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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Alzheimer&apos 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

Age Age Months Aging Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Alzheimer&apos 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

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项目摘要

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）是患有阿尔茨海默氏病有关的痴呆症（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通向CAA。 CAA的特征是大脑中的小皮质微粒仅导致毁灭性自发的脑出血，但也有助于老年人的血管痴呆。有趣的是，阿尔茨海默氏病（AD），一种疾病淀粉样蛋白沉积物主要在脑实质中，而不是在大脑中血管越来越被认为是一种性二态性疾病。在广告患者中，妇女在口头记忆任务上的表现不佳，与男人。但是，这种差异在CAA中被研究了，它具有非常相似的疾病淀粉样沉积的病理学。我们和其他人在鼠标模型中发现性别差异 CAA在整个生命周期中。我们发现纤维蛋白水解和炎症途径是 CAA小鼠模型中的性二态性。该项目的重点将放在纤维蛋白原上，已知会在淀粉样蛋白沉积部位积聚，并激活小胶质细胞，导致炎症，微粒，纤维化和进一步的认知下降。在此提案中，我们将使用老鼠纤维蛋白原的遗传缺失以确定纤维蛋白诱导的炎症在 CAA。我们还将使用该药物使用CAA的小鼠对纤维蛋白/纤维化的药理抑制作用 Pirfenidone，目前已批准用于肺纤维化患者。通过使用遗传和药理学操纵，我们将检查纤维蛋白与小胶质细胞及其下游炎症途径。我们还将研究这一点的效果认知的相互作用，大脑中的微孔人数量和淀粉样蛋白负担在不同年龄段在男性和女性中。这将是理解复杂互动的第一步这些与CAA进展的性别和年龄的途径。这项工作将填补我们的空白了解CAA病理学和血管中性别差异的潜在机制痴呆症，可能导致这种毁灭性疾病的性别疗法的发展。