The Influence of APOE Genotype, DHA, and Flavanol Intervention on Brain DHA and Lipidomics Profile in Aged Transgenic Mice

Abstract

The apolipoprotein E4 (APOE4) genotype is predictive of Alzheimer's disease (AD). The brain is highly enriched with the omega-3 polyunsaturated fatty acid (n3-PUFA), docosahexaenoic acid (DHA). DHA's metabolism is defective in APOE4 carriers. Flavanol intake can play a role in modulating DHA levels. However, the impact of flavanol co-supplementation with fish oil on brain DHA uptake, status and partitioning, and according to APOE genotype is currently unknown. Here, using a humanised APOE3 and APOE4 targeted replacement transgenic mouse model, the interactive influence of cocoa flavanols (FLAV) and APOE genotype on the blood and subcortical brain PUFA status following the supplementation of a high fat (HF) enriched with DHA from fish oil (FO) was investigated. DHA levels increased in the blood (p < 0.001) and brain (p = 0.001) following supplementation. Compared to APOE3, a higher red blood cell (RBC) DHA (p < 0.001) was evident in APOE4 mice following FO and FLAV supplementation. Although FO did not increase the percentage of brain DHA in APOE4, a 17.1% (p < 0.05) and 20.0% (p < 0.001) higher DHA level in the phosphatidylcholine (PC) fraction in the HF FO and HF FO FLAV groups, and a 14.5% (p < 0.05) higher DHA level in the phosphatidylethanolamine (PE) fraction in the HF FO FLAV group was evident in these animals relative to the HF controls. The addition of FLAV (+/- FO) did not significantly increase the percentage of brain DHA in the group as a whole. However, a higher brain: RBC DHA ratio was evident in APOE3 only (p < 0.05) for HF FLAV versus HF. In conclusion, our data shows only modest effects of FLAV on the brain DHA status, which is limited to APOE3.

Keywords: Alzheimer’s disease; PUFAs; apolipoprotein E; brain; docosahexaenoic acid; flavonoids; phospholipids.

Figure 1

Effect of diet on brain, plasma, and red blood cells DHA content in mice, expressed in nmol/g of brain tissue (A), mmol/mL of plasma (B), and as % of total fatty acids (D,E). (C,F) are ratios of brain to plasma and brain to RBCs DHA concentrations respectively. Values are expressed as means ± SEM. One-way ANOVA Tukey’s post-hoc test adjusted p-values. a, b, c: columns (groups) with different letters are significantly different at p = 0.05, while columns sharing the same letters are not significantly different. Data of each dietary group was obtained from APOE3 and APOE4 mice combined. Number of mice per dietary group: LF n = 20, HF n = 21, HF FO n = 19, HF FLAV n = 19, and HF FO + FLAV n = 19.

Figure 2

Effect of diet and genotype in the brain, plasma, and red blood cells DHA content of APOE3 and APOE4-TR mice, expressed in % of total fatty acids (A–C) and ratios of brain: plasma (D) and brain: RBC DHA (E). Values are expressed as means ± SEM. a, b, c, d: columns (groups) with different letters are significantly different at p = 0.05, while columns sharing the same letters are not significantly different. Number of mice in each dietary and genotype group are: LF APOE3 n = 11, LF APOE4 n = 9, HF APOE3 n = 13, HF APOE4 n = 8, HF FO APOE3 n = 11, HF FO APOE4 n = 8, HF FLAV APOE3 n = 10, HF FLAV APOE4 n = 9, HF FO + FLAV APOE3 n = 10, and HF FO + FLAV APOE4 n = 8. P-diet*genotype: significance of diet and genotype interactive effect.