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. 2017 Jun 21;4(8):564-574.
doi: 10.1002/acn3.431. eCollection 2017 Aug.

Extra-virgin Olive Oil Ameliorates Cognition and Neuropathology of the 3xTg Mice: Role of Autophagy

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Free PMC article

Extra-virgin Olive Oil Ameliorates Cognition and Neuropathology of the 3xTg Mice: Role of Autophagy

Elisabetta Lauretti et al. Ann Clin Transl Neurol. .
Free PMC article

Abstract

Objective: Consumption of extra virgin olive oil (EVOO), a major component of the Mediterranean diet, has been associated with reduced incidence of Alzheimer's disease (AD). However, the mechanisms involved in this protective action remain to be fully elucidated.

Methods: Herein, we investigated the effect of daily consumption of EVOO on the AD-like phenotype of a mouse mode of the disease with plaques and tangles.

Results: Triple transgenic mice (3xTg) received either regular chow or a chow diet supplemented with EVOO starting at 6 months of age for 6 months, then assessed for the effect of the diet on the AD-like neuropathology and behavioral changes. Compared with controls, mice receiving the EVOO-rich diet had an amelioration of their behavioral deficits, and a significant increase in the steady state levels of synaptophysin, a protein marker of synaptic integrity. In addition, they had a significant reduction in insoluble Aβ peptide levels and deposition, lower amount of phosphorylated tau protein at specific epitopes, which were secondary to an activation of cell autophagy.

Interpretation: Taken together, our findings support a beneficial effect of EVOO consumption on all major features of the AD phenotype (behavioral deficits, synaptic pathology, Aβ and tau neuropathology), and demonstrate that autophagy activation is the mechanism underlying these biological actions.

Figures

Figure 1
Figure 1
Chronic administration of EVOO‐rich diet ameliorates behavioral impairments in 3xTg mice. Starting at 6 months of age, 3xTg mice were randomized to receive regular chow diet (CTR) or diet enriched with EVOO (EVOO) until they were 12‐month‐old. (A) Monthly body weight of CTR (n = 12) and EVOO (n = 10) mice from the beginning until the end of the study. (B) The same mice were tested in the Y‐maze paradigm for the number of entries and the percentage of alternation (*< 0.05, **P < 0.01). (C) Percentage of freezing in the contextual and cued phase of the fear conditioning paradigm (CTR n = 11, EVOO, n = 10). (D) Mice were also assessed in the Morris water maze paradigm for the number of entries to the platform zone, the time spent in the platform zone, and the time spent in the NE zone (CTR n = 11, EVOO, n = 10) (*P < 0.05). Values represent mean ± SEM.
Figure 2
Figure 2
Chronic administration of EVOO‐rich diet decreases brain Aβ levels and deposition in 3xTg mice. (A,B) RIPA‐soluble (RIPA) and formic acid soluble (F.A.) Aβ1‐40 and Aβ1‐42 levels in brain cortex homogenates of 3xTg receiving EVOO (n = 8) or vehicle (CTR) (n = 8) (C) Representative images of brain sections of 3xTg mice receiving EVOO or vehicle (CTR) immunostained with 4G8 primary antibody (Scale bar 100 μm). (D) Quantification of the area occupied by Aβ immunoreactivity in brains of 3xTg mice receiving EVOO (n = 4) or vehicle (CTR) (n = 4) (*P < 0.05). E. Representative Western blots of APP, sAPP α, sAPP β, BACE1, ADAM10, APH1, Nicastrin, Pen2, PS1, ApoE, IDE, and CD10 in the brain cortex homogenates from 3xTg mice receiving EVOO (n = 4) or vehicle (CTR) (n = 4). (F) Densitometric analyses of the immunoreactivities to the antibodies shown in the previous panel (*P < 0.05). Values represent mean ± SEM.
Figure 3
Figure 3
Chronic administration of EVOO‐rich diet reduces tau neuropathology in 3xTg mice. (A) Representative Western blots of total soluble tau (HT7), phosphorylated tau at residues ser202/thr205 (AT8), thr231/ser235 (AT180), and thr181 (AT270), and ser396 (PHF13) in brain cortex homogenates from 3xTg mice receiving EVOO (n = 6) or vehicle (CTR) (n = 6). (B) Densitometric analyses of the immunoreactivities to the antibodies shown in the previous panel (*P < 0.05, **P < 0.01). (C) Representative images of brain sections from 3xTg mice receiving EVOO or vehicle (CTR) immunostained with HT7, AT8 and PHF13antibodies. (D) Quantification of the integrated optical density (IOD) by the immunoreactivity to the same antibodies shown in the previous panel (*P < 0.05, *P < 0.01). (E) Representative Western blot analysis of PP2A, CDK5, P35, P25., P38 and pP38 in brain cortex homogenates from 3xTg mice receiving EVOO (n = 4) or vehicle (CTR) (n = 4). (F) Densitometric analyses of the immunoreactivities to the antibodies shown in the previous panel; (**P < 0.01). Values represent mean ± SEM.
Figure 4
Figure 4
Effect of chronic administration of EVOO‐rich diet on synaptic integrity and neuroinflammation. (A) Representative western blot analyses of synaptophysin (SYP) and postsynaptic density protein 95 (PSD95) in brain cortex homogenates of 3xTg mice treated with EVOO (n = 4) or vehicle (CTR) (n = 4). (B) Densitometric analyses of the immunoreactivities to the antibodies shown in the previous panel (*P < 0.05). (C) Representative images of brain sections from 3xTg mice receiving EVOO or vehicle (CTR) immunostained with SYP antibody. (D) Quantification of the integrated optical density (IOD) by the immunoreactivity to the same antibody shown in the previous panel (*P < 0.05). (E) Representative western blot analyses of GFAP and IBA1 in brain cortex homogenates of 3xTg mice treated with EVOO (n = 4) or vehicle (CTR) (n = 4). (F) Densitometric analyses of the immunoreactivities to the antibodies shown in the previous panel (*P < 0.05). (G) Representative images of brain sections from 3xTg mice receiving EVOO or vehicle (CTR) immunostained with IBA1 antibody. (H) Quantification of the integrated optical density (IOD) by the immunoreactivity to the same antibody shown in the previous panel (**P < 0.01). Values represent mean ± SEM.
Figure 5
Figure 5
Effect of chronic administration of EVOO‐rich diet on autophagy. (A) Representative Western blot analyses of CREB, p‐CREB, c‐Fos, BDNF, in brain cortex homogenates of 3xTg mice receiving vehicle (CTR) or EVOO. (B). Densitometric analyses of the immunoreactivities to the antibodies shown in the previous panel. (C) Representative Western blot analyses of ATG7, ATG5/12 and LC3I/II in brain cortex homogenates of 3xTg mice receiving vehicle (CTR) or EVOO. (D) Densitometric analyses of the immunoreactivities to the antibodies shown in the previous panel (*P < 0.05) (n = 5, n = 5). Values represent mean ± SEM.

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Grant support

This work was funded by Wanda Simone Endowment for Neuroscience grant .

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