Polyunsaturated fatty acids protect against prion-mediated synapse damage in vitro.
A loss of synapses is characteristic of the early stages of the prion diseases. Here we modelled the synapse damage that occurs in prion diseases by measuring the amount of synaptophysin, a pre-synaptic membrane protein essential for neurotransmission, in cortical or hippocampal neurones incubated with the disease associated isoform of the prion protein (PrP(Sc)), or with the prion-derived peptide PrP82-146. The addition of PrP(Sc) or PrP82-146 caused a dose-dependent reduction in the synaptophysin content of PrP wildtype neurones indicative of synapse damage. They did not affect the synaptophysin content of PrP null neurones. The loss of synaptophysin in PrP wildtype neurones was preceded by the accumulation of PrP82-146 within synapses. Since supplements containing polyunsaturated fatty acids (PUFA) are frequently taken for their perceived health benefits including reported amelioration of neurodegenerative conditions, the effects of some common PUFA on prion-mediated synapse damage were examined. Pre-treatment of cortical or hippocampal neurones with docosahexaenoic (DHA) or eicosapentaenoic acids (EPA) protected neurones against the loss of synaptophysin induced by PrP82-146 or PrP(Sc). This effect of DHA and EPA was selective as they did not alter the loss of synaptophysin induced by a snakevenom neurotoxin. The effects of DHA and EPA were associated with a significant reduction in the amount of FITC-PrP82-146 that accumulated within synapses. Such observations raise the possibility that supplements containing PUFA may protect against the synapse damage and cognitive loss seen during the early stages of prion diseases.
Bate
Clive
C
Department of Pathology and Infectious Diseases, Royal Veterinary College, North Mymms, Herts, AL9 7TA, UK. cbate@rvc.ac.uk
Tayebi
Mourad
M
Salmona
Mario
M
Diomede
Luisa
L
Williams
Alun
A
D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D015118:Eicosapentaenoic Acid / Q000494:pharmacology; D004622:Embryo, Mammalian; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D011328:Prions / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology; D016708:Synaptophysin / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism
D005231:Fatty Acids, Unsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011328:Prions; D016708:Synaptophysin; C477930:prion protein (82-146); D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; D019821:Simvastatin; D053148:Caspase 3