Inflammation and delayed cognitive dysfunction after stroke

项目摘要 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。然而，血管对认知障碍的贡献， 痴呆症（VCID）仍不清楚。中风后，有一种慢性炎症反应， 在动物模型中，中风损伤导致延迟的认知障碍。因此，慢性炎症 对中风的反应是潜在的VCID。我们最近证明，在分子水平上， 中风的炎症反应与动脉粥样硬化非常相似。在这方面，众所周知， 髓样细胞内过度的脂质加工是动脉粥样硬化的驱动因素，其特征是 巨噬细胞内脂质代谢失调和高浓度神经毒性细胞因子的产生 和降解酶。脂质是髓鞘的主要结构成分，因此是主要的 人类大脑的组成部分。因此，我们的总体假设是，中风后， 巨噬细胞和常驻的小胶质细胞被大量的胆固醇和其他脂质所淹没 来源于髓鞘和细胞膜的分解，结果导致慢性炎症 上面描述的答案。我们认为，细胞因子和降解酶的渗透产生 脑梗塞内进入邻近脑区是脑软化，或“软化”， 发生在慢性中风梗塞周围的组织。因此，帮助吞噬细胞 处理脑组织分解产生的大量脂质碎片可能会缓和慢性 炎症反应中风和保护周围的脑组织，从而促进更健康的愈合 大脑和改善恢复。在梗塞位于脑内或邻近脑区的情况下， 这种治疗对认知很重要，甚至可以预防痴呆症。因此，本提案的目标是 确定脂质分解产生的促炎脂质种类和触发的途径 脑卒中后的脑成分（目标1）;定义促炎性脂质传感器在 驱动中风的慢性炎症反应（目的2）;并确定是否脂质清除和免疫 慢性炎症区域内的细胞转录重编程可以改善中风的恢复， 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. 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).