Developmental Determinants of Sexually Divergent Neuroinflammatory Processes

Our goal is to identify the developmental factors that program immune cell responses leading to sex differences in Alzheimer’s disease onset and progression. The immune cells of the brain are critical in brain development and drive inflammatory processes that promote Alzheimer’s disease (AD). These cells show intrinsic sex differences, and we believe this contributes to women being disproportionally affected by AD. Each part of this project will examine the potential ways these differences are established during development – the sex chromosomes (Aim 1) and hormones (Aim 2), to see if they instruct the immune cells of the brain to behave in sex-specific ways that promote or protect against the initiation and progression of AD.

Thus far, broad anti-inflammatory therapies and estrogen replacement strategies have been ineffective in treating Alzheimer’s disease or yielded mix results, highlighting the need to focus on AD-specific immune cell function and differences. The innovation in this proposal comes from three places: 1) we are focusing on sex in ways not previously considered in AD models, 2) we are considering the development of immune cells to AD risk in ways not previously determined, and 3) we are thinking about the expression rather than function of immune molecules. Upon completion of this project, we will have identified the roles of sex chromosomes and hormones in the developmental processes defining the immune response in Alzheimer’s disease. This will provide new insights into AD-specific immune cell biology, opening new lines of research that could identify novel therapeutic targets and improved strategies for more efficacious treatment paradigms.

Thus far, broad anti-inflammatory therapies and estrogen replacement strategies have been been ineffective in treating Alzheimer’s disease or yielded mix results, highlighting the need to focus on AD-specific immune cell function and differences. The innovation in this proposal comes from three places: 1) we are focusing on sex in ways not previously considered in AD models, 2) we are considering the development of immune cells to AD risk in ways not previously determined, and 3) we are thinking about the expression rather than function of immune molecules.

Upon completion of this project, we will have identified the roles of sex chromosomes and hormones in the developmental processes defining the immune response in Alzheimer’s disease. This will provide new insights into AD-specific immune cell biology, opening new lines of research that could identify novel therapeutic targets and improved strategies for more efficacious treatment paradigms.