Amyloid-β-Peptide Reduces the Expression Level of Mitochondrial Cytochrome Oxidase Subunits

Abstract

Mitochondrial dysfunction is an important cause of neurological disorder including Alzheimer's disease (AD). Mitochondria play a key role in the generation of reactive oxygen species (ROS), resulting in oxidative damage to neuronal cell and cellular compartments in the AD brain. Cytotoxicity induced by amyloid-beta (Abeta), a protein fragment of 25-35 amino acids in amyloid plaques has been shown to have neuro-toxic properties. They seem to involve mitochondrial dysfunction, but the underlying mechanisms are not clearly understood. The purpose of this study was to assess whether Abeta induced mitochondrial dysfunction involves changes in cytochrome c oxidase (COX) expression. We measured the activities of COX after expose of SK-N-SH cells (a human neuroblastoma cell line) to Abeta. We found that levels of mRNAs expressing mitochondrial COX subunits decreased significantly in Abeta-treated SK-N-SH cells in a dose-dependent manner. Human mitochondrial transcription factor-1 (TFAM) mRNA level also decreased after Abeta-treatment. These results suggest that Abeta modulates the mitochondrial gene expression through a decrease in TFAM.

Sporadic inclusion-body myositis: Conformational multifactorial ageing-related degenerative muscle disease associated with proteasomal and lysosomal inhibition, endoplasmic reticulum stress, and accumulation of amyloid-β42 oligomers and phosphorylated tau

“…We have shown that excessive APP and Ab contributes to the mitochondrial abnormalities [160]. This concept of AbPP/Ab mitochondrialtoxicity is now supported by studies in other systems, especially as putatively related to AD and Parkinson brain [156,161,162]. a-synuclein accumulated in s-IBM muscle fibers may, in oligomeric and misfolded forms, also contribute to mitochondrial toxicity [161].…”

Mitochondrial Dysfunction in Skeletal Muscle of Amyloid Precursor Protein-overexpressing Mice

“…Although the specific effects of these peptides on mitochondria are still under investigation, A␤ has been demonstrated to accumulate into this organelle and destabilize its membrane properties (35,36). Deleterious effects of A␤ on the mitochondrial function include reduced cytochrome c oxidase activity (35,37) caused by inhibition of its gene expression (37), decreased respiration and ATP synthesis, and cytochrome c release (35,38).…”

The Mitochondrial Secret(ase) of Alzheimer's Disease

“…1). Supporters of the amyloid cascade hypothesis have used it to explain AD-related mitochondrial pathology because: 1) AβPP and Aβ accumulates in mitochondria from brains of transgenic mice and AD subjects [144][145][146][147]; 2) binding of Aβ to the mitochondrial proteins Aβ-binding alcohol dehydrogenase and cyclophilin D is associated with increased oxidative stress, cytochrome c release, reduced mitochondrial membrane potential, and neuronal cell death [146,148]; 3) features of reduced Krebs cycle and ETC enzymatic activity, impaired state 3 and state 4 respiration, and in vivo elevation of oxidative stress demonstrated in AD and transgenic mouse brains were associated with Aβ [126,[149][150][151][152][153][154][155]; and 4) the direct reduction of cytochrome oxidase expression and activity by Aβ 42 and Aβ 25−35 (a toxic Aβ fragment) supported this hypothesis [48,156,157]. Though evidence for Aβ-induced pathology is plentiful, PET-scan measured reductions in brain glucose metabolism in MCI and AD individuals [158][159][160][161] warrant a further look at the role mitochondrial bioenergetics play.…”