posted on 2015-04-15, 00:00authored byDiego Mastroeni, Omar M. Khdour, Pablo M. Arce, Sidney M. Hecht, Paul D. Coleman
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.