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

项目概要/摘要 脑淀粉样血管病 (CAA) 是一种阿尔茨海默病相关痴呆 (ADRD)。的 淀粉样蛋白沉积在大脑血管周围会导致 CAA。 CAA 的特点是 由大脑中的小皮层微出血引起，这不仅会导致毁灭性的自发性 脑出血，还会导致老年人血管性痴呆。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 淀粉样蛋白沉积物主要存在于脑实质而非脑实质的疾病 脑血管疾病，已越来越被认为是一种性二态性疾病。 在 AD 患者中，女性在言语记忆任务上表现不佳，但认知能力较快 与男性相比下降。然而，CAA 并未对此类差异进行充分研究，CAA 具有以下共同点： 淀粉样蛋白沉积的疾病病理学非常相似。使用 CAA 小鼠模型，我们将研究 整个生命周期中 CAA 的潜在性别差异。我们将通过研究认知、核磁共振成像来做到这一点 以及不同年龄段大脑中淀粉样蛋白的负担。目标是理解复杂的 性别和年龄在 CAA 进展中的相互作用。 与许多其他疾病一样，CAA 病理机制在男性和女性中可能有所不同。 已知纤溶途径参与阿尔茨海默病中淀粉样蛋白的清除 疾病。我们发现这条途径是两性二态的。我们最初的重点是 纤溶酶原激活剂抑制剂 1 (PAI-1)，是组织纤溶酶原激活剂的抑制剂 激活纤溶酶原并协助淀粉样蛋白清除。在本提案中，我们将使用 药理学抑制和 PAI-1 基因缺失小鼠以确定 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理解上的空白 CAA 病理学和血管性痴呆中的性别二分法，并协助发展 性别特异性疗法。

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.