Glymphatic Clearance of Abeta is Impaired by Fibronectin in the Basement Membrane

Abeta 的类淋巴清除受到基底膜中纤连蛋白的损害

基本信息

批准号：
9429442
负责人：
Akihiko Urayama
金额：
$ 216.04万
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：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9429442
关键词：
Abeta clearance Affect Affinity Age-Months Aging Alzheimer&apos s Disease Amyloid beta-Protein Animals Astrocytes Astrocytosis Attenuated Automobile Driving Basement membrane Behavioral Bilateral Biochemical Blood - brain barrier anatomy Blood Vessels Blood capillaries Brain Cerebral Amyloid Angiopathy Cerebral hemisphere hemorrhage Cerebrospinal Fluid Cerebrum Contralateral Data Dementia Deposition Development Dextrans Disease Distal Elderly Endothelial Cells Exhibits Fibronectins Fibrosis Functional disorder Gliosis Global Change Goals Hemorrhage Human Impaired cognition Impairment Individual Injectable Injury Ischemic Stroke Knock-out Laboratories Lead Liquid substance Measures Mediating Microscopy Microvascular Dysfunction Middle Cerebral Artery Occlusion Modeling Monitor Mus Nerve Degeneration Pathology Patients Penetration Pharmacology Physiological Production Proteomics Pulsatile Flow Recurrence Research Route Secondary to Signal Transduction Stroke Structure Survivors Testing Tg2576 Tracer Transforming Growth Factor beta Receptors Transforming Growth Factors Trees Vascular Dementia Wild Type Mouse Work abeta accumulation abeta deposition age related aged arteriole astrogliosis base behavioral outcome capillary cerebrospinal fluid flow cerebrovascular driving force experimental study glymphatic system improved in vivo macromolecule mouse model new therapeutic target novel novel therapeutics older patient prevent public health relevance therapeutic target two-photon

项目摘要

PROJECT SUMMARY Cerebral amyloid angiopathy (CAA) is a neurodegenerative condition that is characterized by the deposition of toxic amyloid-β aggregates in the basement membrane (BM) of brain arterioles and capillaries, leading to recurrent stroke, cerebral hemorrhage and cognitive decline in patients. CAA may develop in part from impaired clearance of amyloid-β from the BM blood vessels after stroke. The recently discovered glymphatic system facilitates the clearance of amyloid-β by enabling the bulk flow of cerebrospinal fluid (CSF) within the BM of cerebral vessels. It is not known whether BM fibrosis alters the clearance of amyloid-β through the glymphatic system. We hypothesize that stroke induces global perivascular reactive astrocytosis and fibrosis via enhanced systemic TGF-β signaling, and that this is increased with aging. It is further hypothesized that BM fibrosis impairs glymphatic flow, leading to reduced clearance of amyloid-β. Το assess the global effects of stroke on the BM, glymphatic flow and amyloid-β clearance, distal middle cerebral artery occlusion (pDMCAO) will be performed in young and aged mice. We will examine if stroke alters BM composition via increased TGF-β signaling in perivascular astrocytes in mice, and determine whether inhibition of TGF-β signaling in astrocytes prevents these changes and enhances the clearance of amyloid-β. The effect of stroke-induced fibrosis on glymphatic flow and clearance of injected amyloid-β will be evaluated. Preliminary data indicates that unilateral stroke in young mice induces profound changes in the contralateral cortex, including enhanced TGF-β (Smad2/3) signaling, reactive astrocytosis, and BM fibronectin deposition. Furthermore, these changes were associated with reduced penetration of injected CSF dextran tracers, indicating impaired glymphatic flow. Finally, injected CSF amyloid- β exhibited a higher association with the BM after stroke. Based on these data and work from our laboratory showing enhanced gliosis in aged animals after stroke, it is expected that stroke will further impair glymphatic amyloid-β clearance in aged animals due to increased fibrosis, leading to progressive cognitive decline. As a final proof of concept, we will utilize a mouse model of CAA to determine if stroke-induced changes in the BM leads to accelerated CAA pathology. This research is significant as it identifies BM fibrosis as a novel mechanism of glymphatic impairment and amyloid-β accumulation, providing an elusive ‘driving force’ in the development of CAA that is translationally relevant in understanding how disease progresses in elderly individuals, as well as those suffering from ischemic stroke. If successful, this study will identify TGF-β inhibition as a potential disease- modifying therapy to reduce fibrosis, enhance glymphatic flow and reduce CAA.

项目摘要脑淀粉样血管病（CAA）是一种神经退行性疾病，其特征在于沉积脑小动脉和毛细血管的基底膜（BM）中的有毒淀粉样蛋白β聚集体，导致患者的复发性中风，脑出血和认知能力下降。 CAA可能会因受损而部分发展中风后从BM血管中清除淀粉样蛋白-β。最近发现的糖基系统通过在BM内实现脑脊液（CSF）的大部分流动来促进淀粉样蛋白β的清除脑视频。尚不清楚BM纤维化是否会通过糖胶质改变淀粉样蛋白的清除率系统。我们假设中风会通过增强引起全局血管性反应性星形胶质细胞增多和纤维化全身性TGF-β信号传导，并且随着衰老而增加。进一步假设BM纤维化会损害胶状流，导致淀粉样蛋白β的清除降低。 το评估中风对BM的全球影响，胶囊流量和淀粉样蛋白β清除率，远端大脑动脉闭塞（PDMCAO）将进行在年轻小鼠中。我们将检查中风是否通过增加的TGF-β信号传导来改变BM组成小鼠的血管周星形胶质细胞，并确定抑制星形胶质细胞中TGF-β信号传导是否可以防止这些变化并增强淀粉样蛋白β的清除率。中风诱导的纤维化对糖基流动的影响和将评估注射淀粉样蛋白β的清除。初步数据表明年轻小鼠单侧中风诱导对比皮层的深刻变化，包括增强的TGF-β（SMAD2/3）信号，反应性星形细胞增多症和BM纤连蛋白沉积。此外，这些变化与减少有关注射的CSF葡萄糖示踪剂的穿透，表明糖糖流量受损。最后，注射的CSF淀粉样蛋白 β在中风后与BM表现出较高的关联。基于这些数据并从我们的实验室工作在中风后显示出衰老动物的神经胶质增强，预计中风会进一步损害糖糖菌由于纤维化增加而导致老年动物的淀粉样蛋白β清除率，导致认知逐渐下降。作为最终的概念证明，我们将利用CAA的鼠标模型来确定中风诱导的BM的变化是否导致加速CAA病理。这项研究很重要，因为它将BM纤维化识别为一种新机制糖性损伤和淀粉样蛋白β的积累，在开发中提供了弹性的“驱动力” CAA与了解老年人以及疾病如何进展以及那些患有缺血性中风的人。如果成功，这项研究将确定TGF-β作为潜在疾病 - 修饰治疗以减少纤维化，增强糖基流量并减少CAA。