Neuroinflammatory mechanisms of aging-related vascular cognitive impairment (VCI)

项目摘要 血管认知障碍(VCI)是仅次于阿尔茨海默病的第二大痴呆病因 (Ad)。VCI的发病机制目前知之甚少，目前尚无特效的治疗方法来预防 或者治疗VCI。我们之前已经观察到酶可溶环氧化物的表达和活性增加。 人脑组织微血管内皮细胞水解酶活性的研究 VCI。我们还在老鼠身上观察到，高脂饮食(HFD)诱导的2型糖尿病会导致类似的增加 在脑血管疾病中。我们的初步数据表明，具有结构性过度表达的转基因小鼠 人血管内皮细胞中的sEH(Tie2-hsEH)会损害空间记忆(Morris水迷宫)，这表明 内皮细胞高血压与认知障碍有因果关系。拟议的研究将确定内皮细胞sEH 上调通过脑组织渗透介导的神经炎性机制损害认知 单核细胞来源的巨噬细胞。研究还将确定具有内皮特异性sEH缺失的小鼠 (Tie2-CRE/FLOXED-sEH)可防止HFD诱导的神经元丢失、神经炎症和认知 减损。最后，我们将使用两种不同的疗法，一种旨在抑制sEH，另一种旨在预防 单核/巨噬细胞渗透，以确定这些药物是否可以预防(如果在认知之前给予 Tie2-hsEH小鼠的年龄相关认知缺陷(在认知障碍后给予)或逆转(如果给予) 和野生型小鼠服用HFD。

Project Summary Vascular cognitive impairment (VCI) is the second most common cause of dementia after Alzheimer's disease (AD). The mechanisms underlying VCI are poorly understood, with no specific therapy currently exists to prevent or treat VCI. We have previously observed increased expression and activity of the enzyme soluble epoxide hydrolase (sEH) in microvascular endothelium of human brain tissue from deceased patients with pre-mortem VCI. We have also observed in mice that high-fat diet (HFD)-induced type 2 diabetes causes a similar increase in cerebrovascular sEH. Our preliminary data demonstrate that transgenic mice with constitutive overexpression of human sEH in endothelium (Tie2-hsEH) have impaired spatial memory (Morris Water Maze), suggesting that endothelial sEH is causally linked to cognitive impairment. Proposed studies will determine if endothelial sEH upregulation impairs cognition by a neuro-inflammatory mechanism mediated by infiltration of brain tissue by monocyte-derived macrophages. Studies will also determine if mice with endothelial-specific deletion of sEH (Tie2-Cre/floxed-sEH) are protected from HFD-induced neuronal loss, neuroinflammation and cognitive impairment. Finally, we will use two different therapies, one aimed at inhibiting sEH and one aimed at preventing monocyte/macrophage infiltration, to determine if these agents can prevent (when given prior to cognitive decline) or reverse (when given after cognitive impairment) the age-related cognitive deficit in Tie2-hsEH mice and wild-type mice on HFD.