Study of Biomolecular Interactions of Mitochondrial Proteins Related to Alzheimer’s Disease: Toward Multi-Interaction Biomolecular Processes

Abstract

Progressive mitochondrial dysfunction due to the accumulation of amyloid beta (Aβ) peptide within the mitochondrial matrix represents one of the key characteristics of Alzheimer’s disease (AD) and appears already in its early stages. Inside the mitochondria, Aβ interacts with a number of biomolecules, including cyclophilin D (cypD) and 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10), and affects their physiological functions. However, despite intensive ongoing research, the exact mechanisms through which Aβ impairs mitochondrial functions remain to be explained. In this work, we studied the interactions of Aβ with cypD and 17β-HSD10 in vitro using the surface plasmon resonance (SPR) method and determined the kinetic parameters (association and dissociation rates) of these interactions. This is the first work which determines all these parameters under the same conditions, thus, enabling direct comparison of relative affinities of Aβ to its mitochondrial binding partners. Moreover, we used the determined characteristics of the individual interactions to simulate the concurrent interactions of Aβ with cypD and 17β-HSD10 in different model situations associated with the progression of AD. This study not only advances the understanding of Aβ-induced processes in mitochondria during AD, but it also provides a new perspective on research into complex multi-interaction biomolecular processes in general.

Ionic Environment Affects Biomolecular Interactions of Amyloid-β: SPR Biosensor Study

“…In our previous study, we showed that processes related to AD such as increased production of Aβ, unbalanced production of Aβ fragments favoring Aβ 1–42 or oligomerization of Aβ 1–42 significantly affect the interactions between Aβ and mitochondrial proteins and enhance the binding of Aβ 1–42 to both cypD and 17β-HSD10 [ 23 ]. In this work, we demonstrate that the mitochondrial ionic environment also plays an important role in biomolecular processes taking place in the mitochondrial matrix, and we show that the conditions causing decreased concentrations of K + and increased concentrations of Mg 2+ may further enhance the binding of Aβ 1–42 to both cypD and 17β-HSD10.…”

“…In this work, Aβ 1–40 and Aβ 1–42 fragments with different oligomerization states were prepared using the procedures described in our previous study [ 23 ]. The oligomeric forms of Aβ 1–40 and Aβ 1–42 were prepared using Preparation A, whereas monomeric Aβ 1–40 and monomeric Aβ 1–42 were prepared using Preparation C and Preparation B, respectively.…”

“…Although there are differences in the biological characteristics of natural (obtained from biological samples) and synthetic oligomers, the differences are mainly in the efficiency of their action rather than in their function in biological processes [ 21 , 22 ]. In our recent work, we studied interactions of Aβ with cypD and 17β-HSD10, and with the use of a multi-interaction model, we demonstrated that the processes associated with early stages of AD such as the oligomerization of Aβ and increased/favored production of Aβ 1–42 affect the equilibrium between these biomolecules in the mitochondrial matrix [ 23 ]. We also showed that 17β-HSD10 specifically binds cypD and thus regulates levels of free cypD in the mitochondrial matrix [ 24 , 25 ].…”