Amyloid-β Peptide Binds to Cytochrome C Oxidase Subunit 1

Abstract

Extracellular and intraneuronal accumulation of amyloid-beta aggregates has been demonstrated to be involved in the pathogenesis of Alzheimer's disease (AD). However, the precise mechanism of amyloid-beta neurotoxicity is not completely understood. Previous studies suggest that binding of amyloid-beta to a number of macromolecules has deleterious effects on cellular functions. Mitochondria were found to be the target for amyloid-beta, and mitochondrial dysfunction is well documented in AD. In the present study we have shown for the first time that Aβ 1–42 bound to a peptide comprising the amino-terminal region of cytochrome c oxidase subunit 1. Phage clone, selected after screening of a human brain cDNA library expressed on M13 phage and bearing a 61 amino acid fragment of cytochrome c oxidase subunit 1, bound to Aβ 1–42 in ELISA as well as to Aβ aggregates present in AD brain. Aβ 1–42 and cytochrome c oxidase subunit 1 co-immunoprecipitated from mitochondrial fraction of differentiated human neuroblastoma cells. Likewise, molecular dynamics simulation of the cytochrome c oxidase subunit 1 and the Aβ 1–42 peptide complex resulted in a reliable helix-helix interaction, supporting the experimental results. The interaction between Aβ 1–42 and cytochrome c oxidase subunit 1 may explain, in part, the diminished enzymatic activity of respiratory chain complex IV and subsequent neuronal metabolic dysfunction observed in AD.

Deciphering an interplay of proteins associated with amyloid β 1-42 peptide and molecular mechanisms of Alzheimer’s disease

“…These metabolic alterations in early stages of the disease and in patients diagnosed with AD correspond to ETC damage, particularly in the activity of the cytochrome C oxidase enzyme (Hernández-Zimbrón et al, 2012;Bobba et al, 2013). Experiments in transgenic mice have demonstrated the presence of this peptide within cellular organelles, which correlate with the magnitude of mitochondrial dysfunction caused by the inhibition of the ETC and with the degree of cognitive damage observed in this model of AD (Ghosh et al, 2013).…”

Mitochondria and aging: A role for the mitochondrial transition pore?

“…This is particularly true for Alzheimer's disease which is characterized by the presence of extracellular senile plaques, mainly composed of amyloid‐β (Aβ) peptide and intracellular neurofibrillary tangles made up of hyperphosphorylated tau protein (Selkoe, 2004). Several studies demonstrate that the Aβ peptide accumulates progressively into mitochondria (Hansson Petersen et al., 2008; Manczak et al., 2006) where it inhibits the activities of the respiratory chain complex and thus oxidative phosphorylation ( Hernandez‐Zimbron et al., 2012; Lahmy, Long, Morin, Villard, & Maurice, 2015; Tillement, Lecanu, & Papadopoulos, 2011; Tsukada et al., 2014). The Aβ peptide can also potentially cause mPTP opening in vivo as it induces mitochondrial swelling, decreases mitochondrial membrane potential, and potentiates the effect of mPTP inducers in isolated brain mitochondria (Du et al., 2008; Moreira, Santos, Moreno, & Oliveira, 2001; Shevtzova, Kireeva, & Bachurin, 2001).…”

Alzheimer’s Disease: A Heme–Aβ Perspective

“…60 Recent studies have shown that the Aβ can interact with cytochromes. 61 Addition of a stoichiometric amount of oxidized Cyt c (Soret at 410 nm) to reduced heme−Aβ (Soret at 383 nm) results in the appearance of a Soret band at 416 nm corresponding to reduced cytochrome c, with a shoulder at 364 nm corresponding to oxidized heme−Aβ. The formation of sharp Q bands at 520 and 550 nm characteristic of reduced …”