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STALLED CAPILLARY FLOW: A NOVEL MECHANISM FOR HYPOPERFUSION IN ALZHEIMER DISEASE

毛细血管血流停滞：阿尔茨海默病低灌注的一种新机制

基本信息

批准号：
9756240
负责人：
CHRIS B SCHAFFER
金额：
$ 32.73万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-15 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9756240
关键词：
Abeta clearance Acute Adhesions Affect Aftercare Age Albumins Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Amyloid beta-Protein Amyloid deposition Animal Diseases Animal Model Animals Antibodies Autopsy Autoradiography Blood Vessels Blood capillaries Blood flow Brain Brain Diseases Cells Cellular Stress Cerebrovascular Circulation Chronic Cognition Disorders Cognitive Cognitive deficits Control Animal Data Dementia Deposition Disease Progression Drops Encephalitis Endothelial Cells Endothelium Exposure to Feedback Fluorescence Fluorescence Microscopy Functional disorder Goals Grant Histology Human Image Impaired cognition Individual Inflammation Inflammatory Injections Label Lead Leukocytes Ligands Location Measures Mediating Microscopy Modeling Mus NADPH Oxidase Neurological outcome Outcome Pathologic Pathology Pathway interactions Patients Perfusion Physiological Plug-in Production Reactive Oxygen Species Regulation Research Senile Plaques Site Stress Superoxide Dismutase Symptoms Testing Time Toxic effect Transgenic Mice Transgenic Organisms Trees Work abeta accumulation adhesion receptor arteriole behavior test cell injury cell type cerebral capillary cerebrovascular cognitive function cognitive performance experimental study hypoperfusion improved improved functioning in vivo in vivo imaging macrophage monomer mouse model neuron loss neutrophil new therapeutic target novel novel therapeutics public health relevance receptor relating to nervous system therapeutic target two-photon vascular inflammation venule

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is characterized by a loss of cognitive function caused by the dysfunction and death of neurons and other cells in the brain. This cell injury is largely due to the toxic effects of aggregates of amyloid-beta (Aß), whch accumulates into dense plaques in the brain. There is also increased brain inflammation, mediated by reactive oxygen species (ROS) produced by cells stressed by Aß aggregates, suggesting that Aß aggregates create a toxic microenvironment that could affect many functions. Research in humans and in animals suggests that brain blood flow is reduced in AD by ~30%. Although it likely contributes to cognitive impairment and disease progression, no physiological explanation for this hypoperfusion has emerged. Chronic in vivo two-photon excited fluorescence microscopy was used to study cerebrovascular blood flow in mouse models of AD. While no blood flow disruption in cortical arterioles or venules were observed, blood flow was found to be stalled in an average of 1.8% of cortical capillaries in mouse models of AD, as compared to 0.25% in wild type controls (p<0.005). These capillary stalls appeared early in disease progression, before any amyloid deposition. Because one stalled capillary reduces flow in several downstream vessels, even ~2% of capillaries stalled could have a large impact on brain blood flow. Indeed, when leukocytes were depleted in AD mice and the fraction of capillary stalls dropped to near zero, brain blood flow improved by ~30%, suggesting that capillary stalling may cause brain hypoperfusion in AD. About 80% of the capillary stalls were caused by leukocytes that plugged a capillary segment, suggesting increased vascular inflammation in the AD brain as the mechanism that leads to capillary stalling. These data suggest a working model to explain the origin of hypoperfusion in AD: Aß accumulation leads to increased production of ROS that stresses endothelial cells and leads to increases in inflammatory receptors on the vessel lumen. This vascular inflammation causes leukocytes to adhere and plug capillaries, resulting in decreases in perfusion. This blood flow deficit could contribute to dementia independently of the direct effects of Aß and could also accelerate Aß aggregation by decreasing clearance of Aß monomers. In this proposal, this leukocyte plugging of capillaries in mouse models of AD is carefully characterized and then three important hypotheses are tested: First, that leukocyte adhesion occurs at sites of vascular inflammation that result from endothelial activation by ROS. Second, that the collective effect of the capillary plugs is to substantially reduce global cerebral blood flow and that blocking leukocyte adhesion can improve flow. Third, that eliminating capillary plugs and improving blood flow will lead to an acute improvement in cognitive performance and that chronically blocking capillary plugging over time will lead to decreased amyloid burden and chronically improved cognitive performance. The hypothesis that brain hypoperfusion in AD is due to leukocyte plugging in capillaries is both novel and supported by preliminary data, and directly suggests therapeutic targets that are complementary to anti-amyloid approaches.

描述（由申请人提供）：阿尔茨海默病（AD）的特征在于由脑中神经元和其它细胞的功能障碍和死亡引起的认知功能丧失。这种细胞损伤主要是由于淀粉样蛋白-β（AAPs）聚集体的毒性作用，其在脑中积累成致密斑块。也有增加的脑炎症，由活性氧（ROS）介导的细胞产生的压力，由Ablastine聚集体，这表明Ablastine聚集体创建一个有毒的微环境，可能会影响许多功能。对人类和动物的研究表明，AD患者的脑血流量减少了约30%。虽然它可能有助于认知障碍和疾病进展，但没有出现这种灌注不足的生理学解释。慢性在体双光子激发荧光显微镜用于研究AD小鼠模型的脑血管血流。虽然在皮质小动脉或小静脉中没有观察到血流中断，但发现AD小鼠模型中平均1.8%的皮质毛细血管中血流停滞，而野生型对照中为0.25%（p<0.005）。这些毛细血管失速出现在疾病进展的早期，在任何淀粉样蛋白沉积之前。由于一个停滞的毛细血管减少了几个下游血管的流量，即使是2%的毛细血管停滞也会对脑血流产生很大的影响。事实上，当AD小鼠中的白细胞耗尽并且毛细血管停滞的分数下降到接近零时，脑血流量改善约30%，这表明毛细血管停滞可能导致AD中的脑灌注不足。约80%的毛细血管失速是由堵塞毛细血管段的白细胞引起的，表明AD脑中血管炎症增加是导致毛细血管失速的机制。这些数据表明了一个解释AD中低灌注起源的工作模型：腺苷累积导致ROS产生增加，ROS对内皮细胞产生压力，并导致血管腔上炎性受体增加。这种血管炎症导致白细胞粘附并堵塞毛细血管，导致灌注减少。这种血流量不足可能导致痴呆，独立于Ablation的直接作用，也可能通过减少Ablation单体的清除而加速Ablation聚集。在这个建议中，这种白细胞堵塞的毛细血管在小鼠模型的AD仔细的特点，然后三个重要的假设进行了测试：首先，白细胞粘附发生在血管炎症的网站，导致由ROS内皮细胞激活。第二，毛细血管的集体效应栓塞的目的是实质上减少整体脑血流量，阻断白细胞粘附可以改善流量。第三，消除毛细血管堵塞和改善血液流动将导致认知能力的急性改善，并且随着时间的推移长期阻断毛细血管堵塞将导致淀粉样蛋白负担减少和认知能力的长期改善。AD中脑灌注不足是由于白细胞堵塞在毛细血管中的假设是新颖的，并且得到了初步数据的支持，并且直接表明了与抗淀粉样蛋白方法互补的治疗靶点。