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.

Oleic acid ameliorates Aβ-induced inflammation by downregulation of COX-2 and iNOS via NFκB signaling pathway

“…Furthermore, the level of MUFA, including OA, was significantly lower in the frontal cortex and hippocampus of AD brains (Cunnane et al, 2012;Prasad, Lovell, Yatin, Dhillon, & Markesbery, 1998) and the concentration of plasma free MUFA, especially OA was almost 80% lower in AD patients compared with those with no cognitive impairment (Mitchell & Hatch, 2011). Amtul et al (2011) demonstrated that secreted Aβ levels were reduced in both APP695-transfected Cos-7 cells and AD transgenic mouse models supplemented with OA.…”

“…Previous study revealed that OA decreased brain levels of Aβ through decreasing BACE1 and PS1 levels in transgenic mice and OA was reported to suppress the activity of prolyl endopeptidase (PEP) (Amtul, Westaway, Cechetto, & Richard, 2011;Park, Jang, Lee, Hahn, & Park, 2006). However, to date, the molecular mechanism that underlies the protective effect of OA on Aβ25-35-induced neurotoxicity and inflammatory signaling pathway has not been fully understood.…”

Lipid metabolism in Alzheimer’s disease

“…Increased cholesterol levels in the lipid bilayers enhance Aβ conformation changes from a helix-rich to a beta-sheet-rich structure, which facilitates amyloid accumulation [89] . In contrast, lowering the membrane cholesterol with statin causes decreased Aβ production due to cholesterol interfering with glycosylation in the protein secretory pathway [90] .…”

“…Similarly, MUFAs, mainly oleic acid, inhibit the production of Aβ and amyloid plaque formation both in vitro and in vivo [90] . In contrast, arachidonic acid increases Aβ production and the formation of amyloid plaques and other neuropathology [91] .…”

“…Increased cholesterol levels in the lipid bilayers enhance Aβ conformation changes from a helix-rich to a beta-sheet-rich structure, which facilitates amyloid accumulation [89] . In contrast, lowering the membrane cholesterol with statin causes decreased Aβ production due to cholesterol interfering with glycosylation in the protein secretory pathway [90] .However, moderate reduction of membrane cholesterol in hippocampal neurons from rodent models causes an increase in Aβ production, suggesting a delicate balance between cholesterol and Aβ levels [91] .Free cellular cholesterol can be converted into cholesteryl esters by the enzyme sterol O-acyltransferase 1 (ACAT1 Cholesterol metabolism also has a significant impact on tau phosphorylation and aggregation in AD. Inhibiting cholesterol biosynthesis in cultured neurons results in hyperphosphorylation of tau and axonal degeneration [100] .…”