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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

基本信息

批准号：
9811044
负责人：
Qin Wang
金额：
$ 41.12万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9811044
关键词：
Address Adrenergic Receptor Affinity Agonist Allosteric Site Alzheimer&apos s Disease Amyloid 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 Modeling Molecular Molecular Conformation Molecular Genetics Morphology Multiprotein Complexes Mus Neuronal Dysfunction Neurons Pathologic Pathology Patients Peptides Process Protein phosphatase Role Severities Signal Transduction Synapses System Techniques Testing Toxic effect Vertebral column Viral Virulence Factors 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

项目摘要

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 Our unpublished data revealed that Aβ42 oligomers (the major toxic species of Aβ peptides) act as allosteric modulators with nanomolar affinity for the α2A-adrenergic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