Dysregulation of the neurovascular unit in Alzheimer's Disease.

描述(由申请人提供)：本提案研究与阿尔茨海默病(AD)相关的微出血。阿尔茨海默病(AD)是一种以细胞外淀粉样斑块、细胞内神经原纤维缠结和神经元丢失为特征的慢性神经退行性疾病。在血管系统中也有一个由淀粉样物沉积组成的血管成分，称为脑淀粉样血管病(CAA)。微出血常见于CAA。我们观察到对这些微小出血的炎症反应，包括小胶质细胞和星形胶质细胞的激活。虽然淀粉样斑块和神经原纤维缠结已经并将继续得到广泛的研究，但对AD的血管成分的研究相对较少。这项研究提案的目的是确定导致微出血的事件的顺序。我们将使用两个转基因小鼠模型APPSwDI/ApoE4和APPswe/NOS2-/-来探讨这一问题。这些模型特别有用，因为APPSwDI/ApoE4小鼠发生CAA但不发生任何微出血，而APPswe/NOS2-/-小鼠只发生中度CAA，但出现多发性微出血。我们将使用免疫组织化学和分子方法来建立病理和基因表达的时间进程。然后，我们将使用抗炎化合物来控制这些小鼠，以减少炎症，并使用脂多糖来诱导更多的炎症。我们将在淀粉样蛋白沉积之前的年轻小鼠和淀粉样蛋白沉积显著的老年小鼠中进行这些研究，并将评估任何病理或基因表达的变化。这将有助于我们确定在阿尔茨海默病微出血和神经血管单位崩溃的发展过程中血管淀粉样蛋白与炎症之间的关系。在抗炎研究中，还将使用放射臂水迷宫进行空间记忆测试，以确定这些血管变化的功能后果。总体而言，这项研究计划中将要进行的研究将促进对微出血原因和神经血管单位在阿尔茨海默病中的作用的理解。

DESCRIPTION (provided by applicant): This proposal studies microhemorrhages that are associated with Alzheimer's disease (AD). Alzheimer's disease (AD) is a chronic, neurodegenerative disease characterized by extracellular amyloid plaques, intracellular neurofibrillary tangles and neuron loss. There is also a vascular component consisting of amyloid deposition in the vasculature termed cerebral amyloid angiopathy (CAA). Microhemorrhages are frequently observed in association with CAA. We observe an inflammatory response to these microhemorrhages consisting of activation of microglia and astrocytes. While the amyloid plaques and neurofibrillary tangles have been, and continues to be, extensively studied, the vascular component of AD remains relatively understudied. The aim of this research proposal is to determine the sequence of events leading to microhemorrhage. We will approach this by using two transgenic mouse models, the APPSwDI/ApoE4 and the APPswe/NOS2-/-. These models are particularly useful since the APPSwDI/ApoE4 mouse develops CAA but does not develop any microhemorrhages while the APPswe/NOS2-/- mouse develops only moderate CAA, but multiple microhemorrhages. We will use immunohistochemical and molecular methods to establish a time-course of pathology and gene expression. We will then manipulate these mice using anti-inflammatory compounds to reduce inflammation and also lipopolysaccharide to induce more inflammation. We will perform these studies in young mice, prior to amyloid deposition, and old mice, with significant amyloid deposition, and will assess any changes in pathology or gene expression. This will assist us in determining the relationship between vascular amyloid and inflammation in the development of microhemorrhages and breakdown of the neurovascular unit in Alzheimer's disease. Spatial memory testing using the radial-arm water maze will also be performed in the anti-inflammatory study to determine the functional consequence of these vascular changes. Overall, the studies to be performed in this research proposal will advance the understanding of the causes of microhemorrhage and the role of the neurovascular unit in Alzheimer's disease.