Mechanisms underlying Sex differences in Cerebral Amyloid Angiopathy: The Fibrin-Microglia Crosstalk

项目摘要/摘要 脑淀粉样血管病(CAA)是一种阿尔茨海默病相关性痴呆(ADRD)，具有 高死亡率和高残疾负担。血管周围淀粉样蛋白的沉积 大脑通向CAA。CAA的特点是大脑中有少量皮质微出血，而不是 不仅会导致毁灭性的自发性脑出血，而且还会导致 老年人中的血管性痴呆。有趣的是，阿尔茨海默病(AD)是一种 淀粉样蛋白沉积主要存在于脑实质，而不是大脑。 血管疾病，已被越来越多地认为是一种性二形性疾病。在AD患者中， 与女性相比，女性在言语记忆任务中表现不佳，认知能力下降更快 男人。然而，这种差异在CAA中没有得到充分的研究，CAA有着非常相似的疾病 淀粉样蛋白沉积的病理学。我们和其他人在小鼠模型中发现了性别差异 生命周期中的CAA。我们发现纤溶和炎症途径是 慢性再生障碍性贫血小鼠模型中的性二型。这个项目的重点将是纤维蛋白原，它 已知在淀粉样蛋白沉积部位积聚，并激活小胶质细胞，导致 炎症、微出血、纤维化和进一步的认知能力下降。在本提案中，我们将使用鼠标 用纤维蛋白原基因缺失来确定纤维蛋白诱导的炎症的作用 CAA。我们还将使用该药物对患有CAA的小鼠进行纤维蛋白/纤维化的药物抑制 吡非尼酮，目前被批准用于肺纤维化患者。通过使用 遗传和药物操作，我们将研究纤维蛋白与 小胶质细胞及其下游的炎症途径。我们还将研究这一点的影响 不同年龄对认知、脑内微出血数和淀粉样蛋白负荷的交互作用 无论是男性还是女性。这将是理解复杂相互作用的第一步 在CAA进展中，这些通路与性别和年龄有关。这项工作将填补我们在这方面的空白 对CAA病理和血管性别差异潜在机制的认识 痴呆症，并可能导致针对这种毁灭性疾病的性别特异性治疗的发展。

PROJECT SUMMARY/ ABSTRACT Cerebral amyloid angiopathy (CAA) is an Alzheimer's disease related dementia (ADRD) that has a high mortality and disability burden. The deposition of amyloid around the blood vessels in the brain leads to CAA. CAA is characterized by small cortical microbleeds in the brain, which not only leads to devastating spontaneous intracerebral hemorrhages, but also contributes to vascular dementia in the elderly. Interestingly, Alzheimer's disease (AD), a disease in which amyloid deposits are found predominantly in the brain parenchyma rather than in the cerebral blood vessels, has been increasingly recognized as a sexually dimorphic disease. In AD patients, women perform poorly on verbal memory tasks and have a faster cognitive decline compared to men. However, such differences are understudied in CAA, which shares a very similar disease pathology of amyloid deposition. We and others have found sex differences in mouse models of CAA across the lifespan. We have found that the fibrinolytic and inflammatory pathways are sexually dimorphic in mouse models of CAA. The focus of this project will be on fibrinogen, which is known to accumulate at sites of amyloid deposition, and activates microglia, leading to inflammation, microbleeds, fibrosis and further cognitive decline. In this proposal, we will use mice with genetic deletion of fibrinogen to determine the contributions of fibrin induced inflammation in CAA. We will also use pharmacological inhibition of fibrin/fibrosis in mice with CAA using the drug Pirfenidone, which is currently approved for use in patients with pulmonary fibrosis. By using genetic and pharmacological manipulation, we will examine the complex interaction of fibrin with microglia and it's downstream inflammatory pathways. We will also study the effect of this interaction on cognition, number of microbleeds and amyloid burden in the brain at different ages in both males and females. This will be the first step in understanding the complex interactions of these pathways with sex and age in CAA progression. This work will fill the gap in our understanding of the underlying mechanisms of sex differences in CAA pathology and vascular dementia and may lead to the development of sex specific therapies for this devastating disease.