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以下假设：鉴于目前令人失望的临床情况，α1A-肾上腺素能受体（AR）激动剂可能有助于改善阿尔茨海默氏病（AD）的认知能力下降。迫切需要使用抗淀粉样蛋白 β 抗体进行试验，这是一种可以保护大脑并增强认知功能的药物方法。α-AR 1 亚型（α1A、α1B、α1D）。 G 蛋白偶联受体蛋白家族的成员与内源性神经递质去甲肾上腺素结合，α-AR 的信号转导参与神经传递，但其在 CNS 中的作用尚不清楚。 α1A、α1B、α1D）很复杂；然而，大多数动物研究表明，慢性 α1B-AR 活性具有神经退行性，而 α1A-AR 具有神经保护作用（已审查） 1). 先前评估 α1-AR 在认知中的作用的研究各不相同且存在争议，大多数研究是在 20 世纪 90 年代发表的，之前的受体克隆、小鼠模型的生成和现有配体的全面表征。使用注射轻度选择性 α1-AR 激动剂或拮抗剂并分析急性认知效应。由于不同的 α1-AR 亚型可以调节大脑中相反的表型，因此药物的选择性可能受到质疑 (1)。还有记录表明，药物可能对认知产生不同甚至相反的影响，具体取决于治疗是急性还是慢性 (2-5) 或通过神经发生 (9-11) 或慢性药物暴露可导致突触可塑性的适应性变化。基因调控 (12). 长期记忆的形成需要基因表达的协调调控 (6-8)。一个独特的为了解决这一争议，我们使用了我们为 α1-AR 生成的独特小鼠模型，这些模型系统性地过度表达组成型活性突变体 (CAM)，并且即使在不存在激动剂时也会长期激活。这些小鼠在 α1-AR 中提供了最大的选择性。 AR 亚型信号传导。我们建议建立另一种新型小鼠模型，该模型将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氏病 (AD) 的认知能力下降。 α1A-AR 亚型可以增加认知和突触可塑性，我们已经发表了长期刺激 α1A-AR 亚型的小鼠模型在大脑认知中枢 (14) 中表达，增加了成人神经发生 (15)、海马突触可塑性和长寿命。 - 足月增强 (LTP) 和认知 (16) 用 α1A-AR 选择性激动剂 cirazoline 治疗的正常小鼠至少 2 Mo 重现神经发生。 (15) 和认知增强 (16)，而 α1A-KO 小鼠存在损伤，文献综述表明 LTP 诱导缺陷与 AD 相关，并且越来越多的证据表明 LTP 受损是 AD 病理学早期发生的事件。目前专注于淀粉样蛋白免疫疗法的临床试验令人失望，认知功效值得怀疑(17-8)，并且当前的抗痴呆药物只能提供暂时的缓解作用。具体目标是确定长期与短期 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。我们还将生成转基因过表达 CAM α1A-AR 小鼠与 3xTg AD 小鼠模型的杂交。确定选择性 α1A-AR 激活是否可以降低认知障碍的发生率。