Docosahexaenoic and eicosapentaenoic acids increase neuronal death in response to HuPrP82-146 and Aβ1-42

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 A beta(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 A(2) (cPLA(2)) into caveolin-1 containing rafts, and increased prostaglandin E(2) production. Activation of cPLA(2) and prostaglandin E(2) 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 cPLA(2), prostaglandin E(2) 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. (C ) 2008 Elsevier Ltd. All rights reserved.