Na,K-ATPase Acts as a Beta-Amyloid Receptor Triggering Src Kinase Activation

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 Aβ42 oligomers on Na,K-ATPase contributes to neuronal dysfunction in Alzheimer’s disease. Still, the physiological role of the monomeric form of Aβ42 interaction with Na,K-ATPase remains unclear. We report that Na,K-ATPase serves as a receptor for Aβ42 monomer, triggering Src kinase activation. The co-localization of Aβ42 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 Aβ42 causes Src kinase activation, but does not alter Na,K-ATPase transport activity. The interaction of Aβ42 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 Aβ42 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 Aβ42 receptor, thus opening a prospect on exploring the physiological and pathological Src kinase activation caused by Aβ42 in the nervous system

Distinct Effects of Beta-Amyloid, Its Isomerized and Phosphorylated Forms on the Redox Status and Mitochondrial Functioning of the Blood–Brain Barrier Endothelium

The Alzheimer’s disease (AD)-associated breakdown of the blood–brain barrier (BBB) promotes the accumulation of beta-amyloid peptide (Aβ) in the brain as the BBB cells provide Aβ transport from the brain parenchyma to the blood, and vice versa. The breakdown of the BBB during AD may be caused by the emergence of blood-borne Aβ pathogenic forms, such as structurally and chemically modified Aβ species; their effect on the BBB cells has not yet been studied. Here, we report that the effects of Aβ42, Aβ42, containing isomerized Asp7 residue (iso-Aβ42) or phosphorylated Ser8 residue (p-Aβ42) on the mitochondrial potential and respiration are closely related to the redox status changes in the mouse brain endothelial cells bEnd.3. Aβ42 and iso-Aβ42 cause a significant increase in nitric oxide, reactive oxygen species, glutathione, cytosolic calcium and the mitochondrial potential after 4 h of incubation. P-Aβ42 either does not affect or its effect develops after 24 h of incubation. Aβ42 and iso-Aβ42 activate mitochondrial respiration compared to p-Aβ42. The isomerized form promotes a greater cytotoxicity and mitochondrial dysfunction, causing maximum oxidative stress. Thus, Aβ42, p-Aβ42 and iso-Aβ42 isoforms differently affect the BBBs’ cell redox parameters, significantly modulating the functioning of the mitochondria. The changes in the level of modified Aβ forms can contribute to the BBBs’ breakdown during AD

Na,K-ATPase Acts as a Beta-Amyloid Receptor Triggering Src Kinase Activation

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 Aβ42 oligomers on Na,K-ATPase contributes to neuronal dysfunction in Alzheimer’s disease. Still, the physiological role of the monomeric form of Aβ42 interaction with Na,K-ATPase remains unclear. We report that Na,K-ATPase serves as a receptor for Aβ42 monomer, triggering Src kinase activation. The co-localization of Aβ42 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 Aβ42 causes Src kinase activation, but does not alter Na,K-ATPase transport activity. The interaction of Aβ42 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 Aβ42 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 Aβ42 receptor, thus opening a prospect on exploring the physiological and pathological Src kinase activation caused by Aβ42 in the nervous system