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. 2015 Dec;26(12):1479-90.
doi: 10.1016/j.jnutbio.2015.07.022. Epub 2015 Aug 13.

Extra-virgin olive oil attenuates amyloid-β and tau pathologies in the brains of TgSwDI mice

Hisham Qosa  1 , Loqman A Mohamed  1 , Yazan S Batarseh  1 , Saeed Alqahtani  1 , Baher Ibrahim  1 , Harry LeVine 3rd  2 , Jeffrey N Keller  3 , Amal Kaddoumi  4
Affiliations

Extra-virgin olive oil attenuates amyloid-β and tau pathologies in the brains of TgSwDI mice

Hisham Qosa et al. J Nutr Biochem. 2015 Dec.

Abstract

Extra-virgin olive oil (EVOO) is one of the main elements of Mediterranean diet. Several studies have suggested that EVOO has several health promoting effects that could protect from and decrease the risk of Alzheimer's disease (AD). In this study, we investigated the effect of consumption of EVOO-enriched diet on amyloid- and tau-related pathological alterations that are associated with the progression of AD and cerebral amyloid angiopathy (CAA) in TgSwDI mice. Feeding mice with EVOO-enriched diet for 6months, beginning at an age before amyloid-β (Aβ) accumulation starts, has significantly reduced total Aβ and tau brain levels with a significant improvement in mouse cognitive behavior. This reduction in brain Aβ was explained by the enhanced Aβ clearance pathways and reduced brain production of Aβ via modulation of amyloid-β precursor protein processing. On the other hand, although feeding mice with EVOO-enriched diet for 3months, beginning at an age after Aβ accumulation starts, showed improved clearance across the blood-brain barrier and significant reduction in Aβ levels, it did not affect tau levels or improve cognitive functions of TgSwDI mouse. Collectively, results of this study suggest that the long-term consumption of EVOO-containing diet starting at early age provides a protective effect against AD and its related disorder CAA.

Keywords: Amyloid-β; Blood–brain barrier; Clearance; Extra-virgin olive oil; Tau.

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Conflict of interest statement

Conflict of interest

The authors have declared that no conflict interests exist.

Figures

Figure 1
Figure 1
EVOO reduces amyloid burden in the brains of TgSwDI. ELISA quantitative analysis of the levels of human Aβ40 (A) and Aβ42 (B) in the brain of TgSwDI mice after consumption of EVOO. Consumption of EVOO-enriched diet for 3 months beginning at age 4 months or for 6 months beginning at age of 1 month significantly reduced total Aβ40 and Aβ42 levels in the brain of TgSwDI mice. All-size Aβ-oligomer ELISA analysis of DEA (C) and SDS (D) fractions show a significant reduction of Aβ oligomers content of both fractions only in EVOO-6m group. Data is presented as mean±SEM of 4–6 mice in each group (ns, not significant; * P<0.05, ** P<0.01 and *** P<0.001).
Figure 2
Figure 2
EVOO consumption reduces Aβ burden in the hippocampus of TgSwDI mice. (A) Representative hippocampus sections stained with 6E10 (green) antibody against Aβ to detect Aβ load and DAPI (blue) to stain nuclei. (B) Representative hippocampus sections stained with thioflavin-S to detect Aβ-plaque burden. Quantitative analysis of total Aβ load (A) and Aβ plaque load (B) showed a significant reduction in Aβ load (measured as a % of Aβ-covered area) and Aβ plaque load (measured as number of the plaque per 15 µm section) in the hippocampus of all EVOO-fed mice. Data is presented as mean±SEM of 4–6 mice in each group (* P<0.05 and ** P<0.01). Scale bar, 50 µm.
Figure 3
Figure 3
Immunohistochemical analysis of cerebrovascular Aβ deposition in the hippocampus of CNTRL (control), EVOO-3m and EVOO-6m TgSwDI mice. Representative hippocampus sections from all treatment groups were double-immunostained with 6E10 for detection of Aβ (Green) and collagen-VI to identify brain microvessels (Red). Quantification of cerebrovascular Aβ deposition (CAA pathogenesis) as a % of Aβ-immunoreactive vessels demonstrated a significant reduction in microvascular Aβ deposits only in the hippocampus of EVOO-6m group. Data is presented as mean±SEM of 4–6 mice in each group. Scale bar, 50 µm (ns, not significant; ** P<0.01).
Figure 4
Figure 4
In-vivo clearance of 125I-Aβ40 from brain of TgSwDI mice. Enhanced total brain clearance (BCI-Total (%)) (A) and BBB clearance (BCI-BBB (%)) (B) of 125I-Aβ40 was observed in all EVOO-fed mice. Increase in the brain clearance of 125I-Aβ40 was associated with up-regulation in the expressions of P-gp and LRP1 in the brains’ microvessels as shown in the representative blots (C) and densitometry analyses (D and E). Data is presented as mean±SEM of 4–6 mice in each group (* P<0.05 and ** P<0.01).
Figure 5
Figure 5
EVOO-enriched diet stimulated the ApoE-dependent clearance pathway of Aβ through the activation of PPARγ. (A) Representative blots and densitometry analysis of ABCA1 and ApoE showed significant up-regulation in their expressions in the brain tissue of TgSwDI mice after consumption of EVOO-enriched diet. (B) Representative blot and densitometry analysis show significant induction in the expression of PPARγ in both groups while expression of LXR was enhanced only in EVOO-6m group. Data is presented as mean±SEM of 4–6 mice in each group (ns, not significant; and * P<0.05).
Figure 6
Figure 6
Effect of EVOO consumption for 3 or 6 months on APP processing. Representative blots and densitometry analysis of full length APP (APP-FL), sAPPα and sAPPβ. EVOO-6m group demonstrated a significant modulation in the processing of APP with a reduction trend in the expression of full length APP, significant increase in sAPPα and significant decrease in sAPPβ. Data is presented as mean±SEM of 4–6 mice in each group (ns, not significant; * P<0.05 and ** P<0.01).
Figure 7
Figure 7
Representative blots and densitometry analysis of total tau and tau phosphorylation at amino acid residues serine 214 and 262 and threonine 212 and 231. Significant reduction in total tau and its phosphorylation at amino acid residues serine 214 and threonine 212 were observed in EVOO-6m mice. Data is presented as mean±SEM of 4–6 mice in each group (ns, not significant; * P<0.05; ** P<0.01 and *** P<0.001).
Figure 8
Figure 8
Burrowing (A) and nest construction (B) behavioral studies demonstrated positive effect of EVOO consumption in TgSwDI mice of EVOO-6m group only while EVOO-3mfeeding paradigm failed to rescue behavioral deterioration in TgSwDI mice. Data is presented as mean±SEM of 10–12 mice in each group (ns, not significant; * P<0.05 and ** P<0.01).
Scheme 1
Scheme 1
Schematic presentation of the time, age, number and study groups involved in the assessment of the effect of EVOO consumption on Aβ pathology in the brain of TgSwDI mice.
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