Actions of Nuclear Receptors on TREM2+ myeloid cells and in microglia in the AD brain
Case Western Reserve University School of Medicine
Supervising Advisor: Dr. Gary Landreth
The Alzheimer’s disease (AD) brain is characterized by an inflammatory environment supported by brain immune cells, which is thought to be a key feature in disease progression. These cells are generally believed to be brain “resident” cells known as microglia, however, our preliminary results suggest that the cells responsible for this chronic inflammation have been misidentified, and are actually macrophages derived from peripheral blood borne monocytes, which we also found to be the main cell type surrounding amyloid plaques. The myeloid receptor TREM2 is essential for the infiltration and/or persistence of these monocytes in the AD brain, and is selectively expressed in these cells, rather than in microglia. Importantly, it has been recently described that variant forms of the TREM2 gene confer a higher risk of developing AD. TREM2 along with an array of functionally related genes are coordinately regulated by nuclear receptors in myeloid cells. These genes act towards the acquisition of an “alternative activation” state, comprising the suppression of inflammation and promotion of phagocytosis. Interestingly, nuclear receptors agonists have consistently been shown to ameliorate AD related phenotypes. This project aims to better understand the role of nuclear receptors in AD, first by assessing their role in monocyte infiltration and lifetime in the brain, by ascertaining which gene cohorts are activated distinctively in microglia and monocyte-derived lineages, and by assessing which of these two cell types is crucial for the beneficial effects of nuclear receptors activation in AD. These results will help us to better understand AD pathogenesis and progression, enabling us to find novel therapeutic strategies.