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 Our unpublished data revealed that Aβ42 oligomers (the major toxic species of Aβ peptides) act as allosteric modulators with nanomolar affinity for the α2A-adrenergic receptor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.

阿尔茨海默氏病（AD）是唯一无法预防，治愈， 甚至放慢速度，因此迫切需要识别新的AD治疗靶标。普遍接受 毒性淀粉样β（Aβ）肽是AD的关键致病因素。但是，广告的进展和临床 呈现是高度异质性的，由多个遗传和环境因素决定。所以， 为了开发有效的疾病改良疗法，有必要充分了解Aβ和 确定调节其对认知功能影响的基本机制。我们未发表的数据揭示了 Aβ42低聚物（AβPepperides的主要有毒物种）充当具有纳摩尔亲和力的变构调节剂 对于α2A-肾上腺素能受体（α2AAR）。这是Aβ充当变构调节剂的第一个例子 G蛋白偶联受体（GPCR）具有纳摩尔亲和力。我们发现与α2AAR结合的Aβ42导致 在异常耦合α2AAR与促进神经元功能障碍的新信号效应子的激活中 认知障碍。 α2AAR信号的Aβ依赖性病理耦合提供了一种新型机制 潜在的Aβ诱导的对脑功能的毒性，并表明Aβ-α2AAR相互作用代表A 广告治疗的潜在疾病特异性靶标。该提案的主要目的是解决细胞 Aβ-α2AAR相互作用在加剧广告相关的Aβ-α2AAR相互作用的分子机制和体内相关性 使用组合的细胞，分子和遗传方法的神经元功能障碍和认知障碍。我们 将首先确定神经元Aβ-α2AAR相互作用引起的有害作用的细胞方面。 其次，我们将确定对α2AAR的Aβ依赖性病理偶联至关重要的分子机制 信号传导和确定G蛋白和βarrestin在此过程中的作用。第三，我们将确定体内 Aβ-α2AAR相互作用在加剧广告相关的认知缺陷中的功能相关性。成功地 完成这项研究将大大提高我们对分子和细胞机制的理解 Aβ在破坏AD中的认知功能方面的基本作用。针对特定疾病的相互作用 Aβ低聚物和α2AAR代表了一种潜在的安全有效方法，可改善AD的认知功能。

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