Beta amyloid-adrenergic receptor interaction in Alzheimer's Disease

阿尔茨海默病(AD)是十大疾病中唯一无法预防、治愈、 甚至放缓，这使得迫切需要为AD的治疗寻找新的治疗靶点。这是被普遍接受的 毒性淀粉样蛋白A(Aβ，Aβ)是AD的关键致病因素。然而，AD的进展和临床 表型具有高度的异质性，并由多种遗传和环境因素决定。因此， 为了开发有效的疾病修改疗法，有必要充分了解Aβ和 找出调节其对认知功能影响的潜在机制。我们未公布的数据显示 Aβ42寡聚体(Aβ多肽的主要毒性物种)作为具有纳摩尔亲和力的变构调节剂 α2A-肾上腺素能受体(α2AAR)。这是第一个β作为变构调节剂的例子 具有纳摩尔亲和力的G蛋白偶联受体(GPCR)。我们发现β42与α2AAR结合 在α2AAR与一个新的信号效应器的异常偶联中，新的信号效应器促进神经元功能障碍和 认知障碍。β依赖的α2AAR信号的病理偶联提供了一种新的机制 潜在的β诱导的脑功能毒性，并表明Aβ-α2AAR的相互作用代表 AD治疗的潜在疾病特异性靶点。这项提案的主要目标是解决蜂窝网络 Aβ-α2AAR相互作用在AD发病中的分子机制及体内相关性 使用细胞、分子和遗传学相结合的方法研究神经元功能障碍和认知障碍。我们 将首先确定Aβ-α2AAR相互作用在神经元中引起的有害影响的细胞方面。 第二，我们将确定β依赖的α2AAR病理偶联的关键分子机制 并确定G蛋白和β拦阻蛋白在这一过程中的作用。第三，我们将测定体内的 Aβ-α2AAR相互作用在加重AD相关认知障碍中的功能相关性。成功 完成这项研究将极大地促进我们对分子和细胞机制的理解 潜在的Aβ在AD认知功能紊乱中的作用。以疾病特异性相互作用为目标 β寡聚体和α2AAR是一种潜在的安全有效的改善AD认知功能的方法。

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 Our unpublished data revealed that Aβ42 oligomers (the major toxic species of Aβ peptides) act as allosteric modulators with nanomolar affinity for the α2A-adrenergic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