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

AR) 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.