Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia.
Department of Microbiology, Immunology, and Tropical Medicine, Washington University School of Medicine and Health Sciences, Washington, DC 63110-1010, USA.
Cells. 2022 Sep 3;11(17):2753. doi: 10.3390/cells11172753.
Beta-amyloid (Aβ) has a dual role, both as an important factor in the pathology of Alzheimer's disease and as a regulator in brain physiology. The inhibitory effect of Aβ oligomers on Na,K-ATPase contributes to neuronal dysfunction in Alzheimer's disease. Still, the physiological role of the monomeric form of Aβ interaction with Na,K-ATPase remains unclear. We report that Na,K-ATPase serves as a receptor for Aβ monomer, triggering Src kinase activation. The co-localization of Aβ with α1- and β1-subunits of Na,K-ATPase, and Na,K-ATPase with Src kinase in SH-SY5Y neuroblastoma cells, was observed. Treatment of cells with 100 nM Aβ causes Src kinase activation, but does not alter Na,K-ATPase transport activity. The interaction of Aβ with α1β1 Na,K-ATPase isozyme leads to activation of Src kinase associated with the enzyme. Notably, prevention of Na,K-ATPase:Src kinase interaction by a specific inhibitor pNaKtide disrupts the Aβ-induced Src kinase activation. Stimulatory effect of Aβ on Src kinase was lost under hypoxic conditions, which was similar to the effect of specific Na,K-ATPase ligands, the cardiotonic steroids. Our findings identify Na,K-ATPase as a Aβ receptor, thus opening a prospect on exploring the physiological and pathological Src kinase activation caused by Aβ in the nervous system.
β-淀粉样蛋白（Aβ）具有双重作用，既是阿尔茨海默病病理的重要因素，又是大脑生理学的调节剂。Aβ 寡聚物对 Na,K-ATP 酶的抑制作用导致阿尔茨海默病神经元功能障碍。然而，Aβ 单体与 Na,K-ATP 酶相互作用的生理作用仍不清楚。我们报告称，Na,K-ATP 酶是 Aβ 单体的受体，触发Src 激酶激活。在 SH-SY5Y 神经母细胞瘤细胞中观察到 Aβ 与 Na,K-ATP 酶的α1-和β1-亚基共定位，以及 Na,K-ATP 酶与 Src 激酶共定位。用 100 nM Aβ 处理细胞会导致 Src 激酶激活，但不会改变 Na,K-ATP 酶转运活性。Aβ 与α1β1 Na,K-ATP 酶同工酶的相互作用导致与该酶相关的 Src 激酶激活。值得注意的是，通过特异性抑制剂 pNaKtide 阻止 Na,K-ATP 酶：Src 激酶相互作用会破坏 Aβ 诱导的 Src 激酶激活。在缺氧条件下，Aβ 对 Src 激酶的刺激作用丧失，这与特定的 Na,K-ATP 酶配体，强心甾类相似。我们的发现确定了 Na,K-ATP 酶是 Aβ 的受体，从而为探索 Aβ 在神经系统中引起的生理和病理 Src 激酶激活开辟了前景。
