[200424 저널발표] β-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3β/tau cascade.
최현정 │ 2020-04-21
Sci Transl Med. 2020 Jan 15;12(526). pii: eaay6931. doi: 10.1126/scitranslmed.aay6931.
β-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3β/tau cascade.
Zhang F1, Gannon M1, Chen Y1, Yan S2, Zhang S3, Feng W1, Tao J1, Sha B1, Liu Z4, Saito T5, Saido T5, Keene CD6, Jiao K2, Roberson ED7, Xu H8, Wang Q9.
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 α2A adrenergic receptor (α2AAR) 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.
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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