β-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3β/tau cascade.

The noradrenergic link: Norepinephrine (NE) and the noradrenergic system play a main role in cognition and noradrenergic changes have been documented in patients with Alzheimer's disease (AD). However, the role of NE in AD has not been completely elucidated. Here, Zhang et al. show that β-amyloid oligomers are allosteric ligands of the α2A adrenergic receptor (α2AAR) and modulate NE signaling, redirecting the pathway toward GSK3β activation and subsequent tau hyperphosphorylation. Blocking α2AAR reduced tau phosphorylation and ameliorated pathological and cognitive abnormalities in AD mouse models. The brain noradrenergic system is critical for normal cognition and is affected at early stages in Alzheimer's disease (AD). Here, we reveal a previously unappreciated direct role of norepinephrine signaling in connecting β-amyloid (Aβ) and tau, two key pathological components of AD pathogenesis. Our results show that Aβ oligomers bind to an allosteric site on α_2A adrenergic receptor (α_2AAR) to redirect norepinephrine-elicited signaling 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- to 100-fold lower than the amount required to activate GSK3β by Aβ alone. 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. [ABSTRACT FROM AUTHOR]