Interaction Interface of Aβ42 with Human Na,K-ATPase Studied by MD and ITC and Inhibitor Screening by MD

Alzheimer's disease (AD) is a neurodegenerative disease accompanied by progressive cognitive and memory dysfunction due to disruption of normal electrotonic properties of neurons and neuronal loss. The Na,K-ATPase interaction with beta amyloid (A beta) plays an important role in AD pathogenesis. It has been shown that Na,K-ATPase activity in the AD brain was significantly lower than those in age-matched control brain. The interaction of A beta(42) with Na,K-ATPase and subsequent oligomerization leads to inhibition of the enzyme activity. In this study interaction interfaces between three common A beta(42) isoforms, and different conformations of human Na,K-ATPase (alpha 1 beta 1) have been obtained using molecular modeling, including docking and molecular dynamics (MD). Interaction sites of Na,K-ATPase with A(3 42 are localized between extracellular parts of alpha- and beta-subunits and are practically identical for Na,K-ATPase at different conformations. Thermodynamic parameters for the formation of Na,K-ATPase:A beta(42) complex at different conformations acquired by isothermal titration calorimetry (ITC) are similar, which is in line with the data of molecular modeling. Similarity of Na,K-ATPase interaction interfaces with A beta in all conformations allowed us to cross-screen potential inhibitors for this interaction and find pharmaceutical compounds that could block it.

Automated summary

Alzheimer's disease (AD) is a neurodegenerative disease characterized by disrupted neuronal properties and loss, affecting cognitive and memory functions. The interaction between Na,K-ATPase and beta amyloid (A beta) is important in AD pathogenesis. This study used molecular modeling to identify interaction sites between A beta(42) isoforms and Na,K-ATPase, providing insights for potential inhibitors. The findings contribute to understanding the underlying mechanisms and developing targeted interventions for AD.