Plasma cholesterol level determines in vivo prion propagation

Area of Science:

• Neurodegenerative diseases
• Prion biology
• Lipid metabolism

Background:

• Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative conditions requiring novel treatments.
• Prions, specifically the scrapie prion protein (PrPSc), bind to cholesterol-carrying lipoproteins in blood.
• The role of circulating lipoproteins in prion disease progression in vivo remains unclear.

Purpose of the Study:

• To investigate the in vivo relationship between circulating cholesterol-containing lipoproteins and prion pathogenicity.
• To assess the impact of altered cholesterol levels on prion disease progression and survival.

Main Methods:

• Utilized genetically engineered mice deficient in phospholipid transfer protein (PLTP) to manipulate circulating cholesterol levels.
• Administered the 22L prion strain via intraperitoneal inoculation.
• Monitored survival times and quantified PrPSc accumulation in the brain under varying cholesterol concentrations.

Main Results:

• PLTP-deficient mice with low cholesterol exhibited significantly prolonged survival after prion inoculation.
• Increasing cholesterol levels in PLTP-deficient mice (via lipid-enriched diet) reduced survival time.
• Elevated cholesterol correlated with an increased rate of PrPSc deposition in the brain.

Conclusions:

• Circulating cholesterol levels are a critical determinant of prion propagation in vivo.
• Cholesterol-lowering strategies show promise as a potential therapeutic approach for prion diseases.
• Targeting lipoprotein metabolism could offer a novel avenue for managing neurodegenerative prion conditions.