Plasma cholesterol level determines in vivo prion propagation

Véronique Perrier,Thibaud Imberdis,Pierre-André Lafon,Marina Cefis,Yunyun Wang,Elisabeth Huetter,Jacques-Damien Arnaud,Teresa Alvarez-Martinez,Naig Le Guern,Guillaume Maquart,Laurent Lagrost,Catherine Desrumaux

doi:10.1194/jlr.m073718

Abstract

Transmissible spongiform encephalopathies are fatal neurodegenerative diseases with an urgent need for therapeutic and prophylactic strategies. At the time when the blood-mediated transmission of prions was demonstrated, in vitro studies indicated a high binding affinity of the scrapie prion protein (PrPSc) with apoB-containing lipoproteins, i.e., the main carriers of cholesterol in human blood. The aim of the present study was to explore the relationship between circulating cholesterol-containing lipoproteins and the pathogenicity of prions in vivo. We showed that, in mice with a genetically engineered deficiency for the plasma lipid transporter, phospholipid transfer protein (PLTP), abnormally low circulating cholesterol concentrations were associated with a significant prolongation of survival time after intraperitoneal inoculation of the 22L prion strain. Moreover, when circulating cholesterol levels rose after feeding PLTP-deficient mice a lipid-enriched diet, a significant reduction in survival time of mice together with a marked increase in the accumulation rate of PrPSc deposits in their brain were observed. Our results suggest that the circulating cholesterol level is a determinant of prion propagation in vivo and that cholesterol-lowering strategies might be a successful therapeutic approach for patients suffering from prion diseases.

Highlights

Transmissible spongiform encephalopathies are fatal neurodegenerative diseases with an urgent need for therapeutic and prophylactic strategies
Cholesterol and triglyceride levels were measured in the plasma of phospholipid transfer protein (PLTP) / and WT mice fed a standard diet
Because PLTP / mice exhibit reduced cholesterol levels in plasma, but no difference in cholesterol levels in the brain [19, 31, 32], we chose to evaluate the impact of PLTP deficiency on prion propagation using two different routes of administration, i.e., ic and ip

Summary

Introduction

Transmissible spongiform encephalopathies are fatal neurodegenerative diseases with an urgent need for therapeutic and prophylactic strategies. In mice with a genetically engineered deficiency for the plasma lipid transporter, phospholipid transfer protein (PLTP), abnormally low circulating cholesterol concentrations were associated with a significant prolongation of survival time after intraperitoneal inoculation of the 22L prion strain. When circulating cholesterol levels rose after feeding PLTP-deficient mice a lipid-enriched diet, a significant reduction in survival time of mice together with a marked increase in the accumulation rate of PrPSc deposits in their brain were observed. Two key events can be targeted to develop therapeutic strategies against transmissible spongiform encephalopathies: first, the conversion of PrPC into the pathological scrapie isoform, PrPSc, which occurs through an autocatalytic process, called prion replication [8]; second, the propagation of PrPSc from the peripheral circulation to the brain, where it accumulates and causes spongiosis and neurodegeneration [9].

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