Inflammation and delayed cognitive dysfunction after stroke

项目总结 数十年的研究表明，包括中风在内的脑血管疾病与 随后的认知障碍和痴呆症。然而，血管对认知障碍的贡献和 痴呆症(VCID)仍不清楚。我们已经证明中风后会有慢性炎症反应。 这会加剧中风后的损伤，在动物模型中，会导致迟发性认知障碍。因此， 卒中的慢性炎症反应是一种潜在的VCID。我们最近在分子水平上证明了这一点 水平，中风的慢性炎症反应与动脉粥样硬化非常相似，这是由于 泡沫细胞、胆固醇结晶的存在，以及非常相似的特定细胞因子和降解物的表达 酵素。在这方面，众所周知，髓系细胞内过度的脂质处理是导致 动脉粥样硬化，其特征是巨噬细胞内脂质代谢紊乱，并产生高水平的 神经毒性细胞因子和降解酶的浓度。脂类是中药的主要结构成分。 因此，髓鞘是人类大脑的主要成分。因此，我们的首要假设是 中风后，渗入的巨噬细胞和驻留的小胶质细胞会被巨大的体积淹没 由于髓鞘和其他细胞膜的破裂而产生的胆固醇和其他脂质，因此， 引起上述慢性炎症反应。我们认为细胞因子和细胞因子的渗透 梗塞内产生的降解酶进入邻近的脑区是导致脑梗塞的主要原因。 脑软化症，或“软化”，发生在慢性中风梗死周围的组织。因此， 帮助吞噬细胞处理因细胞分解而产生的大量脂质碎片的治疗 脑组织可以缓和中风后的慢性炎症反应，保护周围的脑组织， 从而促进大脑更健康的愈合，促进康复。在梗塞所在的情况下 在对认知有重要影响的大脑区域内或附近，这样的治疗甚至可以预防痴呆症。 因此，这项建议的目标是确定产生的促炎脂质种类和途径 由中风后大脑脂质成分的分解触发(目标1)；定义个体 促炎脂质感受器在推动中风慢性炎症反应中的作用(目标2)；以及 优化我们在慢性炎症领域的去脂方法，以促进恢复和预防 迟发性认知障碍(目标3)。

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).