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

项目总结/摘要 脑淀粉样血管病（CAA）是阿尔茨海默病相关性痴呆（ADRD）。的 淀粉样蛋白在脑血管周围的沉积导致CAA。CAA的特点是 大脑皮层微出血，这不仅会导致毁灭性的自发性 脑内血管病，但也有助于老年人的血管性痴呆。因此，我们认为， 这种疾病的死亡率和残疾负担很高。有趣的是，阿尔茨海默病（AD），一种 淀粉样蛋白沉积主要在脑实质中而不是脑实质中的疾病 脑血管疾病，已越来越多地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中表现不佳，并且具有更快的认知能力。 与男性相比下降。然而，这种差异在CAA中没有得到充分研究，CAA与CAA共享一个 与淀粉样蛋白沉积非常相似的疾病病理学。使用CAA小鼠模型，我们将研究 CAA在整个生命周期中的潜在性别差异。我们将通过研究认知，核磁共振成像 和淀粉样蛋白的含量。我们的目标是了解复杂的 CAA进展中性别和年龄的相互作用。 与许多其他疾病一样，CAA病理机制在男性和女性中可能不同。 纤维蛋白溶解途径是已知的参与清除淀粉样蛋白在阿尔茨海默氏症 疾病我们已经发现这条途径是两性异形的。我们的重点将首先放在 纤溶酶原激活物抑制剂1（PAI-1），其是组织纤溶酶原激活物的抑制剂 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基因缺失的小鼠，以确定PAI-1是否是 可行的CAA性别特异性药物靶点。这项研究旨在填补我们对以下问题的理解上的差距： CAA病理学和血管性痴呆中的性别二分法，并有助于 性特异性治疗

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.