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

脑淀粉样血管病性别差异的潜在机制：纤维蛋白-小胶质细胞串扰

• 批准号: 10662862
• 负责人: Bharti Manwani
• 金额: $ 56.71万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662862
• 关键词: Age; Age Months; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Amyloid deposition; Biological; Blood; Blood Vessels; Brain; Brain Pathology; Cerebral Amyloid Angiopathy; Cerebral cortex; Cerebral hemisphere hemorrhage; Cerebrovascular system; Clinical; Cognition; Complex; Data; Dementia; Deposition; Development; Diagnosis; Disease; Disease Progression; Drug usage; Elderly; Elderly woman; Enzyme-Linked Immunosorbent Assay; Female; Fibrin; Fibrinogen; Fibrosis; Flow Cytometry; Genetic; Hemorrhage; Histology; Human; ITGAM gene; ITGB2 gene; Immunohistochemistry; Impaired cognition; Inflammation; Inflammatory; Integrins; Interleukin-1 beta; Iowa; Lead; Ligands; Link; Longevity; Magnetic Resonance Imaging; Measurement; Mediating; Memory; Microglia; Modeling; Multiple Sclerosis; Mus; Nerve Degeneration; Neurons; Oral Administration; Outcome; Pathologic; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Pirfenidone; Plasma; Plasmin; Plasminogen Activator Inhibitor 1; Play; Prevalence; Probability; Pulmonary Fibrosis; Radial; Role; Severity of illness; Sex Differences; Site; Specificity; System; TNF gene; Testing; Therapeutic; Therapeutic Intervention; Tissue Sample; Transforming Growth Factor beta; Tunica Adventitia; Vascular Dementia; Widespread Disease; Woman; Work; abeta deposition; advanced disease; aged; amyloid pathology; arm; behavioral outcome; brain parenchyma; brain tissue; burden of illness; cerebral microbleeds; cognitive function; conditioned fear; design; disability burden; expectation; glial activation; immune cell infiltrate; inhibitor; lifetime risk; male; men; middle age; monocyte; mortality; mouse model; neuroprotection; novel; peripheral blood; pharmacologic; receptor; response; sex; sexual dimorphism; single-cell RNA sequencing; targeted treatment; verbal; water maze; β-amyloid burden

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.

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）， 高死亡率和残疾负担。淀粉样蛋白在血管周围的沉积， 大脑导致CAA。CAA的特征是大脑中的小皮质微出血， 不仅导致毁灭性的自发性脑内出血，而且还有助于 老年血管性痴呆有趣的是，阿尔茨海默病（AD），一种 淀粉样沉积物主要存在于脑实质中，而不是在大脑中。 血管，已越来越多地被认为是一种性二态性疾病。在AD患者中， 女性在非文字记忆任务中表现不佳，与男性相比， 男人然而，这种差异在CAA中没有得到充分研究，因为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已经发现，在小鼠模型中， CAA贯穿整个生命周期。我们已经发现，纤维蛋白溶解和炎症途径是 CAA小鼠模型中的性二态性。该项目的重点将是纤维蛋白原， 已知在淀粉样蛋白沉积的部位积累，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。在这个提案中，我们将使用老鼠 用纤维蛋白原的基因缺失，以确定纤维蛋白诱导的炎症的贡献， CAA。我们还将使用药物在CAA小鼠中使用纤维蛋白/纤维化的药理学抑制 吡非尼酮，目前已被批准用于肺纤维化患者。通过使用 遗传和药理学操作，我们将研究纤维蛋白与 小胶质细胞及其下游炎症通路。我们也将研究这一影响 在不同年龄对认知、微出血数量和脑中淀粉样蛋白负荷的相互作用 无论是男性还是女性。这将是理解复杂的相互作用的第一步， 这些途径与CAA进展中的性别和年龄有关。这项工作将填补我们的差距。 了解CAA病理学和血管病理学中性别差异的潜在机制， 痴呆症，并可能导致针对这种毁灭性疾病的性别特异性疗法的发展。