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.

中文翻译：

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β-淀粉样蛋白重定向去甲肾上腺素信号以激活致病性 GSK3β/tau 级联。

大脑去甲肾上腺素能系统对正常认知至关重要，并且在阿尔茨海默病 (AD) 的早期阶段受到影响。在这里，我们揭示了去甲肾上腺素信号传导在连接 β-淀粉样蛋白 (Aβ) 和 tau（AD 发病机制的两个关键病理成分）中的先前未被认识的直接作用。我们的结果表明，Aβ 寡聚体与 α2A 肾上腺素能受体 (α2AAR) 上的变构位点结合，将去甲肾上腺素引发的信号转导至糖原合酶激酶 3β (GSK3β) 激活和 tau 过度磷酸化。这种去甲肾上腺素依赖性机制使病理性 GSK3β/tau 激活敏感，以响应细胞外 Aβ 的纳摩尔积累，这比单独通过 Aβ 激活 GSK3β 所需的量低 50 到 100 倍。我们发现的重要性得到了两种小鼠模型的体内证据的支持，人体组织样本分析和纵向临床数据。我们的研究提供了对 Aβ 蛋白毒性潜在机制的转化见解，这可能对解释 Aβ 清除试验结果和未来药物设计以及了解 AD 中去甲肾上腺素能神经元的选择性脆弱性具有重要意义。