Urokinase-type Plasminogen Activator in the Ischemic Brain

缺血脑中的尿激酶型纤溶酶原激活剂

基本信息

批准号：
10489882
负责人：
Manuel Salvador Yepes
金额：
$ 45.5万
依托单位：
EMORY 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：
2015-09-15 至 2023-01-08
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10489882
关键词：
Administrative Supplement Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient Amyloid beta-Protein Award Axon Binding Brain Brain Injuries Cerebrum Data Dendrites Development Event Excitatory Synapse Foundations Functional disorder Funding Generations Genes Genetic Polymorphism Hippocampus (Brain)Human Impaired cognition Impairment In Vitro Late Onset Alzheimer Disease Lead Memory Loss Mus Neurons Nucleotides Pathogenesis Pathway interactions Pharmacology Plasmin Plasminogen Activator Inhibitor 1 Plasminogen Inactivators Play Publishing Recombinants Role Serine Protease Signal Pathway Signal Transduction Structure Study Section Synapses Testing Therapeutic Intervention Urokinase Work amyloid precursor protein processing base beta catenin cognitive development excitatory neuron extracellular in vivo ischemic injury neurogenesis neuron loss nonhuman primate novel preservation prevent receptor repaired restoration synaptogenesis tau phosphorylation therapeutic target tool

项目摘要

ABSTRACT Soluble Aβ-induced synaptic dysfunction causes progressive cognitive decline in Alzheimer’s disease (AD) patients. This is an early event that precedes neuronal death and thus is amenable to therapeutic interventions before the progression to irreversible brain damage. Urokinase-type plasminogen activator (uPA) is a serine proteinase that upon binding to its receptor (uPAR) not only generates plasmin but also activates cell signaling pathways. Work funded by the active award supporting this Administrative Supplement application has revealed that uPA is abundantly found in synapses of excitatory neurons located in the II/III and V cortical layers of the mature murine, non-human primate and human brain, and that its release, triggered by synaptic activity, promotes the formation of synaptic contacts and the repair of synapses damaged by an ischemic injury. Activation of the Wnt-β-catenin pathway is crucial for synapse formation and preservation of synaptic structure and function. Soluble Aβ inhibits the Wnt-β-catenin pathway in the brain of AD patients, and the resultant impairment of β-catenin signaling causes synaptic dysfunction, amyloidogenic processing of the amyloid precursor protein (APP), tau phosphorylation and memory loss. In line with these observations, restoration of Wnt-β-catenin pathway function prevents soluble Aβ-induced synaptic dysfunction and cognitive decline. In this Administrative Supplement application we will use in vitro and in vivo experimental approaches to test the hypothesis that uPA protects the synapse from the harmful effects of soluble Aβ by its ability to activate the Wingless/Int1 (Wnt)-β-catenin pathway via a mechanism that does not require plasmin generation. Our hypothesis is within the scope of the active award, and supported by the following observations described in Preliminary Studies of this application: i) the abundance of uPA is significantly decreased in the synapse of AD patients; ii) uPA is an efficient activator of the Wnt-β-catenin pathway in cerebral cortical neurons by a mechanism that does not require plasmin generation; iii) uPA abrogates the inhibitory effect of soluble Aβ on the Wnt-β-catenin pathway; iv) uPA prevents Aβ-induced synaptic loss via Wnt-β-catenin pathway activation. And v) treatment with recombinant uPA (ruPA) protects the synapse from the harmful effects of soluble Aβ. Importantly, the relevance of uPA in the pathogenesis of AD is supported by findings that nucleotide polymorphisms of the uPA encoding gene are associated with late onset AD, and that the activity of uPA’s inhibitor [plasminogen activator inhibitor–1 (PAI-1)] is increased in the brain of AD patients. Thus, the hypothesis that will be tested in this Administrative Supplement application is novel and may lead to the discovery a new pathophysiological mechanism of AD and a potential therapeutic target to protect the synapse of AD patients.

抽象的可溶性Aβ诱导的突触功能障碍会导致阿尔茨海默氏病（AD）的进行性认知下降患者。这是一个早期的事件，在神经元死亡之前，因此可以接受治疗干预措施在发展为不可逆转的大脑损伤之前。尿激酶型纤溶酶原激活剂（UPA）是串行蛋白酶与其接收器结合后（UPAR）不仅会产生纤溶酶，还会激活细胞信号传导途径。由支持该行政补充申请的主动奖励资助的工作已显示在II/III和V皮层的兴奋神经元的突触中，显然发现了UPA 成熟的鼠，非人类灵长类动物和人脑，其释放是由合成活动触发的，促进突触接触的形成，并修复因缺血性损伤损坏的突触。 Wnt-β-catenin途径的激活对于突触形成和突触结构的保存至关重要和功能。可溶性Aβ抑制AD患者大脑中的Wnt-β-catenin途径，结果 β-catenin信号的损害会导致突触功能障碍，淀粉样蛋白的淀粉样蛋白生成加工前体蛋白（APP），tau磷酸化和记忆丧失。根据这些观察，恢复 Wnt-β-catenin途径功能可防止固体Aβ诱导的突触功能障碍和认知能力下降。在这个行政补充应用我们将使用体外和体内实验方法来测试 UPA通过激活固体Aβ的有害作用的假设可以保护突触免受有害影响无翅/int1（Wnt）-β-catenin途径通过不需要纤溶酶产生的机制。我们的假设在主动奖励的范围内，并得到以下观察结果的支持。该应用的初步研究：i）AD的突触中UPA的抽象显着降低患者; ii）UPA是A脑皮质神经元中Wnt-β-catenin途径的有效激活剂不需要纤溶酶产生的机制； iii）UPA废除了固体Aβ对 Wnt-β-catenin途径； iv）UPA通过Wnt-β-catenin途径激活Aβ诱导的突触损失。 v）重组UPA（RUPA）治疗可保护突触免受固体Aβ的有害作用。重要的是，核苷酸的发现支持了UPA在AD发病机理中的相关性 UPA编码基因的多态性与晚期AD有关，并且UPA的活性 AD患者的大脑中，抑制剂[纤溶酶原激活剂抑制剂– 1（PAI-1）]增加。那是假设这将在此行政补充应用程序中进行测试是新颖的，可能会导致发现新的 AD的病理生理机制和保护AD患者突触的潜在治疗靶点。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Neurological Complications of SARS-CoV-2 Infection and COVID-19 Vaccines: From Molecular Mechanisms to Clinical Manifestations.

SARS-CoV-2 感染和 COVID-19 疫苗的神经并发症：从分子机制到临床表现。

DOI：
10.2174/1389450123666220919123029
发表时间：
2022
期刊：
Current drug targets
影响因子：
3.2
作者：
Yepes,Manuel
通讯作者：
Yepes,Manuel

Tissue-type plasminogen activator regulates the neuronal uptake of glucose in the ischemic brain.

组织型纤溶酶原激活剂调节缺血脑中神经元对葡萄糖的摄取

DOI：
10.1523/jneurosci.1241-12.2012
发表时间：
2012-07-18
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Wu F;Wu J;Nicholson AD;Echeverry R;Haile WB;Catano M;An J;Lee AK;Duong D;Dammer EB;Seyfried NT;Tong FC;Votaw JR;Medcalf RL;Yepes M
通讯作者：
Yepes M

Tissue-type plasminogen activator mediates neuroglial coupling in the central nervous system.