tPA and Cerebrovascular Regulation in a Model of ß-amyloid Pathology

β-淀粉样蛋白病理模型中的 tPA 和脑血管调节

• 批准号: 10659770
• 负责人: Laibaik Park
• 金额: $ 38.34万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659770
• 关键词: Activities of Daily Living; Address; Affect; Alteplase; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Behavioral; Blood Vessels; Blood flow; Bone Marrow; Bone Marrow Transplantation; Brain; Brain Pathology; Cells; Cerebral Amyloid Angiopathy; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; Cerebrum; Chimera organism; Cognition; Cognitive; Cognitive deficits; Couples; Cre driver; Deposition; Disease; Endothelium; Ensure; Enzymes; Functional disorder; Funding; Gene Deletion; Gene Targeting; Genes; Genetic; Glutamates; Histopathology; Hyperemia; Impaired cognition; Impairment; In Vitro; Individual; Knockout Mice; Knowledge; Lasers; Leptomeninges; Long-Term Effects; MAPT gene; Macrophage; Mediating; Methods; Microglia; Modeling; Morbidity - disease rate; Mus; Myeloid Cells; NADPH Oxidase; Natural Immunity; Neurofibrillary Tangles; Neurons; Nitric Oxide; Pathogenicity; Pathology; Pathway interactions; Penetration; Perfusion; Personal Satisfaction; Phenotype; Plasminogen Activator Inhibitor 1; Plasminogen Inactivators; Process; Production; Reactive Oxygen Species; Regulation; Risk; Senile Plaques; Sex Differences; Source; Structure; Swedish mutation; Synapses; Tamoxifen; Techniques; Testing; Tg2576; Therapeutic Intervention; Transgenic Mice; Up-Regulation; Vasodilator Agents; abeta accumulation; abeta deposition; aged; amyloid pathology; attenuation; beta amyloid pathology; blood flow measurement; brain dysfunction; cerebrovascular; cognitive function; extracellular; in vivo; interdisciplinary approach; mortality; mouse model; neural; neuropathology; neurovascular; novel; novel strategies; overexpression; pharmacologic; receptor; response; sex; targeted treatment; tool

PROJECT SUMMARY AND ABSTRACT: Alzheimer's disease and related dementias (ADRD) are disabling conditions that progressively deprive affected individuals of their cognitive functions, ultimately leading to their inability to perform basic activities of daily living. The brain depends on continuous and well-regulated delivery of energy substrates through the brain blood flow, which is accomplished by elaborate neurovascular control mechanisms that always ensure sufficient cerebral perfusion. One such mechanism, termed functional hyperemia, couples local neural activity with the delivery of blood flow and requires tissue plasminogen activator (tPA) for its full expression, since tPA enables the production of the potent vasodilator nitric oxide during glutamatergic synaptic activity. Neurovascular alterations are observed early in the disease course of ADRD and may promote the expression of cognitive impairment. Amyloid-beta, a significant pathogenic contributor to AD, suppresses functional hyperemia by upregulating the tPA inhibitor PAI-1 resulting in a reduction in tPA activity. However, the cellular sources of PAI-1 remain unclear, and their identification would suggest new approaches to rescue the neurovascular dysfunction induced by amyloid- beta. Perivascular macrophages (PVM), brain resident myeloid cells distinct from microglia located in the perivascular space, can produce large amounts of reactive oxygen species (ROS) which are critical drivers of PAI-1 upregulation. Therefore, we will test the central hypothesis that PVM are the major source of the PAI-1 that leads to tPA deficiency, neurovascular dysfunction, and cognitive deficits induced by amyloid-beta. This hypothesis will be tested in 3 specific aims: (1) PVM are the source of PAI-1 mediating tPA deficiency and neurovascular uncoupling induced by amyloid-beta, (2) PVM CD36 and Nox2, which are responsible for the ROS production in these cells, mediate the PAI-1 upregulation, and (3) PVM PAI-1 contributes to the effects of long-term accumulation of amyloid-beta. These specific aims will be accomplished by employing tour de force approaches, including in vivo and in vitro techniques. The application will widen our knowledge basis for the cellular mechanisms of harmful neurovascular effects of amyloid-beta.

项目总结和摘要： 阿尔茨海默氏病和相关痴呆症（ADRD）是一种致残性疾病， 剥夺患者的认知功能，最终导致他们无法 进行基本的日常生活活动。大脑依赖于持续的和良好的调节 通过脑血流输送能量基质，这是通过精心设计的 神经血管控制机制始终确保足够的脑灌注。一个这样 一种称为功能性充血的机制将局部神经活动与血液输送相结合 流动，并需要组织纤溶酶原激活剂（tPA）的充分表达，因为tPA使 在神经元兴奋性突触活动期间产生有效的血管扩张剂一氧化氮。 在ADRD病程早期观察到神经血管改变， 认知障碍的表现。β淀粉样蛋白是AD的重要致病因素， 通过上调tPA抑制剂派-1抑制功能性充血， tPA活性。然而，派-1的细胞来源仍不清楚，它们的鉴定 将提出新的方法来挽救淀粉样蛋白诱导的神经血管功能障碍， β的血管周围巨噬细胞（PVM），与小胶质细胞不同的脑驻留髓样细胞 位于血管周围间隙，可产生大量活性氧（ROS） 它们是派-1上调的关键驱动因素。因此，我们将检验中心假设 PVM是派-1的主要来源，导致tPA缺乏，神经血管 功能障碍和β淀粉样蛋白诱导的认知缺陷。这一假设将在3 具体目的：（1）PVM是派-1介导tPA缺陷和神经血管损伤的来源， β淀粉样蛋白诱导的解偶联，（2）PVM CD 36和Nox 2，它们负责 这些细胞中ROS的产生介导派-1的上调，并且（3）PVM派-1有助于 长期积累的β淀粉样蛋白的影响这些具体目标将是 通过采用tour de force方法，包括体内和体外技术来完成。 这一应用将拓宽我们对有害的细胞机制的认识基础 β淀粉样蛋白对神经血管的影响