PROJECT SUMMARY Decades of research have shown a strong association between cerebrovascular disease, including stroke, and subsequent cognitive impairment and dementia. However, vascular contributions to cognitive impairment and dementia (VCID) are still unclear. Following stroke, there is a chronic inflammatory response that intensifies post- stroke injury, and in animal models, causes delayed cognitive impairment. As such, the chronic inflammatory response to stroke is a potential VCID. We recently demonstrated that at the molecular level, the chronic inflammatory response to stroke strongly resembles that seen in atherosclerosis. In that regard, it is known that overwhelmed lipid processing within myeloid cells is a driver of atherosclerosis, features of which are dysregulated lipid metabolism within macrophages and production of high concentrations of neurotoxic cytokines and degradative enzymes. Lipids are principal structural components of myelin and are therefore major constituents of the human brain. Consequently, our overarching hypothesis is that following stroke, infiltrating macrophages and resident microglia become overwhelmed by the sheer volume of cholesterol and other lipids derived from the breakdown of myelin and cell membranes and, as a result, cause the chronic inflammatory response described above. We propose that the permeation of cytokines and degradative enzymes produced within the infarct into neighboring brain regions is the principal cause of the encephalomalacia, or “softening,” that occurs to the tissue that surrounds chronic stroke infarcts. Thus, treatments that help phagocytic cells process the large amounts of lipid debris generated by the breakdown of brain tissue may temper the chronic inflammatory response to stroke and protect the surrounding brain tissue, thereby promoting healthier healing of the brain and improving recovery. In cases where the infarct is located within or adjacent to a brain region important for cognition, such treatments may even prevent dementia. Therefore, the goals of this proposal are to identify the pro-inflammatory lipid species generated, and pathways triggered, by the break-down of the lipid component of the brain following stroke (Aim 1); define the individual roles of pro-inflammatory lipid sensors in driving the chronic inflammatory response to stroke (Aim 2); and determine whether lipid removal and immune cell transcriptional reprogramming within the area of chronic inflammation can improve recovery from stroke and prevent delayed cognitive impairment (Aim 3).