Docosahexaenoic and eicosapentaenoic acids increase neuronal death in response to HuPrP82-146 and Abeta 1-42.
Dietary supplements containing polyunsaturated fatty acids (PUFA) are frequently taken for their perceived health benefits including a possible reduction in cognitive decline in the elderly. Here we report that pre-treatment with docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) significantly reduced the survival of cortical or cerebellar neurons incubated with HuPrP82-146, a peptide derived from the prion protein, or with Abeta 1-42, a peptide found in Alzheimer's disease. Treatment with DHA or EPA reduced the free cholesterol content of neuronal membranes. This did not affect the amount of FITC-HuPrP82-146 ingested by neurons, but increased the kinetics of incorporation. In untreated neurons, FITC-HuPrP82-146 migrated to caveolin-1 containing lipid rafts. The addition of HuPrP82-146 also triggered the migration of cytoplasmic phospholipase A2 (cPLA2) into caveolin-1 containing rafts, and increased prostaglandin E2 production. Activation of cPLA2 and prostaglandin E2 production were both increased in neurons pre-treated with DHA. These results are consistent with DHA or EPA altering cell membranes resulting in increased amounts of HuPrP82-146 localising to caveolin-1 containing rafts, increased activation of cPLA2, prostaglandin E2 production, caspase-3 activity and reduced neuronal survival. Such observations raise the possibility that some PUFA supplements may accelerate neuronal loss in the terminal stages of prion or Alzheimer's diseases.
Bate
Clive
C
Department of Pathology and Infectious Diseases, Royal Veterinary College, Hawkshead Lane, AL9 7TA North Mymms, Herts, UK.
Marshall
Victoria
V
Colombo
Laura
L
Diomede
Luisa
L
Salmona
Mario
M
Williams
Alun
A
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis; D004281:Docosahexaenoic Acids / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D015118:Eicosapentaenoic Acid / Q000633:toxicity*; D004797:Enzyme-Linked Immunosorbent Assay; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology*; D054467:Phospholipases A2 / Q000378:metabolism; D011328:Prions / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D051242:Caveolin 1; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D011328:Prions; C075222:amyloid beta-protein (1-42); C477930:prion protein (82-146); D004281:Docosahexaenoic Acids; D002784:Cholesterol; D015118:Eicosapentaenoic Acid; D054467:Phospholipases A2; D053148:Caspase 3; D015232:Dinoprostone