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.
Highlights
Alzheimer’s disease (AD) is the most widespread neurodegenerative disorder, which is characterized by decline of memory and cognitive functions due to extensive neuronal death
We present a model describing the parallel interactions between cyclophilin D (cypD), 17β-HSD10, and different fragments of Aβ in different oligomerization states, and show that the model allows estimation of the evolution of levels of free biomolecules and their complexes under selected conditions associated with the progression of AD
These results contradict previously published studies; for instance, under the conditions used for the preparation of Sample 2, Aβ1–42 was demonstrated to oligomerize by Garai et al [13]
Summary
Alzheimer’s disease (AD) is the most widespread neurodegenerative disorder, which is characterized by decline of memory and cognitive functions due to extensive neuronal death. The different fragments of Aβ exhibit different oligomerization dispositions, with Aβ1-42 being more prone to form oligomers than Aβ1–40 [12,13]. Such oligomerization is known to increase neuronal toxicity of Aβ [14]. The major Aβ binding partners associated with AD are cyclophilin D (cypD) and 17β-hydroxysteroid dehydrogenase 10 (17β-HSD10) These interactions have been shown to lead to mitochondrial dysfunctions [3,19], including impaired energy metabolism [20], production of reactive oxygen species (ROS) [21], perturbation in calcium homeostasis [22], and formation and opening of the mitochondrial permeability transition pores (mPTPs) [23]. The exact mechanisms behind these processes remain largely unknown
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