Role of Microvascular Lesions in Alzheimer's Disease

微血管病变在阿尔茨海默病中的作用

• 批准号: 8140740
• 负责人: Nozomi Nishimura
• 金额: $ 5.77万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-14 至 2013-02-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8140740
• 关键词: Ablation; Address; Affect; Alzheimer' s Disease; Amyloid; Animal Model; Animals; Antibodies; Autopsy; Biological; Biological Assay; Blood Vessels; Blood capillaries; Blood flow; Brain; Cells; Cerebrovascular Disorders; Cerebrum; Characteristics; Clinical; Clinical Research; Coagulation Process; Cognition Disorders; Data; Dementia; Deposition; Development; Diabetic Angiopathies; Disease; Disease Progression; Disease model; Elderly; Erythrocytes; Extravasation; Fluorescence; Fluorescence Microscopy; Functional disorder; Future; Health; Hemorrhage; Histology; Image; Impaired cognition; Individual; Inflammation; Inherited; Injury; Label; Lasers; Lesion; Life; Link; Location; Maps; Measures; Methods; Microglia; Modeling; Molecular; Mus; Optics; Pathogenesis; Pathology; Patients; Peptides; Physiologic pulse; Play; Predisposition; Production; Proteins; Reactive Oxygen Species; Relative (related person); Rodent; Role; Seeds; Senile Plaques; Severities; Surface; Techniques; Testing; Time; Transgenic Mice; Transgenic Organisms; Traumatic Brain Injury; Trees; Vascular Dementia; Vascular Diseases; Work; abeta accumulation; aged; arteriole; capillary; cell type; hydroethidine; in vivo; mouse model; novel; prevent; research study; tool; two-photon; venule

DESCRIPTION (provided by applicant): Recently, cerebral microvessel disease has been identified as an important component of Alzheimer's disease. The mechanism of interaction between the diseases is still unclear in part because animal models of microvascular disease are lacking. The proposed work studies the interrelationship between microvascular damage and the accumulation of Ap, the dominant characteristic of Alzheimer's disease. This work builds on the clinical observation that the severity of dementia in Alzheimer's disease is often related to the presence of vascular disease. We use novel optical tools to induce microvascular lesions in transgenic mouse models of Alzheimer's disease and then image the progression of the resulting pathology. Our lesioning technique, femtosecond laser ablation, can disrupt individual microvessels as deep as 500 pm beneath the cortical surface. The study includes multiple types of microvascular lesions, including hemorrhages, ischemic occlusions and transient leakages, all of which potentially contribute to disease progression. Two-photon excited fluorescence microscopy is used to image amyloid plaque development and to measure blood flow and leakage in the microvasculature. This allows time-lapsed study of both the microvascular lesion and amyloid plaque. Post-mortem labeling with A(3 antibodies will be used to further elucidate the impact of the microvascular lesion on Ap accumulation. In Aim 1, we test whether microvascular clots and hemorrhages trigger rapid amyloid plaque formation at different locations in the vascular tree. In Aim 2, we ask if vascular lesions earlier in life can induce a predisposition to plaques later. In the final aim, we determine where plaques that are seeded by vascular lesions are relative to different cell types and determine whether inflammation or reactive oxygen species are factors through colocalization studies. In addition, we use histological and immunohistological assays to identify the affected cells and map the Ap accumulation. Our preliminary findings predict that the presence of a microvascular clot will accelerate the local deposition of Ap plaques. These data suggest that microvascular lesions could play an important role in Alzheimer's disease pathogenesis. Relevance ~ Alzheimer's disease is the most common cause of dementia in the elderly. Clinically, Alzheimer's disease is often entangled with vascular disease, suggesting that the two diseases are intimately interrelated. In many patients, sucessful treatment will have to address both aspects. This work investigates how the two conditions might worsen each other and will help identify strategies for preventing dementia.

描述（由申请人提供）：最近，脑微血管疾病已被确定为阿尔茨海默氏病的重要组成部分。疾病之间相互作用的机制仍然不清楚，部分原因是缺乏微血管疾病的动物模型。拟议的工作研究微血管损伤与AP的积累之间的相互关系，AP的积累是阿尔茨海默氏病的主要特征。这项工作的基础是临床观察，即阿尔茨海默氏病的痴呆症的严重程度通常与血管疾病的存在有关。我们使用新颖的光学工具来诱导阿尔茨海默氏病的转基因小鼠模型中的微血管病变，然后对所得病理的进展进行想象。我们的病变技术，即飞秒激光消融，可能会破坏在皮质表面下方500 pm深处的单个微血管。该研究包括多种类型的微血管病变，包括出血，缺血性阻塞和瞬态泄漏，所有这些都可能导致疾病进展。两光子激发荧光显微镜用于成像淀粉样菌斑的发育，并测量微脉管系统中的血流和泄漏。这允许对微血管病变和淀粉样斑块的时间序列研究。用A（3种抗体将使用3种抗体来进一步阐明微血管病变对AP积累的影响。在AIM 1中，我们测试微血管凝块和出血是否会触发快速的淀粉样plaque形成在AIM 2中的不同位置。在AIM 2中，我们会在生命中提出偏见，我们是否会在pla中构成pla，我们是否会鉴定出一种偏爱，我们是否会在pla中提出偏见，我们是否会偏向于pla，我们是否会偏向于生命，我们是否会估算出来，我们是否会鉴定出一个偏见，我们是否会偏向于生命，我们是否会偏向于生命，我们是否会偏向于生命，我们是否会偏向于生命，我们是否会偏向于生命，我们是否会偏向于生命，我们是否会偏向于生命，我们是否会偏向于生命，我们是否会偏向于生命，我们是否会在生命中提出质疑。如果血管病变与不同的细胞类型相对，则通过共定位研究来确定炎症或反应性氧气是否是通过组织学和免疫组织学测定识别AP积累的，我们的初步数据会在这些局部使用局部植物。在阿尔茨海默氏病发病机理中起重要作用。从临床上讲，阿尔茨海默氏病通常与血管疾病纠缠在一起，这表明两种疾病是密切相关的。在许多患者中，成功治疗将必须解决这两个方面。这项工作调查了这两个条件如何互相恶化，并将有助于确定预防痴呆症的策略。

项目成果

Cortical microhemorrhages cause local inflammation but do not trigger widespread dendrite degeneration.

• DOI: 10.1371/journal.pone.0026612
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Rosidi NL;Zhou J;Pattanaik S;Wang P;Jin W;Brophy M;Olbricht WL;Nishimura N;Schaffer CB
• 通讯作者: Schaffer CB

Age-related intimal stiffening enhances endothelial permeability and leukocyte transmigration.

• DOI: 10.1126/scitranslmed.3002761
• 发表时间: 2011-12-07
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Huynh J;Nishimura N;Rana K;Peloquin JM;Califano JP;Montague CR;King MR;Schaffer CB;Reinhart-King CA
• 通讯作者: Reinhart-King CA