Oleic acid ameliorates amyloidosis in cellular and mouse models of Alzheimer's disease

Abstract

Several lines of evidence support protective as well as deleterious effects of oleic acid (OA) on Alzheimer's disease (AD) and other neurological disorders; however, the bases of these effects are unclear. Our investigation demonstrates that amyloid precursor protein (APP) 695 transfected Cos-7 cells supplemented with OA have reduced secreted amyloid-beta (Aβ) levels. An early-onset AD transgenic mouse model expressing the double-mutant form of human APP, Swedish (K670N/M671L) and Indiana (V717F), corroborated our in vitro findings when they were fed a high-protein, low-fat (18% reduction), cholesterol-free diet enriched with OA. These mice exhibited an increase in Aβ40/Aβ42 ratio, reduced levels of beta-site APP cleaving enzyme (BACE) and reduced presenilin levels along with reduced amyloid plaques in the brain. The decrease in BACE levels was accompanied by increased levels of a non-amyloidogenic soluble form of APP (sAPPα). Furthermore, the low-fat/+OA diet resulted in an augmentation of insulin-degrading enzyme and insulin-like growth factor-II. These results suggest that OA supplementation and cholesterol intake restriction in a mouse model of AD reduce AD-type neuropathology.

Figure 1

In vitro and in vivo effects of oleic acid (OA) supplement on amyloid‐beta (Aβ) levels and amyloid plaque burden. A. BSA control normalized Aβ levels in the conditioned media after 12‐h incubation with OA (n = 3). B. Enzyme‐linked immunosorbent assay results for Aβ40 and Aβ42 levels in the hippocampus and adjacent cortices of chow, low‐fat/−OA and low‐fat/+OA mice. C. Photomicrographs of Aβ stained amyloid plaque burden (number and size) in the neocortex (NC), hippocampus (HC) and amygdala (AG) of chow, low‐fat/−OA and low‐fat/+OA mice. Arrows indicate Aβ stained plaques. The plot shows the quantitative analysis of plaque density. The mean ± standard error of the mean are shown for all plots (n = 6 for each experiment). ***P < 0.001, **P < 0.01 and *P < 0.05.

Figure 2

In vivo effects of oleic acid (OA) supplement on brain protein levels. Western blots of mature amyloid precursor protein (APPm), immature amyloid precursor protein (APPim), soluble APPα (sAPPα), β‐site APP cleaving enzyme (BACE), β‐actin and APP–C‐terminal fragments (CTFs) (A) nicastrin (NCT), presenilin 1‐N terminal fragment (PS1‐NTF), insulin‐degrading enzyme (IDE), transthyretin (TTR), insulin‐like growth factor‐II (IGF‐II), prion protein (PrP) and β‐actin protein levels (B) in the frontal cortices of chow, low‐fat/−OA and low‐fat/+OA mice, (n= 6 for each experiment; out of six, only one animal is shown for chow, and three animals are shown for low‐fat/‐OA and low‐fat/+OA mice). Respective molecular weights (kD) are shown on the left. Plots on the right show the quantitative analysis of Western blots. C. Plot shows secretase‐generated APP‐C‐terminal fragment (α/β) ratios vs. OA percentage distribution, The mean +/− standard error for the mean are shown for all plots. **P < 0.01 and *P < 0.05. Abbreviation: Aβ = amyloid‐beta.

Figure 3

Effects of oleic acid (OA) supplement on gene expression levels. Real‐time RT‐PCR of endogenous murine (m), CRND8 transgene‐specific (Tg) amyloid precursor protein (A) and prion protein (B) in chow, low‐fat/−OA and low‐fat/+OA mice, (n=6 for each experiment, out of 6 only 1 animal is shown for each group). Plots show the quantitative analysis (mean ± S.E.M.) of β‐actin‐normalized gene expression levels, ***p < 0.001.