Possible role of amyloid-beta, adenine nucleotide translocase and cyclophilin-D interaction in mitochondrial dysfunction of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a common neurodegenerative disease characterized by both extra- as well as intracellular deposition of amyloid beta peptides (Aβ). The accumulation of Aβ in mitochondria is associated with mitochondrial dysfunction and oxidative stress in AD. Recent evidences suggest the involvement of Aβ interaction with mitochondrial proteins such as cyclophilin-D (CypD) in oxidative stress, mitochondrial permeability transition (MPT) and Alzheimer's associated neurodegeneration. The present study is an effort to elucidate the molecular interaction of Aβ with other proteins involved in MPT like adenine nucleotide translocase (ANT). Based on our prediction for sub-cellular localization using WolfPSORT and other experimental evidences, we suggest that Aβ molecules localize in mitochondrial inner membrane in close vicinity with ANT. Our simulation study for protein–protein interaction clearly suggests that the ANT-Aβ interaction is stronger than CypD-Aβ interaction. Further the lipophilic nature and evidences regarding the localization of Aβ in the mitochondrial inner-membrane also support the possibility of strong interaction between ANT and Aβ. Interaction between ANT and Aβ may affect normal physiological function of ANT i.e. transport of ATP and ADP. Since both the CypD-Aβ as well as ANT-Aβ interaction are energetically favorable and both CypD and ANT are associated with the regulation of MPT, the functional impact of both these interactions warrants more in-depth investigations for elucidating the mechanisms involved in Aβ-induced oxidative stress.

Further Evidence on Mitochondrial Targeting of β-Amyloid and Specificity of β-Amyloid-Induced Mitotoxicity in Neurons

“…A ␤ is also thought to interact with the mitochondrial membrane. A recent study of interactions between A ␤ and proteins of the membrane permeability transition pore (MPTP) suggested that the interaction between A ␤ and adenine nucleotide translocase is stronger than that between A ␤ and cyclophilin-D [15] .…”

“…Its interaction with several membrane proteins such as one involved in the MPTP may increase the permeability of mitochondrial membranes [15] . Indeed, we found that the morphology of the mitochondrial membrane was altered at the highest dose of A ␤ 1-42 used (10 M ).…”

A Direct Interaction Between Mitochondrial Proteins and Amyloid-β Peptide and its Significance for the Progression and Treatment of Alzheimer’s Disease

“…A direct interaction between ANT and Aβ was firstly predicted in a computational simulation and later described using an in vitro assay. In that study Aβ 1-42 fibrils were shown to inhibit ANT1 mediated ADP/ATP exchange in a noncompetitive manner [35,47]. However, the consequences of such an interaction remain elusive as well as characterising the role of ANT in mPT and cell death.…”

“…The binding between CypD and Aβ was also studied using computational simulations [35]. It was suggested that CypD mediated Aβ toxicity could be driven in two ways, indirectly by elevated ROS levels caused by Aβ accumulation inside mitochondria and directly, specifically via the CypD-Aβ interaction [31].…”

New insights into huperzine A for the treatment of Alzheimer's disease

“…This potential independent pharmacological target of huperzine A on mitochondria may further interpret the anti-oxidative stress [30][31][32][33][34][35][36] and anti-apoptotic effects [30,31,[37][38][39] shown by huperzine A administration in various in vivo and in vitro models (Figure 1). Interestingly, several lines of evidence suggest that Aβ directly interacts with several proteins on and inside mitochondria [40] : Aβ could import into mitochondria through a pore formed by the outer membrane (TOM40) and the inner membrane (TIM22) [41] ; Aβ could also interact with mitochondrial proteins from the membrane permeability transition pore (MPTP) [42] , which may in turn affect the mitochondrial membrane potential; Aβ was also reported to bind with β-amyloid binding alcohol dehydrogenase (ABAD) upon entering into mitochondria and leading to mitochondrial dysfunction [43,44] . Although the precise molecular target of huperzine A on Aβ-induced mitochondrial dysfunction remains to be clarified, whether and how huperzine A affects above mentioned Aβ-mitochondrion interactions could be a very promising future project.…”