Eicosapentaenoic acid and docosahexaenoic acid increase the degradation of amyloid-β by affecting insulin-degrading enzyme

Abstract

Omega-3 polyunsaturated fatty acids (PUFAs) have been proposed to be highly beneficial in Alzheimer's disease (AD). AD pathology is closely linked to an overproduction and accumulation of amyloid-β (Aβ) peptides as extracellular senile plaques in the brain. Total Aβ levels are not only dependent on its production by proteolytic processing of the amyloid precursor protein (APP), but also on Aβ-clearance mechanisms, including Aβ-degrading enzymes. Here we show that the omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) increase Aβ-degradation by affecting insulin-degrading enzyme (IDE), the major Aβ-degrading enzyme secreted into the extracellular space of neuronal and microglial cells. The identification of the molecular mechanisms revealed that EPA directly increases IDE enzyme activity and elevates gene expression of IDE. DHA also directly stimulates IDE enzyme activity and affects IDE sorting by increasing exosome release of IDE, resulting in enhanced Aβ-degradation in the extracellular milieu. Apart from the known positive effect of DHA in reducing Aβ production, EPA and DHA might ameliorate AD pathology by increasing Aβ turnover.

Omega-3 fatty acids, lipids, and apoE lipidation in Alzheimer's disease: a rationale for multi-nutrient dementia prevention

“…Accordingly, mutations in PS1 causing FAD showed increased SMase activity (131). Under pathological conditions, high A42 concentrations resulting in oligomers, protofibrils, and fibrils and leading to oxidative stress and inflammatory mechanisms have been demonstrated to additionally activate nSMase (135,136). Similar results have been found by Jana and Pahan (137,138), showing that fibrillary A peptides activate nSMases via NADPH oxidase-mediated mechanisms finally leading to the loss of neurons.…”

The Protective Effect of Antarctic Krill Oil on Cognitive Function by Inhibiting Oxidative Stress in the Brain of Senescence‐Accelerated Prone Mouse Strain 8 (SAMP8) Mice

“…The obtained result suggested that AKO exerted neuroprotective effect by inhibiting Aβ production or promoting Aβ clearance, which might be due to the high proportion of EPA and DHA. Previous studies had shown that EPA could increase Aβ‐degradation by improving insulin‐degrading enzyme activity (Grimm et al., ). Moreover, dietary DHA reduced Aβ level by reducing presenilin‐1 steady‐state level (Green et al., ).…”

Efficacy and Blood Plasmalogen Changes by Oral Administration of Plasmalogen in Patients with Mild Alzheimer's Disease and Mild Cognitive Impairment: A Multicenter, Randomized, Double-blind, Placebo-controlled Trial

“…On the other hand, there have been many reports that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) relate closely to brain functions (Grimm et al, 2016, Hopperton et al, 2016, Ren et al, 2017). Scallop-derived Pls used in the present study presumably contained relatively large amounts of DHA and EPA (Kraffe et al, 2004, Hanuš et al, 2009).…”