title: Novel antioxidants protect mitochondria from the effects of oligomeric amyloid beta and contribute to the maintenance of epigenome function.
abstract: Alzheimer's disease is associated with metabolic deficits and reduced mitochondrial function, with the latter due to the effects of oligomeric amyloid beta peptide (AβO) on the respiratory chain. Recent evidence has demonstrated reduction of epigenetic markers, such as DNA methylation, in Alzheimer's disease. Here we demonstrate a link between metabolic and epigenetic deficits via reduction of mitochondrial function which alters the expression of mediators of epigenetic modifications. AβO-induced loss of mitochondrial function in differentiated neuronal cells was reversed using two novel antioxidants (1 and 2); both have been shown to mitigate the effects of reactive oxygen species (ROS), and compound 1 also restores adenosine triphosphate (ATP) levels. While both compounds were effective in reducing ROS, restoration of ATP levels was associated with a more robust response to AβO treatment. Our in vitro system recapitulates key aspects of data from Alzheimer's brain samples, the expression of epigenetic genes in which are also shown to be normalized by the novel analogues.
authors: †L.J. Roberts Alzheimer's Disease Center, Banner Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, Arizona 85351, United States.|‡School for Mental Health and Neuroscience (MHeNS), Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, European Graduate School of Neuroscience (EURON), Maastricht University Medical Centre, 6229 HX Maastricht, The Netherlands.
authors: Diego
authors: D
authors: Mastroeni
authors: §Center for BioEnergetics, Biodesign Institute, and Department of Chemistry and Biochemistry, Arizona State University, Tempe, Arizona 85287, United States.
authors: Omar M
authors: OM
authors: Khdour
authors: §Center for BioEnergetics, Biodesign Institute, and Department of Chemistry and Biochemistry, Arizona State University, Tempe, Arizona 85287, United States.
authors: Pablo M
authors: PM
authors: Arce
authors: §Center for BioEnergetics, Biodesign Institute, and Department of Chemistry and Biochemistry, Arizona State University, Tempe, Arizona 85287, United States.
authors: Sidney M
authors: SM
authors: Hecht
authors: †L.J. Roberts Alzheimer's Disease Center, Banner Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, Arizona 85351, United States.
authors: Paul D
authors: PD
authors: Coleman
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002843:Chromatin / Q000187:drug effects / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects* / Q000502:physiology; D051548:Histone Acetyltransferases / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D010446:Peptide Fragments / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D013702:Temporal Lobe / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002843:Chromatin; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); D000255:Adenosine Triphosphate; D051548:Histone Acetyltransferases; C487137:KAT6B protein, human
keywords: Alzheimer’s disease; Mitochondria; epigenetics; multifunctional radical quenchers