Inflammation and delayed cognitive dysfunction after stroke - 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. We have shown that there is a chronic inflammatory response following stroke
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 due to the
presence of foam cells, cholesterol crystals, and very similar expression of specific cytokines and degradative
enzymes. 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 other 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
optimize our lipid removal approach within the area of chronic inflammation to improve recovery and prevent
delayed cognitive impairment (Aim 3).
