?-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3?/tau cascade.

ABSTRACT: 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 ?-amyloid (A?) and tau, two key pathological components of AD pathogenesis. Our results show that A? oligomers bind to an allosteric site on ?_2A adrenergic receptor (?_2AAR) to redirect norepinephrine-elicited signaling to glycogen synthase kinase 3? (GSK3?) activation and tau hyperphosphorylation. This norepinephrine-dependent mechanism sensitizes pathological GSK3?/tau activation in response to nanomolar accumulations of extracellular A?, which is 50- to 100-fold lower than the amount required to activate GSK3? by A? 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 A? proteotoxicity, which might have strong implications for the interpretation of A? clearance trial results and future drug design and for understanding the selective vulnerability of noradrenergic neurons in AD.

SUBMITTER: Zhang F 

PROVIDER: S-EPMC7891768 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature