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Alpha1A-Adrenoceptors in Cognition

Alpha1A-肾上腺素受体在认知中的作用

基本信息

批准号：
9052682
负责人：
DIANNE M PEREZ
金额：
$ 7.93万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
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：
2015-04-15 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9052682
关键词：
Acute Address Adrenergic Agonists Adrenergic Receptor Agonist Alzheimer&apos s Disease Amyloid Animals Antibodies Binding Binding Proteins Blood - brain barrier anatomy Brain Breeding Bromodeoxyuridine Chronic Clinical Data Clinical Trials Cloning Cognition Cognitive Complex Data Dementia Disease model Drug Exposure Drug usage Epinephrine Event Family G-Protein-Coupled Receptors Gene Expression Regulation Generations Genetic Genetic Enhancement Grant Health Hippocampus (Brain)Immunotherapy Impaired cognition Impairment Injection of therapeutic agent Knockout Mice Laboratories Lead Learning Ligands Light Long-Term Potentiation Memory Mus Natural regeneration Nerve Degeneration Neurotransmitters Norepinephrine Pathology Pharmaceutical Preparations Pharmacologic Substance Phenotype Positioning Attribute Publishing Receptor Activation Regulation Review Literature Role Series Signal Transduction Signal Transduction Pathway Sympathetic Nervous System Synaptic plasticity Therapeutic Agents Time Transgenic Organisms adult neurogenesis alpha-adrenergic receptor cognitive enhancement cognitive function efficacy testing improved long term memory member mouse model mutant neurogenesis neurotransmission novel overexpression pre-clinical receptor tool

项目摘要

DESCRIPTION (provided by applicant): Our major objective is to generate tools and data to support the hypothesis that α1A-adrenergic receptor (ARs) agonists may be useful in ameliorating the cognitive decline in Alzheimer's Disease (AD). In light of current disappointing clinical trials using anti-amyloid β antibodies, a pharmaceutical approach that can protect the brain and increase cognitive functions is urgently needed. α-AR 1 subtypes (α1A, α1B, α1D) are members of the G-protein-coupled receptor family of proteins that bind the endogenous neurotransmitter, norepinephrine. Signal transduction by α-ARs is involved in neurotransmission, but their roles in the CNS are not well understood. Regulation by the α1-AR subtypes (α1A, α1B, α1D) is complex; however most of the animal studies have shown that chronic α1B-AR activity is neurodegenerative while the α1A-AR is neuroprotective (reviewed in 1). Previous studies assessing the roles of α1-ARs in cognition have been variable and controversial. Most of the studies were published in the 1990s before the cloning of the receptors, generation of mouse models and full characterization of existing ligands. Previous studies used an injection of mildly selective α1-AR agonists or antagonists and analyzed for acute cognitive effects. The selectivity of the drugs can be questioned since the different α1-AR subtypes can regulate opposite phenotypes in the brain (1). There are also documented cases that drugs may have different or even opposite effects on cognition depending upon whether treatment is acute or chronic (2-5). Chronic drug exposure can lead to adaptive changes in synaptic plasticity through neurogenesis (9-11) or gene regulation (12). Long-term memory formation requires coordinated regulation of gene expression (6- 8). In addition, GPCRs also generate novel signal transduction pathways when they become internalized through chronic stimulation (reviewed in 13). Our laboratory is in a unique position to address this controversy with the use of unique mouse models we generated for the α1-ARs that systemically over express constitutively active mutants (CAMs) and are chronically activated even when an agonist is not present. These mice provide the most selectivity in α1-AR subtype signaling. We propose to generate another novel mouse model that will determine the role of these receptors in learning and memory and to potentially reverse the cognitive decline in Alzheimer's Disease (AD). We have preliminary data that activation of the α1A-AR subtype can increase cognition and synaptic plasticity. We have published that our mouse model that chronically stimulates the α1A-AR subtype is expressed in cognitive centers of the brain (14), increased adult neurogenesis (15), hippocampal synaptic plasticity and long-term potentiation (LTP) and cognition (16). Normal mice treated with the α1A-AR selective agonist cirazoline for at least 2 Mo recapitulated neurogenesis (15) and cognitive enhancement (16), while α1A-KO mice had impairments. Review of literature suggests that a deficit in LTP induction is associated with AD and there is increasing evidence that suggests that impaired LTP is an event occurring early in AD pathology. Current clinical trials focused on amyloid immunotherapies have been disappointing and cognitive efficacy is questionable (17-8) and current anti-dementia drugs only offer temporary relief. In order to provide tools to study the mechanism and to provide pre-clinical data, our specific aims are to determine if long-term versus short-term α1A-AR agonist can improve cognitive functions and synaptic plasticity in AD mice. We will also generate a cross of our transgenic overexpressed CAM α1A-AR mouse with the 3xTg AD mouse model to determine if selective α1A-AR activation can decrease the rate of cognitive impairment.

描述(由申请人提供)：我们的主要目标是生成工具和数据来支持α1A-肾上腺素能受体(ARs)激动剂可能有助于改善阿尔茨海默病(AD)认知功能下降的假设。鉴于目前使用抗淀粉样蛋白β抗体的临床试验令人失望，迫切需要一种能够保护大脑和提高认知功能的药物方法。α-AR 1亚型(α1A、α1B、α1D)是G蛋白偶联受体家族的成员，与内源性神经递质去甲肾上腺素结合。α-ARs的信号转导参与神经传递，但其在中枢神经系统中的作用尚不清楚。α1-AR亚型(α1A、α1B、α1D)的调节是复杂的；然而，大多数动物研究表明，慢性α1B-AR活动是神经退行性的，而α1A-AR是神经保护的(综述1)。以前评估α-1-ARs在认知中的作用的研究一直是多种多样和有争议的。大多数研究发表于20世纪90年代，在受体克隆、小鼠模型生成和现有配体的全面表征之前。以前的研究使用了选择性较弱的α1-AR激动剂或拮抗剂，并分析了急性认知效应。药物的选择性受到质疑，因为不同的α1-AR亚型可以调节大脑中相反的表型(1)。也有记录在案的案例表明，药物对认知的影响可能不同，甚至相反，这取决于治疗是急性还是慢性(2-5)。慢性药物暴露可通过神经发生(9-11)或基因调节(12)导致突触可塑性的适应性变化。长期记忆的形成需要基因表达的协调调节(6-8)。此外，当GPCRs通过慢性刺激内化时，GPCRs也会产生新的信号转导途径(见第13章)。我们的实验室在解决这一争议方面处于独特的地位，使用我们为α1-AR建立的独特的小鼠模型，该模型系统地过度表达结构性活性突变体(CAM)，并且即使在没有激动剂的情况下也会长期激活。这些小鼠在α1-AR亚型信号传递中提供了最大的选择性。我们建议建立另一种新的小鼠模型，以确定这些受体在学习和记忆中的作用，并有可能逆转阿尔茨海默病(AD)的认知衰退。我们有初步数据表明，激活α1A-AR亚型可以增加认知和突触可塑性。我们已经发表了我们的慢性刺激α1A-AR亚型的小鼠模型在大脑的认知中心(14)、增加的成人神经发生(15)、海马区突触可塑性和长时程增强(LTP)和认知(16)中表达。用α1A-AR选择性激动剂Crazoline治疗的正常小鼠至少有2个Mo概括了神经发生(15个)和认知增强(16个)，而α1A-KO小鼠有损伤。文献综述表明，LTP诱导缺陷与AD有关，越来越多的证据表明LTP受损是AD病理早期发生的事件。目前专注于淀粉样免疫疗法的临床试验令人失望，认知疗效值得怀疑(17-8)，目前的抗痴呆症药物只能提供暂时的缓解。为了提供研究机制和提供临床前数据的工具，我们的具体目的是确定长期和短期的α1A-AR激动剂是否可以改善AD小鼠的认知功能和突触可塑性。我们还将产生我们的转基因过表达的α1A-AR小鼠与3xTg AD小鼠模型的杂交，以确定选择性激活α1A-AR是否可以降低认知障碍的发生率。