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Ovarian Hormone-Dependent Effects of Dietary Lipids on APP/PS1 Mouse Brain

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Ovarian Hormone-Dependent Effects of Dietary Lipids on APP/PS1 Mouse Brain

Jose Luis Herrera et al. Front Aging Neurosci.

Abstract

The formation of senile plaques through amyloid-β peptide (Aβ) aggregation is a hallmark of Alzheimer's disease (AD). Irrespective of its actual role in the synaptic alterations and cognitive impairment associated with AD, different therapeutic approaches have been proposed to reduce plaque formation. In rodents, daily intake of omega-3 (n-3) long-chain polyunsaturated fatty acids (LC-PUFAs) is required for neural development, and there is experimental and epidemiological evidence that their inclusion in the diet has positive effects on several neurodegenerative diseases. Similarly, estradiol appears to reduce senile plaque formation in primary mouse cell cultures, human cortical neurons and mouse AD models, and it prevents Aβ toxicity in neural cell lines. We previously showed that differences in dietary n-6/n-3 LC-PUFAs ratios modify the lipid composition in the cerebral cortex of female mice and the levels of amyloid precursor protein (APP) in the brain. These effects depended in part on the presence of circulating estradiol. Here we explored whether this potentially synergistic action between diet and ovarian hormones may influence the progression of amyloidosis in an AD mouse model. Our results show that a diet with high n-3 LC-PUFA content, especially DHA (22:6n-3), reduces the hippocampal accumulation of Aβ1 - 4 0, but not amyloid Aβ1 - 42 in female APPswe/PS1 E9A mice, an effect that was counteracted by the loss of the ovaries and that depended on circulating estradiol. In addition, this interaction between dietary lipids and ovarian function also affects the composition of the brain lipidome as well as the expression of certain neuronal signaling and synaptic proteins. These findings provide new insights into how ovarian hormones and dietary composition affect the brain lipidome and amyloid burden. Furthermore, they strongly suggest that when designing dietary or pharmacological strategies to combat human neurodegenerative diseases, hormonal and metabolic status should be specifically taken into consideration as it may affect the therapeutic response.

Keywords: amyloid; cerebral cortex lipidome; docosahexaenoic acid; estradiol; long-chain polyunsaturated fatty acids; ovarian hormones; sphingolipids; synaptic proteins.

Figures

FIGURE 1
FIGURE 1
Effect of different dietary composition on cerebral cortex lipidome in intact female APP/PS1 mice. SF: Standard laboratory food (SF); DI: High n-6/n-3 ratio; DII: Low n-6/n-3 ratio. Data are represented in the units indicated in the vertical axis as mean ± SEM of four mice per group. In this and other figures, the symbols indicate significant differences obtained from the statistical analysis as described in methods section. (A) General ANOVA: p = 0.0004; (a): p = 0.0005 vs. SF; (B) General ANOVA: p = 0.001; (a): p = 0.0009 vs. SF or DII; (C) General ANOVA: p = 0.84; (D) General ANOVA: p = 0.0001; (a): p = 0.0005, and (b) p = 0.02 vs. SF and DII; (E) General ANOVA: p = 0.0004; (a) p = 0.001 vs. SF; (F) General ANOVA: p = 0.0005; (a) p = 0.05, and (b) p = 0.005 vs. SF; (G) General ANOVA: p = 0.18; (H) General ANOVA: p = 0.005; (a) p = 0.02, and (b) p = 0.002 vs. SF; (I) General ANOVA: p = 0.03; (a) 0.04 vs. SF; (J) General ANOVA: p = 0.01; (a): p = 0.007 vs. SF.
FIGURE 2
FIGURE 2
Differential effects of chronic estradiol administration on dietary-dependent cerebral cortex lipidome in ovariectomized female APP/PS1 mice. Clear bars: ovariectomized-placebo treated (OVX); Dark bars: ovariectomized-estradiol treated (OVX-E). Data are represented in the units indicated in the vertical axis as mean ± SEM of four mice per group. (A) General ANOVA: p = 0.05; (a) p = 0.02 vs. OVX; (B) General ANOVA: p = 0.00001; (a) p = 0.0001 vs. OVX; (C) General ANOVA: p = 0.0001; (D) General ANOVA: p = 0.0001; (a): p = 0.009 vs. OVX; (E) General ANOVA: p = 0.05; (a): p = 0.02 vs. OVX; (F) General ANOVA: p = 0.03; (a): 0.01 vs. OVX; (G) General ANOVA: p = 0.07; (a): p = 0.05 vs. OVX; (H) General ANOVA: p = 0.04; (a) p = 0.05 vs. OVX.
FIGURE 3
FIGURE 3
Linear regression between dietary content in n-6 FA and cerebral cortex levels of several complex lipids. Vertical axis represents the means of each compound in pmol/mg protein of four animals per group. Horizontal axis represents the progression of n-6 FA dietary content in gr/kg fresh weight (SF: 10.63; DII: 16.55; DI: 28.84). Significant dose-response effects are shown in intact WT mice for Ceramides (p = 0.00001), dh-Ceramides (p = 0.0004), Sphingomyelins (p = 0.0001), and dh-Sphingomyelins (p = 0.0001) but not in intact APP/PS1 mice. In addition, all slopes were significantly different between WT and APP/PS1 animals for Ceramides (p = 0.001), dh-Ceramides (p = 0.01), Sphingomyelins (p = 0.001), and dh-Sphingomyelins (p = 0.0009).
FIGURE 4
FIGURE 4
Effect of different dietary composition on plasma and hippocampal levels of Aβ140 in female APP/PS1 mice and its dependence on gonadal status. Data are represented in the units indicated in the vertical axis as mean ± SEM of five to six mice per group. (A) General ANOVA: p = 0.34; (B) General ANOVA: p = 0.048; (a) p = 0.017 vs. SF; (C) General ANOVA: p = 0.058; (a) p = 0.01 vs. OVX.
FIGURE 5
FIGURE 5
Effect of different dietary composition on GFAP expression in the cerebral cortex of female APP/PS1 mice under different gonadal conditions. (A) Western blots of GFAP and β-Actin. (B) Vertical axis represents relative units of densitometric quantification as mean ± SEM of four mice per group, normalized with respect to the loading control, β-Actin. Clear bars correspond to high n-6/n-3 ratio (DI), and dark bars correspond to low n-6/n-3 ratio (DII). Horizontal axis indicates the different gonadal status as follows: SHAM, intact sham-operated; OVX, ovariectomized, placebo-treated; OVX-E, ovariectomized, estradiol-treated. General ANOVA: p = 0.0004; (a) p = 0.0001.
FIGURE 6
FIGURE 6
Effect of different dietary composition on the expression of signaling proteins in the cerebral cortex of female APP/PS1 mice under different gonadal conditions. (A) Western blots for PI3K, AKT, GSK3, GSK3-pSer (p-GSK3), and β-Actin. (B–E) Vertical axis represents relative units of densitometric quantification as mean ± SEM of four mice per group, normalized with respect to the loading control, β-Actin. Clear bars correspond to high n-6/n-3 ratio (DI), and dark bars correspond to low n-6/n-3 ratio (DII). Horizontal axis indicates the different gonadal status as follows: SHAM, intact sham-operated; OVX, ovariectomized, placebo-treated; OVX-E, ovariectomized, estradiol-treated. (B) General ANOVA: p = 0.000001; (a) p = 0.00001; Global effect of DII vs. DI: p = 0.0003. (C) General ANOVA: p = 0.02; (a) p = 0.0004; Global effect of DII vs. DI: p = 0.01. (D) General ANOVA: p = 0.02; (a) p = 0.03; (b) p = 0.008; Global effect of DII vs. DI: p = 0.002. (E) General ANOVA: p = 0.0004; (a) p = 0.0005.
FIGURE 7
FIGURE 7
Effect of different dietary composition on the expression of synaptic proteins in the cerebral cortex of female APP/PS1 mice under different reproductive conditions. (A) Western blots for synapsin, p-synapsin, synaptophysin, PSD95, and β-Actin. (B–E) Vertical axis represents relative units of densitometric quantification as mean ± SEM of four mice per group, normalized with respect to the loading control, β-Actin. Clear bars correspond to high n-6/n-3 ratio (DI), and dark bars correspond to low n-6/n-3 ratio (DII). Horizontal axis indicates the different gonadal status as follows: SHAM, intact sham-operated; OVX, ovariectomized, placebo-treated; OVX-E, ovariectomized, estradiol-treated. (B) General ANOVA: p = 0.0005; (a) p = 0.01; (b) p = 0.001. (C) General ANOVA: p = 0.0006; (a) p = 0.003; (b) p = 0.01; (c) p = 0.0005; Global effect of DII vs. DI: p < 0.0000001. (D) General ANOVA: p = 0.0005; (a) p = 0.0006; (b) p = 0.003; (c) p = 0.009; Global effect of DII vs. DI: p < 0.0000001. (E) General ANOVA: p = 0.008; (a) p = 0.007.

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