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-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.
a Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.|b Neurodegeneration and Neurobiology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.|c Deutsches Institut für DemenzPrävention (DIDP), Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.
Marcus O W
MO
Grimm
a Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.
Janine
J
Mett
a Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.
Christoph P
CP
Stahlmann
a Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.
Viola J
VJ
Haupenthal
a Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.
Tamara
T
Blümel
a Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.
Hannah
H
Stötzel
a Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.
Heike S
HS
Grimm
a Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.|b Neurodegeneration and Neurobiology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.|c Deutsches Institut für DemenzPrävention (DIDP), Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.
Tobias
T
Hartmann
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D007339:Insulysin / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D012333:RNA, Messenger; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; D007339:Insulysin
Aβ-degradation; acide docosahexaénoïque; acide eicosapentaénoïque; acides gras polyinsaturés oméga-3; docosahexaenoic acid; eicosapentaenoic acid; enzyme de dégradation de l’insuline; insulin-degrading enzyme; polyunsaturated omega-3 fatty acids