Polyunsaturated fatty acids protect against prion-mediated synapse damage in vitro

Area of Science:

• Neuroscience
• Prion Biology
• Neurodegenerative Diseases

Background:

• Synapse loss is an early hallmark of prion diseases.
• Prion diseases are linked to the misfolding and aggregation of the prion protein (PrP).
• Understanding mechanisms of synapse damage is crucial for developing treatments.

Purpose of the Study:

• To model synapse damage in prion diseases using in vitro neuronal cultures.
• To investigate the protective effects of polyunsaturated fatty acids (PUFA) against prion-induced neurotoxicity.
• To explore the potential of PUFA as a therapeutic strategy for prion diseases.

Main Methods:

• Cultured cortical and hippocampal neurons from PrP wildtype and PrP null mice.
• Incubation with disease-associated prion protein (PrPSc) or prion-derived peptide (PrP82-146).
• Measurement of synaptophysin levels to assess synapse damage.
• Pre-treatment with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA).
• Assessment of FITC-PrP82-146 accumulation in synapses.

Main Results:

• PrPSc and PrP82-146 induced a dose-dependent loss of synaptophysin in wildtype neurons, indicating synapse damage.
• Prion peptides did not affect synaptophysin levels in PrP null neurons.
• Pre-treatment with DHA and EPA protected neurons against PrP-mediated synaptophysin loss.
• DHA and EPA selectively protected against prion-induced damage, not neurotoxin-induced damage.
• PUFA treatment reduced the accumulation of PrP82-146 within synapses.

Conclusions:

• Prion protein aggregates directly cause synapse damage in a PrP-dependent manner.
• Docosahexaenoic acid and eicosapentaenoic acid demonstrate neuroprotective effects against prion-induced synapse loss.
• PUFA may represent a viable therapeutic approach to mitigate synapse damage and cognitive decline in early-stage prion diseases.