Oleuropein aglycone protects against pyroglutamylated-3 amyloid-ß toxicity: biochemical, epigenetic and functional correlates

Abstract

a b s t r a c tAmyloid-ß (Aß) fragments, oligomeric Aß aggregates, and pyroglutamylated-Aß peptides, as well as epigenetic mechanisms and autophagy dysfunction all appear to contribute in various ways to Alzheimer's disease progression. We previously showed that dietary supplementation of oleuropein aglycone, a natural phenol abundant in the extra virgin olive oil, can be protective by reducing Aß42 deposits in the brain of young and middle-aged TgCRND8 mice. Here, we extended our study to aged TgCRND8 mice showing increased pE3-Aß in the brain deposits. We report that oleuropein aglycone is active against glutaminylcyclase-catalyzed pE3-Aß generation reducing enzyme expression and interferes both with Aß42 and pE3-Aß aggregation. Moreover, the phenol astonishingly activates neuronal autophagy even in mice at advanced stage of pathology, where it increases histone 3 and 4 acetylation, which matches both a decrease of histone deacetylase 2 expression and a significant improvement of synaptic function. The occurrence of these functional, epigenetic, and histopathologic beneficial effects even at a late stage of the pathology suggests that the phenol could be beneficial at the therapeutic, in addition to the prevention, level.

Autophagy in synaptic development, function, and pathology

“…2D), matches the synaptic dysfunction in AD and contributes to the cognitive and memory deficits in patients. This hypothesis is supported by a recent fi nding that oleuropein aglycone protects against pyroglutamylated-3 amyloid β peptide toxicity and synaptic dysfunction by activating neuronal autophagic machinery as determined by elevated Beclin 1 and LC3 immunoreactivity along with enhanced degradation of autophagy substrates [71] .…”

Mediterranean diet and health status: Active ingredients and pharmacological mechanisms

“…In a mouse model of neurodegenerative diseases, oleuropein elicited histone modifications (increased acetylation of H3 and H4 and reduced expression of histone deacetylase 2). This was accompanied by improved synaptic function and increased neuronal autophagy (Luccarini et al, ). In an in vitro breast cancer cell study, an EVOO extract rich in oleuropein favoured a hyperacetylated status in H3, which could be associated with a reduced frequency of cellular mitosis (Oliveras‐Ferraros et al, ).…”

An overview of the pharmacology of olive oil and its active ingredients

“…After supplementation with OLE aglycone, TgCRND8 mice showed improved cognitive performance, presenting a reduction in Aβ formation and deposition in brain regions (Luccarini et al, ). This was linked with a reduction of expression levels of glutaminyl cyclase (Luccarini et al, ) and to an up‐regulation of autophagy‐related genes, such as Beclin‐1, LC3II, p62, and cathepsin B (Grossi et al, ). Although HT mildly benefited cognitive behaviour in APP/PS1 mice, it had no effect on brain Aβ accumulation.…”