PROJECT SUMMARYDecades of research have shown a strong association between cerebrovascular disease including stroke andsubsequent cognitive impairment and dementia. However vascular contributions to cognitive impairment anddementia (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 inflammatoryresponse to stroke is a potential VCID. We recently demonstrated that at the molecular level the chronicinflammatory response to stroke strongly resembles that seen in atherosclerosis. In that regard it is known thatoverwhelmed lipid processing within myeloid cells is a driver of atherosclerosis features of which aredysregulated lipid metabolism within macrophages and production of high concentrations of neurotoxic cytokinesand degradative enzymes. Lipids are principal structural components of myelin and are therefore majorconstituents of the human brain. Consequently our overarching hypothesis is that following stroke infiltratingmacrophages and resident microglia become overwhelmed by the sheer volume of cholesterol and other lipidsderived from the breakdown of myelin and cell membranes and as a result cause the chronic inflammatoryresponse described above. We propose that the permeation of cytokines and degradative enzymes producedwithin the infarct into neighboring brain regions is the principal cause of the encephalomalacia or softeningthat occurs to the tissue that surrounds chronic stroke infarcts. Thus treatments that help phagocytic cellsprocess the large amounts of lipid debris generated by the breakdown of brain tissue may temper the chronicinflammatory response to stroke and protect the surrounding brain tissue thereby promoting healthier healing ofthe brain and improving recovery. In cases where the infarct is located within or adjacent to a brain regionimportant for cognition such treatments may even prevent dementia. Therefore the goals of this proposal areto identify the pro-inflammatory lipid species generated and pathways triggered by the break-down of the lipidcomponent of the brain following stroke (Aim 1); define the individual roles of pro-inflammatory lipid sensors indriving the chronic inflammatory response to stroke (Aim 2); and determine whether lipid removal and immunecell transcriptional reprogramming within the area of chronic inflammation can improve recovery from stroke andprevent delayed cognitive impairment (Aim 3).