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

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-beta (A beta) peptides as extracellular senile plaques in the brain. Total A beta levels are not only dependent on its production by proteolytic processing of the amyloid precursor protein (APP), but also on A beta-clearance mechanisms, including A beta-degrading enzymes. Here we show that the omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) increase A beta-degradation by affecting insulin-degrading enzyme (IDE), the major A beta-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 A beta-degradation in the extracellular milieu. Apart from the known positive effect of DHA in reducing A beta production, EPA and DHA might ameliorate AD pathology by increasing A beta turnover.