Endothelial Pannexin1 in Alzheimer’s Disease

项目摘要/摘要 阿尔茨海默病是老年人中最常见的痴呆症，与 脑血流量减少，导致慢性脑低灌流状态。阿尔茨海默氏症患者 疾病增加了缺血性中风的死亡率，可能是由于先前存在的脑血管功能障碍所致。 因此，有必要研究阿尔茨海默病血管功能障碍的调节机制，以 确定潜在的治疗靶点以减轻阿尔茨海默病患者的认知能力下降和缺血性损伤 疾病患者。阿尔茨海默病患者脑动脉过度收缩并增强 对核苷酸的反应，如三磷酸腺苷。脑血管内皮细胞中的PAnnexin1通道调节其释放 随后激活下游嘌呤能信号的ATP在血管系统中级联。Pannexin1 阿尔茨海默病小鼠模型的脑组织中蛋白质水平显著增加。我们 最近发现，内皮细胞PAnnexin1的缺失或抑制会降低大脑动脉的肌源性张力 改善脑血流。除了在大脑动脉血管中的作用外，嘌呤能信号还是一种 阿尔茨海默病和缺血性中风的神经炎症的关键调节因子。我们最近也有 血管内皮细胞PAnnexin1的缺失显著改善了缺血性卒中后的脑梗塞体积 通过减少白细胞的渗透。因此，内皮细胞PAnnexin1是大脑和大脑的中枢调节因子 动脉血管张力与缺血性卒中后炎症。然而，内皮细胞PAnnexin1在 阿尔茨海默病及其相关的缺血性中风在阿尔茨海默病期间是完全未知的。我们 假设脑内皮细胞PAnnexin1参与血管功能障碍的发生和发展 阿尔茨海默病中血管张力和炎症增加导致的缺血性卒中严重程度。我们将使用两个 旨在测试这一新颖的概念。目标1将确定内皮细胞PAnnexin 1在调节脑血管中的作用 阿尔茨海默病发展过程中的音调和脑血流。使用阿尔茨海默氏症的小鼠模型 疾病，APP/PS1转基因小鼠，与我们的新转基因小鼠杂交，条件缺失或 过表达内皮Pannexin1，我们将检查认知和生化特征的发展 对阿尔茨海默病的诊断和评估脑动脉肌张力和脑血流量。Aim 2将检查 阿尔茨海默病期间血管内皮细胞膜联蛋白1在缺血性卒中和神经炎症中的作用。我们会 在我们的阿尔茨海默病转基因小鼠中检查缺血性中风的结果，评估治疗前后 缺血性中风神经炎。我们的研究成功完成了将内皮细胞Panx1鉴定为新的 阿尔茨海默病脑血管功能调节因子可能成为未来治疗的靶点 阿尔茨海默病患者改善认知功能和减少缺血性卒中损伤的干预。

PROJECT SUMMARY/ABSTRACT Alzheimer’s Disease is the most prevalent form of dementia in the elderly and is associated with significantly reduced cerebral blood flow resulting in a chronic state of cerebral hypoperfusion. Patients with Alzheimer’s Disease have increased mortality from ischemic stroke possibly due to preexisting cerebral vascular dysfunction. Thus, it is necessary to examine the mechanisms regulating vascular dysfunction in Alzheimer’s Disease to identify potential therapeutic targets to mitigate cognitive decline and reduce ischemic injury in Alzheimer’s Disease patients. Cerebral arteries become hyperconstrictive in Alzheimer’s Disease and have enhanced responses to nucleotides, such as ATP. Pannexin1 channels in cerebral endothelial cells regulate the release ATP, which subsequently activates downstream purinergic signaling cascades in the vasculature. Pannexin1 protein levels are significantly increased in cerebral tissue from mouse models of Alzheimer’s Disease. We recently discovered that deletion or inhibition of endothelial Pannexin1 reduces cerebral artery myogenic tone to improve cerebral blood flow. In addition to the role in the cerebral arterial vasculature, purinergic signaling is a critical regulator of neuroinflammation in both Alzheimer’s Disease and ischemic stroke. We have also recently demonstrated that deletion of endothelial Pannexin1 profoundly improves post-ischemic stroke infarct volume through a reduction in leukocyte infiltration. Thus, endothelial Pannexin1 is a central regulator of both cerebral arterial vascular tone and post-ischemic stroke inflammation. However, the role of endothelial Pannexin1 in Alzheimer’s Disease and associated ischemic stroke during Alzheimer’s Disease is entirely unknown. We hypothesize that cerebral endothelial Pannexin1 contributes to the development of vascular dysfunction and ischemic stroke severity in Alzheimer’s Disease by increasing vascular tone and inflammation. We will use two aims to test this novel concept. Aim 1 will define the role for endothelial Pannexin1 in regulating cerebral vascular tone and cerebral blood flow during development of Alzheimer’s Disease. Using a mouse model of Alzheimer’s Disease, the APP/PS1 transgenic mice, crossed with our novel transgenic mice conditionally lacking or overexpressing endothelial Pannexin1, we will examine the development of cognitive and biochemical hallmarks of Alzheimer’s Disease and evaluate cerebral arterial myogenic tone and cerebral blood flow. Aim 2 will examine the role of endothelial Pannexin1 in ischemic stroke and neuroinflammation during Alzheimer’s Disease. We will examine ischemic stroke outcome in our transgenic mice with Alzheimer’s Disease, evaluating pre- and post- ischemic stroke neuroinflammation. Successful completion of our study identifying endothelial Panx1 as a novel regulator of cerebral vascular function in Alzheimer’s Disease may provide a target for future therapeutic intervention to improve cognitive function and reduce ischemic stroke injury in Alzheimer’s Disease.