Research ArticleAlzheimer’s Disease

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

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Science Translational Medicine  15 Jan 2020:
Vol. 12, Issue 526, eaay6931
DOI: 10.1126/scitranslmed.aay6931

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The noradrenergic link

Norepinephrine (NE) and the noradrenergic system play a main role in cognition and noradrenergic changes have been documented in patients with Alzheimer’s disease (AD). However, the role of NE in AD has not been completely elucidated. Here, Zhang et al. show that β-amyloid oligomers are allosteric ligands of the α2A adrenergic receptor (α2AAR) and modulate NE signaling, redirecting the pathway toward GSK3β activation and subsequent tau hyperphosphorylation. Blocking α2AAR reduced tau phosphorylation and ameliorated pathological and cognitive abnormalities in AD mouse models.

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