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

项目摘要 血管性认知功能障碍（VCI）是仅次于阿尔茨海默病的第二大常见痴呆病因 （AD）。VCI的潜在机制知之甚少，目前没有特异性治疗方法来预防 或治疗VCI。我们先前已经观察到可溶性环氧化物酶的表达和活性增加， 人死后脑组织微血管内皮细胞sEH表达 VCI。我们还在小鼠中观察到，高脂饮食（HFD）诱导的2型糖尿病也会导致类似的增加。 脑血管sEH。我们的初步数据表明，组成型过表达的转基因小鼠， 人sEH内皮细胞（Tie 2-hsEH）的空间记忆受损（Morris水迷宫），表明 内皮sEH与认知损害有因果关系。拟议的研究将确定内皮sEH 上调通过神经炎性机制损害认知，所述神经炎性机制由脑组织浸润介导， 单核细胞衍生的巨噬细胞。研究还将确定内皮特异性sEH缺失的小鼠是否 （Tie 2-Cre/caseed-sEH）受到保护免于HFD诱导的神经元损失、神经炎症和认知功能障碍。 损伤最后，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 单核细胞/巨噬细胞浸润，以确定这些药物是否可以预防（当在认知障碍之前给予时）。 下降）或逆转（当在认知损伤后给予时）Tie 2-hsEH小鼠中与年龄相关的认知缺陷 和野生型小鼠进行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.