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。中风后，有一种慢性炎症反应，这种反应在中风后加剧。 在动物模型中，中风损伤会导致迟发性认知障碍。因此，慢性炎症性疾病 对中风的反应是一种潜在的VCID。我们最近证明，在分子水平上，慢性 中风的炎症反应与动脉粥样硬化的炎症反应非常相似。在这方面，众所周知， 髓系细胞内过载的脂质处理是动脉粥样硬化的驱动因素，其特征是 巨噬细胞内脂代谢紊乱与高浓度神经毒性细胞因子的产生 和降解酶。脂类是髓鞘的主要结构成分，因此是主要的 人脑的组成成分。因此，我们的主要假设是中风后， 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淹没 源于髓鞘和细胞膜的破坏，从而导致慢性炎症 上述响应。我们认为，细胞因子和降解酶的渗透产生 邻近脑区的梗塞是脑软化症的主要原因，或称软化， 这种情况发生在慢性中风梗死周围的组织上。因此，帮助吞噬细胞的治疗 加工过程中脑组织分解产生的大量脂质碎片可能会使慢性 对中风的炎症反应和保护周围的脑组织，从而促进更健康的愈合 大脑和提高恢复力。在梗塞位于大脑区域内或邻近区域的情况下 这种治疗对认知很重要，甚至可以预防痴呆症。因此，这项提议的目标是 确定由脂质分解产生的促炎脂质种类和触发的途径 卒中后大脑的组成部分(目标1)；确定促炎脂质感受器在 推动中风的慢性炎症反应(目标2)；并确定是否有脂质清除和免疫 慢性炎症区域内的细胞转录重新编程可以促进中风和 预防延迟性认知损害(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).