Amyloid β redirects norepinephrine signaling to activate the pathogenic GSK3β/tau cascade

Abstract

AbstractBackgroundStrong genetic and experimental evidence indicates toxic amyloid β (Aβ) peptides as a key driving factor of Alzheimer’s disease (AD) pathogenesis. The microtubule‐associated protein tau is an essential mediator of Aβ toxicity. Yet, the molecular pathway from Ab to tau pathology remains elusive, presenting a major gap in in‐depth understanding of the pathological cascade of AD. The brain noradrenergic system is highly vulnerable in AD; despite of being a sensitive target of Aβ and tau toxicity, whether it is directly involved in AD pathogenesis is unknown.MethodWe examined the activity of α2A adrenergic receptor (α2AAR) in AD animal models and human postmortem brains using pharmacological methods, performed bioinformatic analysis of cases from the National Alzheimer’s Coordinating Center, characterized Aβ binding of α2AAR using biochemical, cell biological and pharmacological methods, and performed pathological and behavioral studies with AD animal models.ResultIn AD human brains and animal models, α2AAR activity is elevated as compared with non‐AD controls. Activation of this receptor is associated with worsened cognitive function in patients with cognitive deficits. Aβ oligomers bind to an allosteric site on α2AAR with nanomolar affinity. Aβ oligomer binding redirect norepinephrine‐elicited signaling through this receptor to glycogen synthase kinase 3β (GSK3β) activation and tau hyperphosphorylation. This norepinephrine‐dependent mechanism sensitizes pathological GSK3β/tau activation in response to nanomolar accumulations of extracellular Aβ, which is 50‐100 fold lower than the amount required to activate GSK3β by Aβ alone. In vivo treatment with an α2AAR blocker reduces Aβ‐induced GSK3β activation and tau hyperphosphorylation. Moreover, this treatment ameliorates AD‐related pathological changes and improves cognitive function in the two independent AD mouse models.ConclusionWe reveal a previously unappreicated direct role of norepinephrine signaling in connecting Aβ and tau, two key pathological components of AD pathogenesis. The significance of our findings is supported by in vivo evidence in two mouse models, human tissue sample analysis and longitudinal clinical data. Our study provides translational insights into mechanisms underlying Aβ proteotoxicity, which might have strong implications for the interpretation of Aβ clearance trial results and future drug design, and for understanding the selective vulnerability of noradrenergic neurons in AD.