Overexpression of the amyloid precursor protein and cerebrovascular regulation

淀粉样前体蛋白的过度表达与脑血管调节

• 批准号: 10162672
• 负责人: Costantino Iadecola
• 金额: $ 42.38万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10162672
• 关键词: Affect; Age; Age-associated memory impairment; Aging; Alteplase; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Automobile Driving; Blood Vessels; Blood flow; Brain; Brain region; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; Cerebrum; Cognitive deficits; Consensus; Coupling; Dementia; Deposition; Development; Disease; Elderly; Epidemic; Functional disorder; Funding; Glucose; Grant; Health; Hyperemia; Impaired cognition; Impairment; In Vitro; Knowledge; Lead; Learning; Light; Link; Metabolic; Microcirculation; Microtubules; Modeling; Molecular; Mus; N-Methyl-D-Aspartate Receptors; National Institute of Neurological Disorders and Stroke; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Nitric Oxide; Nitric Oxide Synthase; Oxygen; Pathogenesis; Pathogenicity; Pathologic; Pathology; Peptide Hydrolases; Plasminogen Activator Inhibitor 1; Plasminogen Inactivators; Play; Population; Production; Protein Isoforms; Receptor Signaling; Regulation; Risk Factors; Role; Senile Plaques; Structure; Symptoms; Synapses; Tauopathies; Testing; Therapeutic; Tissues; United States National Institutes of Health; Up-Regulation; Vascular Diseases; Vascular blood supply; Vasodilator Agents; Virulence Factors; age related; aged; attenuation; base; brain dysfunction; brain parenchyma; cerebrovascular; cognitive function; cost; effective therapy; experimental study; hyperphosphorylated tau; in vivo; interdisciplinary approach; mouse model; neocortical; neurophysiology; neurovascular; neurovascular coupling; novel; novel therapeutics; overexpression; relating to nervous system; response; sex; tau Proteins; tau mutation; vascular contributions; virtual

Alzheimer's disease (AD) is the leading cause of age-related cognitive impairment for which there are no treatments. The structural and functional integrity of the brain requires a continuous supply of oxygen and glucose through blood flow, well matched to its dynamic and regionally diverse energy needs. Accordingly, neural activity increases blood flow in active brain regions, a phenomenon termed functional hyperemia. Functional hyperemia depends in large part on the link between NMDA receptor activity and neuronal production of the potent vasodilator nitric oxide (NO), and requires tissue plasminogen activator (tPA) for its full expression. Increasing evidence indicates that alterations in the regulation of the cerebral microcirculation play a significant role in the pathogenesis of AD by reducing the cerebral blood supply, but the mechanisms of such neurovascular dysfunction have not been fully elucidated. Most studies have focused on the damaging cerebrovascular effects of Aβ. However, the role of tau, a key pathogenic factor in AD, remains virtually unexplored. There is a strong rationale for investigating tau. For example, in neurodegenerative diseases caused by tau mutations (tauopathies), in which Aβ is not present, there is evidence of cerebrovascular dysfunction early in the disease course, suggesting that tau exerts pathogenic vascular effects independently of Aβ. Furthermore, hyperphosphorylated tau alters NMDA receptor signaling, which is essential for the neuronal NO production driving functional hyperemia. Based on these scientific premises, we will test the central hypothesis that pathological tau alters neurovascular coupling by impairing the ability of NMDA receptors to trigger NO production, an effect occurring prior to neurodegeneration and cognitive deficits. To this end, we will use state-of-the-art multidisciplinary approaches to investigate neurovascular regulation in mouse models of tauopathies, and in vitro approaches to explore the neurophysiological and molecular mechanisms of the effects. We will test the following hypotheses: (a) Tau disrupts neurovascular function prior to the onset of tau pathology and neurodegeneration; (b) The neurovascular dysfunction induced by tau is due to uncoupling of NMDA receptor activity from NO production; (c) NMDA receptor uncoupling from NO production and neurovascular dysfunction result from a deficit in tPA caused by upregulation of the endogenous tPA inhibitor PAI-1. The findings will begin to shed light on the vascular effects of pathological tau, thereby filling a knowledge gap in our understanding of the neurovascular dysfunction of AD and other tauopathies.

阿尔茨海默病(AD)是与年龄相关的认知障碍的主要原因 没有治疗方法。大脑的结构和功能的完整性需要一个连续的 通过血流供应氧气和葡萄糖，与其动态和地区性相匹配 多样化的能源需求。因此，神经活动增加了大脑活跃区域的血流量， 这一现象称为功能性充血。功能性充血在很大程度上取决于 NMDA受体活性与强效血管扩张剂一氧化氮的神经元产生之间的联系 一氧化氮(NO)，需要组织纤溶酶原激活剂(TPA)才能充分表达。渐增 有证据表明，大脑微循环调节的改变在 减少脑供血在AD发病机制中的重要作用，但 这种神经血管功能障碍的机制尚未完全阐明。大多数研究 都专注于Aβ对脑血管的破坏性影响。然而，tau的作用是一个关键 阿尔茨海默病的致病因素几乎仍未被发现。有一个强有力的理由来支持 调查陶先生。例如，在tau突变引起的神经退行性疾病中 (Tauopathies)，在Aβ不存在的情况下，有证据表明早期有脑血管功能障碍 在疾病过程中，提示tau对血管的致病作用不依赖于 一辆β。此外，过度磷酸化的tau改变了nmda受体信号，这是必不可少的。 对于神经元型NO的产生驱动功能性充血。基于这些科学依据 假设，我们将检验病理性tau改变神经血管偶联的中心假说。 通过削弱NMDA受体触发NO产生的能力，一种发生在 神经退化和认知缺陷。为此，我们将使用最先进的 多学科方法研究小鼠的神经血管调节 肌萎缩侧索硬化症，以及体外探索神经生理学和分子的方法 这些作用的机制。我们将检验以下假设：(A)Tau中断 在tau病理和神经退行性变开始之前的神经血管功能； Tau诱导的神经血管功能障碍是由于NMDA受体活性解偶联引起的 NO的产生；(C)NMDA受体从NO的产生和神经血管解偶联 功能障碍是由于内源性tPA抑制物上调导致tPA缺乏所致 PAI-1。这些发现将开始阐明病理性tau对血管的影响，从而 填补我们对阿尔茨海默病和其他疾病神经血管功能障碍的认识空白 紧张症。