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（申请人提供）：最近，脑微血管疾病已被确定为阿尔茨海默病的重要组成部分。这些疾病之间相互作用的机制仍不清楚，部分原因是缺乏微血管疾病的动物模型。这项工作研究了微血管损伤与 Ap 积累之间的相互关系，Ap 是阿尔茨海默病的主要特征。这项工作建立在临床观察的基础上，即阿尔茨海默病痴呆的严重程度通常与血管疾病的存在有关。我们使用新型光学工具在阿尔茨海默病转基因小鼠模型中诱导微血管病变，然后对由此产生的病理进展进行成像。我们的损伤技术，飞秒激光消融，可以破坏皮层表面以下 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、缺血性闭塞和短暂性渗漏，所有这些都可能导致疾病进展。双光子激发荧光显微镜用于对淀粉样斑块的发育进行成像并测量微脉管系统中的血流量和渗漏。这使得可以对微血管病变和淀粉样斑块进行延时研究。 A(3 抗体的死后标记将用于进一步阐明微血管病变对 Ap 积累的影响。在目标 1 中，我们测试微血管凝块和出血是否会触发血管树中不同位置的快速淀粉样斑块形成。目标 2，我们询问生命早期的血管病变是否会诱发以后出现斑块。最终目标是确定血管病变种植的斑块与不同细胞类型的关系。并通过共定位研究确定炎症或活性氧是否是影响因素。此外，我们使用组织学和免疫组织学测定来识别受影响的细胞并绘制 Ap 积累图谱。我们的初步发现预测微血管凝块的存在会加速局部沉积。这些数据表明，微血管病变可能在阿尔茨海默病的发病机制中发挥重要作用~阿尔茨海默病是老年人痴呆的最常见原因。临床上，阿尔茨海默病常常与血管疾病纠缠在一起，这表明这两种疾病密切相关。对于许多患者来说，成功的治疗必须同时解决这两方面的问题。这项工作研究了这两种情况如何相互恶化，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