Ávila-Gómez Paulo, Shingai Yuto, Dash Sabyasachi, Liu Catherine, Callegari Keri, Meyer Heidi, Khodarkovskaya Anne, Aburakawa Daiki, Uchida Hiroki, Faraco Giuseppe, Garcia-Bonilla Lidia, Anrather Josef, Lee Francis S, Iadecola Costantino, Sanchez Teresa
bioRxiv. 2024 Jun 1:2024.05.28.596050. doi: 10.1101/2024.05.28.596050.
Systemic inflammation has been implicated in the development and progression of neurodegenerative conditions such as cognitive impairment and dementia. Recent clinical studies indicate an association between sepsis, endothelial dysfunction, and cognitive decline. However, the investigations of the role and therapeutic potential of the cerebral microvasculature in systemic inflammation-induced cognitive dysfunction have been limited by the lack of standardized experimental models for evaluating the alterations in the cerebral microvasculature and cognition induced by the systemic inflammatory response. Herein, we validated a mouse model of endotoxemia that recapitulates key pathophysiology related to sepsis-induced cognitive dysfunction, including the induction of an acute systemic hyperinflammatory response, blood-brain barrier (BBB) leakage, neurovascular inflammation, and memory impairment after recovery from the systemic inflammatory response. In the acute phase, we identified novel molecular (e.g. upregulation of plasmalemma vesicle associated protein, a driver of endothelial permeability, and the pro-coagulant plasminogen activator inhibitor-1, PAI-1) and functional perturbations (i.e., albumin and small molecule BBB leakage) in the cerebral microvasculature along with neuroinflammation. Remarkably, small molecule BBB permeability, elevated levels of PAI-1, intra/perivascular fibrin/fibrinogen deposition and microglial activation persisted 1 month after recovery from sepsis. We also highlight molecular neuronal alterations of potential clinical relevance following systemic inflammation including changes in neurofilament phosphorylation and decreases in postsynaptic density protein 95 and brain-derived neurotrophic factor suggesting diffuse axonal injury, synapse degeneration and impaired neurotrophism. Our study serves as a standardized model to support future mechanistic studies of sepsis-associated cognitive dysfunction and to identify novel endothelial therapeutic targets for this devastating condition.
The limited knowledge of how systemic inflammation contributes to cognitive decline is a major obstacle to the development of novel therapies for dementia and other neurodegenerative diseases. Clinical evidence supports a role for the cerebral microvasculature in sepsis-induced neurocognitive dysfunction, but the investigation of the underlying mechanisms has been limited by the lack of standardized experimental models. Herein, we optimized a mouse model that recapitulates important pathophysiological aspects of systemic inflammation-induced cognitive decline and identified key alterations in the cerebral microvasculature associated with cognitive dysfunction. Our study provides a reliable experimental model for mechanistic studies and therapeutic discovery of the impact of systemic inflammation on cerebral microvascular function and the development and progression of cognitive impairment.
全身炎症与认知障碍和痴呆等神经退行性疾病的发生和发展有关。最近的临床研究表明败血症、内皮功能障碍和认知衰退之间存在关联。然而，由于缺乏用于评估全身炎症反应引起的脑微血管系统改变和认知变化的标准化实验模型，对脑微血管系统在全身炎症诱导的认知功能障碍中的作用和治疗潜力的研究受到了限制。在此，我们验证了一种内毒素血症小鼠模型，该模型概括了与败血症诱导的认知功能障碍相关的关键病理生理学，包括急性全身高炎症反应的诱导、血脑屏障（BBB）渗漏、神经血管炎症以及全身炎症反应恢复后的记忆障碍。在急性期，我们在脑微血管系统中发现了新的分子（例如，上调血浆膜囊泡相关蛋白，一种内皮通透性的驱动因子，以及促凝血纤溶酶原激活物抑制剂-1，PAI-1）和功能扰动（即白蛋白和小分子BBB渗漏）以及神经炎症。值得注意的是，小分子BBB通透性、PAI-1水平升高、血管内/血管周围纤维蛋白/纤维蛋白原沉积和小胶质细胞激活在败血症恢复后1个月仍持续存在。我们还强调了全身炎症后具有潜在临床相关性的分子神经元改变，包括神经丝磷酸化的变化以及突触后密度蛋白95和脑源性神经营养因子的减少，提示弥漫性轴突损伤、突触退化和神经营养受损。我们的研究作为一个标准化模型，以支持未来对败血症相关认知功能障碍的机制研究，并为这种破坏性疾病确定新的内皮治疗靶点。
关于全身炎症如何导致认知衰退的知识有限是痴呆和其他神经退行性疾病新疗法开发的主要障碍。临床证据支持脑微血管系统在败血症诱导的神经认知功能障碍中的作用，但由于缺乏标准化实验模型，对潜在机制的研究受到了限制。在此，我们优化了一种小鼠模型，该模型概括了全身炎症诱导的认知衰退的重要病理生理学方面，并确定了与认知功能障碍相关的脑微血管系统的关键改变。我们的研究为全身炎症对脑微血管功能的影响以及认知障碍的发生和发展的机制研究和治疗发现提供了一个可靠的实验模型。
