Abstract
In early stages of Alzheimer’s disease (AD), amyloid beta (Aβ) accumulates in the mitochondrial matrix and interacts with mitochondrial proteins, such as cyclophilin D (cypD) and 17β-hydroxysteroid dehydrogenase 10 (17β-HSD10). Multiple processes associated with AD such as increased production or oligomerization of Aβ affect these interactions and disbalance the equilibrium between the biomolecules, which contributes to mitochondrial dysfunction. Here, we investigate the effect of the ionic environment on the interactions of Aβ (Aβ1–40, Aβ1–42) with cypD and 17β-HSD10 using a surface plasmon resonance (SPR) biosensor. We show that changes in concentrations of K+ and Mg2+ significantly affect the interactions and may increase the binding efficiency between the biomolecules by up to 35% and 65% for the interactions with Aβ1–40 and Aβ1–42, respectively, in comparison with the physiological state. We also demonstrate that while the binding of Aβ1–40 to cypD and 17β-HSD10 takes place preferentially around the physiological concentrations of ions, decreased concentrations of K+ and increased concentrations of Mg2+ promote the interaction of both mitochondrial proteins with Aβ1–42. These results suggest that the ionic environment represents an important factor that should be considered in the investigation of biomolecular interactions taking place in the mitochondrial matrix under physiological as well as AD-associated conditions.
Highlights
Alzheimer’s disease (AD) is currently the most common neurodegenerative disease of the elderly
We studied interactions of Aβ with cyclophilin D (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 Aβ1–42 affect the equilibrium between these biomolecules in the mitochondrial matrix [23]
We showed that processes related to AD such as increased production of Aβ, unbalanced production of Aβ fragments favoring Aβ1–42 or oligomerization of Aβ1–42 significantly affect the interactions between Aβ and mitochondrial proteins and enhance the binding of Aβ1–42 to both cypD and 17β-HSD10 [23]
Summary
Alzheimer’s disease (AD) is currently the most common neurodegenerative disease of the elderly. It is characterized by extensive neuronal failure in which, according to the current understanding of AD, peptide amyloid beta (Aβ) plays a central role. During AD, the production of Aβ is increased and skewed towards Aβ1–42 [2]. Both fragments of Aβ are known to form oligomers (Aβ1–42 more readily than Aβ1–40 [3,4]) which have been shown to cause more substantial neuronal damage than monomers [5].
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