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 Our unpublished data revealed that Aβ42 oligomers (the major toxic species of Aβ peptides) act as allosteric modulators with nanomolar affinity for the α2A-adrenergic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