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 overproductionand accumulation of amyloid-β (Aβ) peptides as extracellular senile plaquesin 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 enzymesecreted 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 exosomerelease of IDE, resulting in enhanced Aβ-degradation in the extracel...