Structural Insight into the Differential Effects of Omega-3 and Omega-6 Fatty Acids on the Production of Aβ Peptides and Amyloid Plaques

Abstract

Several studies have shown the protective effects of dietary enrichment of various lipids in several late-onset animal models of Alzheimer Disease (AD); however, none of the studies has determined which structure within a lipid determines its detrimental or beneficial effects on AD. High-sensitivity enzyme-linked immunosorbent assay (ELISA) shows that saturated fatty acids (SFAs), upstream omega-3 FAs, and arachidonic acid (AA) resulted in significantly higher secretion of both A␤ 40 and 42 peptides compared with long chain downstream omega-3 and monounsaturated FAs (MUFA). Their distinct detrimental action is believed to be due to a structural template found in their fatty acyl chains that lack SFAs, upstream omega-3 FAs, and AA. Immunoblotting experiments and use of APP-C99-transfected COS-7 cells suggest that FAdriven altered production of A␤ is mediated through ␥-secretase cleavage of APP. An early-onset AD transgenic mouse model expressing the double-mutant form of human amyloid precursor protein (APP); Swedish (K670N/M671L) and Indiana (V717F), corroborated in vitro findings by showing lower levels of A␤ and amyloid plaques in the brain, when they were fed a low fat diet enriched in DHA. Our work contributes to the clarification of aspects of structure-activity relationships. Alzheimer Disease (AD)2 is a currently incurable progressive neurological disease that affects higher brain functions, ultimately leading to dementia and death (1). The molecular key event triggering the harmful cascade in AD is generally considered to be increased soluble oligomeric A␤, or more specifically A␤42 levels (2-4). Whereas A␤ generation depends on several factors, the prime event in A␤ generation is cleavage of APP-C99 by ␥-secretase. This is because it is the last essential step in A␤40 versus A␤42 generation, and it is also this cleavage for which most mechanistic information linking lipid homeostasis with A␤ production is available (5, 6).Several studies have shown the protective effects of various lipids on several parameters of AD; however, none of the studies has determined which structure within a lipid decides its detrimental or beneficial effects on A␤ production or the A␤40/42 ratio. Using an AD-cell culture model we identified the parameters, which may define whether a lipid or FA will affect A␤ production. A simple structure-activity relationship (SAR) study was performed in an attempt to examine the following factors: chain length, saturation, position of unsaturation (either at omega-3, -6, -7, or -9 carbon), and orientation (cis, trans) of double bonds as well as the effects of natural and synthetic/conjugated lipids. Based on our in vitro data, we designed a diet high in DHA but low in all deleterious fats and cholesterol, and showed for the first time in an early-onset robust mouse model of AD (which represents individuals who are at high risk of developing early-onset AD due to genetic mutations), that the protective structural template built-in the acyl chain of DHA indeed improves AD-type neuropathology...

Increased ω6-Containing Phospholipids and Primary ω6 Oxidation Products in the Brain Tissue of Rats on an ω3-Deficient Diet

“…At least one ω6-PUFA oxidation product is amyloidogenic while its corresponding ω3-PUFA oxidation product is not [27], suggesting that dietary ω3-PUFA deficiency may render brain tissue more vulnerable to amyloidogenic effects of oxidative stress by increasing the production of ω6-PUFA oxidation products [41,48]. Conversely, dietary DHA supplementation alleviates the histopathological signs of Alzheimer’s disease in mice, and in neuronal cell cultures [33,49–55]. Therefore, the development of amyloid in brain may depend to some extent on the degree to which ω6-PUFAs such as DPA displace ω3-PUFAs such as DHA in a pool that is vulnerable to oxidative damage.…”

Fatting the brain: a brief of recent research

“…These findings were corroborated in vivo by using a transgenic mouse model of early-onset Alzheimer’s disease that expresses the double-mutant form of human APP, which is the precursor protein responsible for the synthesis of Aβ peptide. Decreased levels of Aβ peptide and less accumulation in the form of amyloid plaques were observed in the brain of mice nourished with a diet enriched in n-3 PUFAs, mainly DHA (22:6 n-3; Amtul et al, 2011a). Not only extraneously supplied but endogenously synthesized n-3 PUFAs can suppress the synthesis of Aβ peptide and the formation of amyloid plaques.…”

“…Using APP-C99-transfected COS-7 cells, a cellular model of Alzheimer’s disease-like degeneration, a study was carried out to investigate the class of fatty acids that was thought to influence the production of Aβ peptide, which is a major neuropathological hallmark of disease. It was shown that palmitic acid (16:0), stearic acid (18:0), upstream n-3 PUFAs, and AA (20:4 n-6) triggered higher secretion of Aβ peptide compared to long chain downstream n-3 PUFAs and MUFAs (Amtul et al, 2011a). These findings were corroborated in vivo by using a transgenic mouse model of early-onset Alzheimer’s disease that expresses the double-mutant form of human APP, which is the precursor protein responsible for the synthesis of Aβ peptide.…”

Rehabilitating a brain with Alzheimer's: a proposal

“…Importantly, omega-3 acids have shown the ability to inhibit tau hyperphosphorylation,29 which would allow axonal transport restoration. It has been shown that omega-3 is also capable of reducing amyloid plaque formation 29,30…”