Sexual Dimorphism in Cerebral Amyloid Angiopathy and Vascular Dementia: Investigating the Role of Fibrinolytic System

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)。这个 淀粉样蛋白在脑血管周围沉积导致CAA。CAA的特点是 通过大脑中微小的皮质微出血，这不仅会导致毁灭性的自发 脑内出血，也是导致老年人血管性痴呆的原因。因此， 这种疾病具有很高的死亡率和残疾负担。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脑实质的疾病 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，女性在言语记忆任务中表现不佳，认知能力较强 与男性相比有所下降。然而，这种差异在CAA中没有得到充分的研究，它有一个共同的 淀粉样蛋白沉积的疾病病理非常相似。利用CAA的小鼠模型，我们将研究 CAA患者一生中潜在的性别差异。我们将通过研究认知、核磁共振来实现这一点 以及不同年龄段大脑中的淀粉样蛋白负荷。我们的目标是理解这个复杂的 性别和年龄在CAA进展中的交互作用。 像许多其他疾病一样，CAA的病理机制可能在男性和女性中有所不同。 已知纤溶途径参与阿尔茨海默病患者淀粉样蛋白的清除 疾病。我们发现这条途径是性二态的。我们最初的重点将是 纤溶酶原激活物抑制物1(PAI-1)，它是组织纤溶酶原激活物的抑制物 它能激活纤溶酶原并帮助清除淀粉样蛋白。在本提案中，我们将使用 药理抑制和小鼠PAI-1基因缺失来确定PAI-1是否是 CAA可行的性别特异性药物靶点。这项研究旨在填补我们对 慢性再生障碍性贫血与血管性痴呆的性别二分法及其对发展的帮助 针对性别的治疗。

PROJECT SUMMARY/ ABSTRACT Cerebral amyloid angiopathy (CAA) is an Alzheimer's disease related dementia (ADRD). 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. Therefore, this disease has a high mortality and disability burden. Interestingly, Alzheimer's disease (AD), a disease in which amyloid deposits are found predominantly in the brain parenchyma rather than 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. Using mouse models of CAA, we will study potential sex differences in CAA across the lifespan. We will do this by studying cognition, MRI and amyloid burden in the brain at different ages. The goal is to understand the complex interactions of sex and age in CAA progression. Like in many other diseases, the mechanism of CAA pathology may differ in males and females. The fibrinolytic pathway is known to be involved in the clearance of amyloid in Alzheimer's disease. We have found this pathway is sexually dimorphic. Our focus will initially be on Plasminogen Activator Inhibitor 1 (PAI-1), which is an inhibitor of tissue plasminogen activator that activates plasminogen and assists in amyloid clearance. In this proposal, we will use pharmacological inhibition and mice with genetic deletion of PAI-1 to determine if PAI-1 is a viable sex specific drug target for CAA. This study aims to fill the gap in our understanding of the sexual dichotomies in CAA pathology and vascular dementia and assist in development of sex specific therapies.