, lifestyle and societal factors may impact vulnerability to Alzheimer’s disease. In initial studies, John R. Cirrito, Ph.D., and colleagues found that when mice were stressed, brain levels of beta-amyloid (a protein fragment linked to Alzheimer’s) became higher in female animals than in males. These increases may have occurred because stress promotes the generation of hormones called glucocorticoids. High levels of glucocorticoids have been linked to increased dementia severity in people with Alzheimer’s, but the underlying mechanisms are not yet known. It may have something to do with how glucocorticoids act on the brain through their cellular “docking sites” called glucocorticoid receptors. More research is needed to examine if sex differences in the stress response may contribute to brain changes associated with Alzheimer’s disease.
The actions of glucocorticoids on the brain can happen through two different pathways that may be linked to Alzheimer’s disease: (1) transactivation – the process of turning on certain genes in the brain; and (2) transrepression – the process of turning off genes. For their current grant, Dr. Cirrito and colleagues will use Alzheimer’s-like mice that have been genetically-engineered to have altered glucocorticoid receptor function and stress responses. The researchers will investigate how these genetic changes may contribute to several dementia-related brain changes including toxic beta-amyloid production, brain inflammation, and memory loss. They will also determine whether such changes are more severe in female mice than in males.
Dr. Cirrito’s study could refine our understanding of how stress may impact Alzheimer’s disease risk and shed new light on the molecular mechanisms that could underlie sex differences in the risk for dementia. Clarifying these mechanisms may help identify new targets for the development of treatments to slow or prevent Alzheimer’s disease.