NR ATGF
AU Haviv,Y.; Gabizon,R.; Sharon,R.
TI Delayed disease onset and induced neuroprotection in Scrapie-infected mice treated with Statins
QU International Conference - Prion 2005: Between fundamentals and society's needs - 19.10.-21.10.2005, Congress Center Düsseldorf - Oral sessions ORAL-36
PT Konferenz-Vortrag
AB
Several lines of evidence suggest a role for cholesterol in the normal cell biology of PrPc and in prion disease pathology. Cholesterol is a major component of rafts, the lipid membrane micro-domains to which GPI anchored proteins such as the prion proteins are inserted into. 1) PrPc and PrPsc are enriched on rafts; 2) Rafts mediate the internalization of PrPc ; 3) rafts mediate the conversion of PrPc to PrPsc . Moreover, the formation of PrPsc in cultured cells was inhibited by cholesterol lowering drugs.
Based on these results, we have treated scrapie-infected mice (I.C.) with Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, that specifically inhibits the rate-limiting enzyme in the bio-synthesis of cholesterol. We found that Simvastatin delayed disease symptoms (~ 27 days) and significantly increased survival (~30 day). Interestingly, the beneficial effect of Simvastatin-treatment was associated with increased accumulation of PrPsc levels in the brains of the Simvastatin-treated mice. The increased survival was associated with a dramatic enhancement of reactive astrocites. Most importantly, a neuroprotective effect of Simvastatin was detected in scrapie infected mice. Specifically, the Purkinje cells that degenerate in the scrapie-infected mice were fully protected by the Simvastatin treatment. The involvement of Simvastatin in neuroprotection mechanisms is currently tested.
AD Yaron Haviv, Ruth Gabizon, Hadassah University hospital, Neurology Dep. Ein Kerm Jerusalem, Israel; Yaron Haviv, Ronit Sharon, Hebrew University of Jerusalem, School of Medicine, Dep. of Cellular Biochemistry, Ein Kerem, Jerusalem, Israel
SP englisch
PO Deutschland