Epitope-specific anti-prion antibodies upregulate apolipoprotein E and disrupt membrane cholesterol homeostasis

The mechanisms of neuronal degeneration induced by the transformation of normal cellular prion protein (PrPC) into disease-associated PrPSc are not fully understood. Previous reports have demonstrated that cross-linking cellular prion protein by anti-PrPC antibodies can promote neuronal apoptosis. In this report, we now show that treatment of neuronal cells with anti-prion antibodies leads to sequestration of free cholesterol in cell membranes, significant overexpression of apolipoprotein E, and to cytoplasmic phospholipase A2 activation as well as to production of prostaglandin. These results confirm the in vivo toxic effects and indicate that anti-prion antibody treatment of neurons lead to deleterious effects. Finally, great caution should be exerted when adopting antibody-based therapy for prion diseases.