Identifying compounds that target APOE4 associated brain endothelial dysfunction

摘要 APOE基因型是几种神经退行性疾病的主要遗传危险因素。与APOE 3相比， APOE 4与老年人更大的认知功能障碍有关，增加阿尔茨海默病的风险， 加重血管性痴呆、中风和创伤性脑损伤的进展。有证据表明 在所有这些条件下，APOE 4在血脑屏障处的脑内皮细胞（BEC）功能障碍中的作用。BEC 功能障碍可通过破坏复杂的神经元稳态而导致神经元功能障碍 环境和通过蛋白质和其他毒素的进入，可以直接损害神经元，并通过对神经元的影响， 支持细胞。由于其独特的位置，BEC对来自大脑和血浆的信号敏感， 神经退行性疾病，其可能与炎症特别相关。事实上，APOE 4， 神经炎症、外周炎症和BEC功能障碍与痴呆密切相关 风险/进展。我们新的体外数据表明，APOE 4-BEC具有独特的基础表型， 导致它们的屏障功能被炎性刺激物破坏，这也是我们在体内发现的。基于 基于这些数据，我们的假设是APOE 4相关的BEC功能障碍是一种新的治疗靶点， 神经退行性疾病我们的目标是开发我们的体外试验（R61阶段）并进行筛选 和靶标鉴定（ID）（R33期），以鉴定减轻炎症诱导的炎症反应的新化合物。 APOE 4-BEC的渗透性破坏。我们的生物学原理是APOE 4使BEC倾向于 炎症诱导的屏障缺陷，从而增加成人发病的风险/进展 神经退行性疾病新颖之处在于我们针对炎症的分离方案和测定- 使用APOE 4-BEC诱导细胞旁通透性增加。临床相关性是APOE 4是一种 神经退行性疾病的风险因素，也有体内模型。因此有 靶向APOE 4相关BEC功能障碍的阳性命中从临床前到 临床研究。

ABSTRACT APOE genotype is a major genetic risk factor for several neurodegenerative disorders. Compared to APOE3, APOE4 is associated with greater cognitive dysfunction in older adults, increases Alzheimer's disease risk and exacerbates progression of vascular dementia, stroke, and traumatic brain injury. Evidence supports a major role of APOE4 in brain endothelial cell (BEC) dysfunction at the blood-brain barrier in all these conditions. BEC dysfunction can lead to neuronal dysfunction through disrupting the complex neuronal homeostatic environment and via entry of proteins and other toxins that can damage neurons directly and via effects on supporting cells. Due to their unique location, BEC are susceptible to signals from the brain and plasma in neurodegenerative disorders, which may be particularly relevant for inflammation. Indeed, APOE4, neuroinflammation, peripheral inflammation and BEC dysfunction are intimately linked to dementia risk/progression. Our novel in vitro data demonstrate that APOE4-BECs have a unique basal phenotype that results in disruption of their barrier function with inflammatory stimuli, which we have also found in vivo. Based on these data our hypothesis is that APOE4-associated BEC dysfunction is a novel therapeutic target for neurodegenerative disorders. Our goals are to develop our in vitro assays (R61 Phase) and conduct screening and target identification (ID) (R33 phase) to identify novel compounds that mitigate inflammation-induced permeability disruption in APOE4-BECs. Our biological rationale is that APOE4 predisposes BECs to inflammation-induced barrier deficits, thereby increasing the risk/progression of adult-onset neurodegenerative disorders. The novelty lies in our isolation protocols and assays to target inflammation- induced increases in paracellular permeability using APOE4-BECs. The clinical relevance is that APOE4 is a risk factor for neurodegenerative disorders for which there are also in vivo models. Therefore, there are pathways for the transition of positive hits targeting APOE4-associated BEC dysfunction from preclinical to clinical studies.