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）相关的微血管病变。阿尔茨海默病（Alzheimer's disease，AD）是一种慢性神经退行性疾病，其特征在于细胞外淀粉样斑块、细胞内神经元缠结和神经元损失。还存在由淀粉样蛋白沉积组成的血管组分，其在血管系统中被称为脑淀粉样血管病（CAA）。经常观察到与CAA相关的微血管化。我们观察到对这些微血管的炎症反应，包括小胶质细胞和星形胶质细胞的活化。虽然淀粉样斑块和神经纤维缠结已经并将继续被广泛研究，但AD的血管成分仍然相对研究不足。本研究的目的是确定导致微出血的事件顺序。我们将通过使用两种转基因小鼠模型APPSwDI/ApoE 4和APPswe/NOS 2-/-来实现这一点。这些模型是特别有用的，因为APPSwDI/ApoE 4小鼠发展CAA但不发展任何微血管病变，而APPswe/N 0 S2-/-小鼠仅发展中度CAA，但发展多个微血管病变。我们将使用免疫组化和分子方法来建立病理和基因表达的时间过程。然后，我们将使用抗炎化合物来减少炎症，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具有显著淀粉样蛋白沉积的老年小鼠中进行这些研究，并将评估病理学或基因表达的任何变化。这将有助于我们确定阿尔茨海默病中微血管形成和神经血管单位破坏中血管淀粉样蛋白和炎症之间的关系。在抗炎研究中还将使用径向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。总的来说，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.