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. We have shown that there is a chronic inflammatory response following strokethat intensifies post-stroke injury and in animal models causes delayed cognitive impairment. As such thechronic inflammatory response to stroke is a potential VCID. We recently demonstrated that at the molecularlevel the chronic inflammatory response to stroke strongly resembles that seen in atherosclerosis due to thepresence of foam cells cholesterol crystals and very similar expression of specific cytokines and degradativeenzymes. In that regard it is known that overwhelmed lipid processing within myeloid cells is a driver ofatherosclerosis features of which are dysregulated lipid metabolism within macrophages and production of highconcentrations of neurotoxic cytokines and degradative enzymes. Lipids are principal structural components ofmyelin and are therefore major constituents of the human brain. Consequently our overarching hypothesis isthat following stroke infiltrating macrophages and resident microglia become overwhelmed by the sheer volumeof cholesterol and other lipids derived from the breakdown of myelin and other cell membranes and as a resultcause the chronic inflammatory response described above. We propose that the permeation of cytokines anddegradative enzymes produced within the infarct into neighboring brain regions is the principal cause of theencephalomalacia or softening that occurs to the tissue that surrounds chronic stroke infarcts. Thustreatments that help phagocytic cells process the large amounts of lipid debris generated by the breakdown ofbrain tissue may temper the chronic inflammatory response to stroke and protect the surrounding brain tissuethereby promoting healthier healing of the brain and improving recovery. In cases where the infarct is locatedwithin 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 pathwaystriggered by the break-down of the lipid component of the brain following stroke (Aim 1); define the individualroles of pro-inflammatory lipid sensors in driving the chronic inflammatory response to stroke (Aim 2); andoptimize our lipid removal approach within the area of chronic inflammation to improve recovery and preventdelayed cognitive impairment (Aim 3).