Pharmacologic cholesterol homeostasis affects prion generation in a synergistic manner

It is generally recognised that prion replication in the brain is associated with cholesterol changes. We now show that prion diseases are likely associated with systemic metabolic alterations that involve changes both in the content and distribution of the different pools of cellular cholesterol, free cholesterol and cholesterol esters, as well as of other cellular lipids, including phospholipids and triglycerides. The synergic anti-prion effect showed by drug combinations affecting cholesterol metabolism at different levels suggest that pharmacologic interventions restoring lipid homeostasis may represent a more successful therapeutic approach than drug treatments lowering cholesterol content per se (i.e. statins). Notably, our data also point to neutral lipid accumulation in peripheral cells as an easy-to-detect hallmark associated with disease and/or indicative of increased susceptibility to develop disease following infection.