| First Author | Zhang F | Year | 2020 |
| Journal | Sci Transl Med | Volume | 12 |
| Issue | 526 | PubMed ID | 31941827 |
| Mgi Jnum | J:285209 | Mgi Id | MGI:6385712 |
| Doi | 10.1126/scitranslmed.aay6931 | Citation | Zhang F, et al. (2020) beta-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3beta/tau cascade. Sci Transl Med 12(526) |
| abstractText | 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 beta-amyloid (Abeta) and tau, two key pathological components of AD pathogenesis. Our results show that Abeta oligomers bind to an allosteric site on alpha2A adrenergic receptor (alpha2AAR) to redirect norepinephrine-elicited signaling to glycogen synthase kinase 3beta (GSK3beta) activation and tau hyperphosphorylation. This norepinephrine-dependent mechanism sensitizes pathological GSK3beta/tau activation in response to nanomolar accumulations of extracellular Abeta, which is 50- to 100-fold lower than the amount required to activate GSK3beta by Abeta 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 Abeta proteotoxicity, which might have strong implications for the interpretation of Abeta clearance trial results and future drug design and for understanding the selective vulnerability of noradrenergic neurons in AD. |
