Simvastatin enhances learning and memory independent of amyloid load in mice

Objective: Normal aging is often associated with a decline in learning and memory functions. This decline is manifested to a much greater extent in Alzheimer's disease. Recent studies have indicated statins, a class of cholesterol-lowering drugs, as a potential therapy for Alzheimer's disease. Our objective was to determine whether administering a statin drug (sinivastatin) would protect against the development of behavioral deficits in an established mouse model of Alzheimer's disease. Methods: Tg2576 mice and their nontransgenic littermates were treated with sinivastatin and assessed by behavioral tests and biochemical analyses. Results: Simvastatin treatment not only reversed learning and memory deficits in the Tg2576 mice, but also enhanced learning and memory in the nontransgenic mice. Moreover, levels of amyloid P protein in the brains of treated mice did not differ from those of untreated mice. Simvastatin treatment was associated with increased expression levels of protein kinase B (Akt) and endothelial nitric oxide synthase in the mouse brain. Interpretation: Our findings demonstrate that the effects of simvastatin on learning and memory are independent of amyloid P protein levels. The mechanisms by which sinivastatin exerts its beneficial effects may be related to modulation of signaling pathways in memory formation.