Induced neuroprotection independently from PrPSc accumulation in a mouse model for prion disease treated with simvastatin.
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.


METHODS
Controlled animal study.


METHODS
University medical center research laboratory.


METHODS
Female mice from the FVB/N strain.


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


METHODS
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.
Haviv
Yaron
Y
Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah University Hospital, Jerusalem, Israel.
Avrahami
Dana
D
Ovadia
Haim
H
Ben-Hur
Tamir
T
Gabizon
Ruth
R
Sharon
Ronit
R
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018620:PrPSc Proteins / Q000378:metabolism*; D017096:Prion Diseases / Q000209:etiology / Q000378:metabolism* / Q000401:mortality / Q000517:prevention & control*; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use*; D016019:Survival Analysis
D018696:Neuroprotective Agents; D018620:PrPSc Proteins; D019821:Simvastatin