Beta amyloid-adrenergic receptor interaction in Alzheimer's Disease

阿尔茨海默病中β淀粉样蛋白-肾上腺素能受体的相互作用

• 批准号: 10618668
• 负责人: Qin Wang
• 金额: $ 43.49万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618668
• 关键词: Address; Adrenergic Receptor; Affinity; Agonist; Allosteric Site; Alzheimer' s Disease; Amyloid beta-42; Amyloid beta-Protein; Autopsy; Behavior; Binding; Biological Factors; Brain; CRISPR/Cas technology; Cause of Death; Clinical; Cognition; Cognitive; Cognitive deficits; Complex; Coupling; Data; Databases; Dementia; Disease; Disease Progression; Elderly; Environmental Risk Factor; Functional disorder; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Genetic; Heterogeneity; Human; Impaired cognition; Impairment; In Vitro; Lead; Ligands; Mediating; Mediator of activation protein; Molecular; Molecular Conformation; Molecular Genetics; Morphology; Multiprotein Complexes; Mus; Neuronal Dysfunction; Neurons; Pathologic; Pathology; Patients; Process; Protein phosphatase; Role; Severities; Signal Transduction; Synapses; System; Techniques; Testing; Toxic effect; Vertebral column; Viral; Virulence Factors; abeta accumulation; abeta oligomer; cognitive function; cohort; density; effective therapy; epidemiology study; extracellular; genetic approach; improved; in vivo; monomer; mutant; nanomolar; new therapeutic target; novel; prevent; receptor; tau Proteins; tau phosphorylation; therapeutic target

Alzheimer's disease (AD) is the only cause of death among the top ten that cannot be prevented, cured, or even slowed, making it urgent to identify novel therapeutic targets for treatment of AD. It is generally accepted that toxic amyloid β (Aβ) peptides are the key pathogenic factor for AD. However, AD progression and clinical presentation are highly heterogeneous and determined by multiple genetic and environmental factors. Therefore, in order to develop effective disease-modifying therapies, it is necessary to fully understand the action of Aβ and identify underlying mechanisms that modulate its effects on cognitive functions. Our unpublished data revealed that Aβ42 oligomers (the major toxic species of Aβ peptides) act as allosteric modulators with nanomolar affinity for the α2A-adrenergic receptor (α2AAR). This is the first example in which Aβ functions as an allosteric modulator of a G protein-coupled receptor (GPCR) with nanomolar affinity. We found that Aβ42 binding to α2AAR resulted in aberrant coupling of α2AAR to activation of a new signaling effector that promotes neuronal dysfunction and cognitive impairment. The Aβ-dependent pathological coupling of α2AAR signaling provides a novel mechanism underlying Aβ-induced toxicity to brain function, and suggests that the Aβ-α2AAR interaction represents a potential disease-specific target for AD treatment. The primary objective of this proposal is to address the cellular and molecular mechanisms and in vivo relevance of the Aβ-α2AAR interaction in exacerbating AD-related neuronal dysfunction and cognitive impairment using combined cellular, molecular and genetic approaches. We will first determine the cellular aspect of detrimental effects induced by the Aβ-α2AAR interaction in neurons. Second, we will identify the molecular mechanism critical for Aβ-dependent pathological coupling of α2AAR signaling and determine the role of G proteins and βarrestins in this process. Third, we will determine the in vivo functional relevance of the Aβ-α2AAR interaction in exacerbating AD-related cognitive deficits. Successfully accomplishing this study will significantly advance our understanding of the molecular and cellular mechanisms underlying Aβ actions in disrupting cognitive function in AD. Targeting the disease-specific interaction between Aβ oligomers and α2AAR represents a potential safe and effective approach to improve cognitive function in AD.

阿尔茨海默病（AD）是十大死亡原因中唯一无法预防、治愈， 或甚至减慢，使得迫切需要鉴定用于治疗AD的新的治疗靶点。人们普遍认为 毒性淀粉样β（Aβ）肽是AD的关键致病因子。然而，AD进展和临床 呈现高度异质性，并由多种遗传和环境因素决定。因此，我们认为， 为了开发有效的疾病缓解疗法，有必要充分了解Aβ的作用， 确定调节其对认知功能影响的潜在机制。我们未公开的数据显示 Aβ42寡聚体（Aβ肽的主要毒性物质）作为变构调节剂， α 2A肾上腺素能受体（α2AAR）。这是Aβ作为变构调节剂发挥作用的第一个例子 具有纳摩尔亲和力的G蛋白偶联受体（GPCR）。我们发现，Aβ42与α 2 AAR结合， 在α2AAR异常偶联激活一种新的信号效应物，促进神经元功能障碍， 认知障碍α 2 AAR信号的Aβ依赖性病理偶联提供了一种新的机制 潜在的Aβ诱导的脑功能毒性，并表明Aβ-α2AAR相互作用代表了一种可能的机制。 AD治疗的潜在疾病特异性靶点。该提案的主要目标是解决蜂窝 Aβ-α2AAR相互作用在AD相关性加重中的分子机制和体内相关性 神经元功能障碍和认知障碍的研究。我们 将首先确定神经元中Aβ-α2AAR相互作用诱导的有害作用的细胞方面。 其次，我们将确定α 2 AAR的Aβ依赖性病理偶联的关键分子机制 信号传导，并确定G蛋白和β抑制蛋白在这一过程中的作用。第三，我们将确定在体内 Aβ-α2AAR相互作用在加重AD相关认知缺陷中的功能相关性成功 完成这项研究将大大提高我们对分子和细胞机制的理解， 在AD中破坏认知功能的潜在Aβ作用。针对疾病特异性相互作用， Aβ寡聚体和α 2 AAR代表了改善AD认知功能的潜在安全有效方法。

项目成果

Understanding neuropsychiatric symptoms in Alzheimer's disease: challenges and advances in diagnosis and treatment.

• DOI: 10.3389/fnins.2023.1263771
• 发表时间: 2023
• 期刊: FRONTIERS IN NEUROSCIENCE
• 影响因子: 4.3
• 作者: Pless, Andrew;Ware, Destany;Saggu, Shalini;Rehman, Hasibur;Morgan, John;Wang, Qin
• 通讯作者: Wang, Qin