The developmental effects of sex chromosomes and hormones specify microglial inflammation in Alzheimer's diseaes

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PROJECT SUMMARY/ABSTRACT Although women are known to be disproportionally affected by Alzheimer’s disease (AD), the underlying biology for this difference is unresolved. Our long-term goal is to help develop therapies that can be used in the prevention and treatment of Alzheimer’s disease and other dementias where inflammation plays a critical role. The overall objectives in this application are to (i) define the mechanisms that specify the inflammatory response in the AD brain, and (ii) elucidate whether these are altered in the presence of circulating hormones. Our central hypothesis is that sex differences in the brain’s immune cells are driven by sex chromosomes and gonadal steroid hormones, resulting in divergent inflammatory processes and therefore AD onset and progression. The rationale for this project is that determining how genetic and hormonal mediators contribute to sex differences in the neuroinflammatory processes in AD will provide a strong scientific framework whereby new therapeutic strategies can be developed. The central hypothesis will be tested by pursuing two specific aims: 1) Determine the contribution of sex chromosomes to the inflammatory environment of the AD brain; and 2) Determine the organizational effects of sex hormones in establishing the inflammatory response in the AD brain. Under the first aim, the 5xFAD mouse model of AD will be combined with the Four Core Genotype (FCG) mouse to separate chromosomal and gonadal sex in the context of AD. Inflammation will be assessed using biochemical and molecular techniques to examine immune cell activation and neuronal health and survival. For the second aim, the brains of 5xFAD mice will be masculinized or feminized neonatally to ascertain the effects of gonadal hormones on inflammatory processes. The innovation of this project lies in: 1) the aspects of sex not previously considered in AD models, 2) the contribution of cell differentiation during development to AD risk in ways not previously considered, and 3) the use of methodologies to shift the disease paradigm away from protein functional differences towards expression differences. Providing critical insights to the mechanisms giving rise to immune dysregulation and neuroinflammation in AD are significant because they have the potential to become the basis for new therapeutic strategies.