β-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3β/tau cascade
| Autor: | Bingdong Sha, Zhenghui Liu, Mary C. Gannon, Shun Yan, Jiahui Tao, Qin Wang, Takaomi C. Saido, Takashi Saito, Fang Zhang, C. Dirk Keene, Yunjia Chen, Sixue Zhang, Wendy Feng, Kai Jiao, Erik D. Roberson, Huaxi Xu |
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| Rok vydání: | 2019 |
| Předmět: |
Amyloid beta-Peptides
Glycogen Synthase Kinase 3 beta Adrenergic receptor Chemistry Allosteric regulation tau Proteins General Medicine Article Pathogenesis Norepinephrine Mice Proteotoxicity GSK-3 Extracellular medicine Animals Humans Signal transduction Neuroscience medicine.drug Signal Transduction |
| Zdroj: | Sci Transl Med |
| ISSN: | 1946-6242 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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