The Polyphenol Oleuropein Aglycone Protects TgCRND8 Mice against Aß Plaque Pathology

Abstract

The claimed beneficial effects of the Mediterranean diet include prevention of several age-related dysfunctions including neurodegenerative diseases and Alzheimer-like pathology. These effects have been related to the protection against cognitive decline associated with aging and disease by a number of polyphenols found in red wine and extra virgin olive oil. The double transgenic TgCRND8 mice (overexpressing the Swedish and Indiana mutations in the human amyloid precursor protein), aged 1.5 and 4, and age-matched wild type control mice were used to examine in vivo the effects of 8 weeks dietary supplementation of oleuropein aglycone (50 mg/kg of diet), the main polyphenol found in extra virgin olive oil. We report here that dietary supplementation of oleuropein aglycone strongly improves the cognitive performance of young/middle-aged TgCRND8 mice, a model of amyloid-ß deposition, respect to age-matched littermates with un-supplemented diet. Immunofluorescence analysis of cerebral tissue in oleuropein aglycone-fed transgenic mice showed remarkably reduced ß-amyloid levels and plaque deposits, which appeared less compact and “fluffy”; moreover, microglia migration to the plaques for phagocytosis and a remarkable reduction of the astrocyte reaction were evident. Finally, oleuropein aglycone-fed mice brain displayed an astonishingly intense autophagic reaction, as shown by the increase of autophagic markers expression and of lysosomal activity. Data obtained with cultured cells confirmed the latter evidence, suggesting mTOR regulation by oleuropein aglycone. Our results support, and provide mechanistic insights into, the beneficial effects against Alzheimer-associated neurodegeneration of a polyphenol enriched in the extra virgin olive oil, a major component of the Mediterranean diet.

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

“…6) and piriform and/or entorhinal cortices of OLE-fed Tg mice, as compared with untreated 12-month-old Tg mice. Although to a lesser extent than in OLE-fed Tg mice, Beclin 1 and LC3 IRs were also more intense in OLE-fed wt mice than in untreated animals, in agreement with our previous data (Grossi et al, 2013), supporting a general effect of OLE as an inducer of autophagy.…”

“…As we have recently reported (Grossi et al, 2013) each age group of mice was equally treated for 8 weeks with a modified low-fat (5.0%) AIN-76A diet (10 g/d per mouse) composed of 50.0% sucrose, 5.0% fat, 20.0% casein, 15.0% corn starch, 5.0% powdered cellulose, 3.5% AIN-76 mineral mix, 1.0% AIN-76A vitamin mix, 0.3% DL-methionine, and 0.2% choline bitartrate (Piccioni, Milan, Italy), either as such (untreated mice) or supplemented with OLE (50 mg/kg of diet) (OLE-fed mice). Such OLE dose approximately corresponds to the amount that mice would ingest if the 5.0% fat present in the diet consisted in an extra virgin olive oil very rich in phenols (Galvano et al, 2007).…”

“…Such an activation was considered a major responsible for the marked reduction and disaggregation of Aß42 plaque deposits, which also appeared less compact and more "fluffy" in OLE-fed Tg mice (Grossi et al, 2013). Here, the same intense activation of autophagy was found in the cortex of 12-month-old mice fed with OLE.…”

“…OLE (50 mM) and SAHA (100 mM), dissolved in DMSO and stored at À20 C, were daily diluted in artificial cerebral spinal fluid to a final concentration of 50 mM (a dose known to produce significant effects in cultured cells, that is, autophagy induction as reported in Grossi et al, 2013) and 5.0 mM, respectively. The slices were incubated in the presence of OLE or SAHA for at least 1 hour before electrophysiological recordings and superfused with either substance for the entire time of the experiment.…”

“…We have recently reported that 8-week dietary supplementation of oleuropein aglycone (OLE), a natural phenol (secoiridoid) abundant in the extra virgin olive oil, improves learning and memory, reduces de novo Aß42 deposition, favors preformed Aß42 plaque disassembly and greatly stimulates the autophagic response in the young and middle-aged TgCRND8 (Tg) mouse model of Aß deposition (Grossi et al, 2013). Our aim was to provide more information on the molecular and biological basis of these effects by investigating whether the same dietary supplementation of OLE resulted, directly or indirectly, in a reduction of the toxic pE3-Aß peptide deposits in the brain of the same Tg mouse model at different ages corresponding to early, intermediate, and late stage of Aß deposition.…”