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Yaron Haviv, DMD; Dana Avrahami, MSc; Haim Ovadia, PhD; Tamir Ben-Hur, MD, PhD; Ruth Gabizon, PhD; Ronit Sharon, PhD

Arch Neurol. 2008;65(6):762-775.

Background  The misfolding and aggregation of specific proteins has emerged as a key feature of several neurodegenerative diseases. In prion diseases, progressive disease and neuronal loss are associated with the accumulation of PrP^Sc, the misfolded isoform of PrP^C. Previous in vitro studies suggest that cholesterol-lowering drugs inhibit the conversion of PrP^C to PrP^Sc and the accumulation of the latter, possibly through the disturbance of cholesterol-rich membrane domains (lipid rafts).

Objective  To examine the effect of simvastatin, a cholesterol-lowering drug, on prion disease progression and survival.

Design  Controlled animal study.

Setting  University medical center research laboratory.

Subjects  Female mice from the FVB/N strain.

Interventions  Peripheral and central nervous system inoculations with scrapie Rocky Mountain Laboratory inoculum.

Main Outcome Measures  Clinical, immunological, pathological, and molecular assays were performed.

Results  Simvastatin delayed disease progression, leading to increased survival in peripheral as well as central nervous system inoculations. Simvastatin's beneficial effect is mediated through the L-mevalonate pathway; however, it is independent of brain cholesterol levels. Interestingly, simvastatin treatment induced PrP^Sc accumulation in parallel with an induced neuroprotective effect. In accordance, we found that simvastatin induced immunomodulatory mechanisms in the brains of infected mice, affecting expression levels of specific microglial chemokines and cytokines.

Conclusions  Simvastatin delays prion disease progression and increases survival in vivo, independently of the pathogenic conversion of PrP^C to PrP^Sc. We show that simvastatin's effects on neuroprotection are correlated with downregulation of Cox2 levels and induction of microglial activation in prion-infected mouse brains.

Author Affiliations: Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah University Hospital (Dr Haviv, Mrs Avrahami, and Profs Ovadia, Ben-Hur, and Gabizon), and Department of Cell Biochemistry and Human Genetics, Faculty of Medicine, Hebrew University (Drs Haviv and Sharon), Jerusalem, Israel.

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