Abstract
Alzheimer's disease is associated with cognitive impairments that affect memory and executive functions. Simvastatin is a cholesterol-lowering statin drug that is used to control levels of cholesterol in the blood, particularly in cases of hypercholesterolemia, and may be used in the treatment of aneurysmal subarachnoid hemorrhage. Previous results have indicated that the apoptosis of hippocampal cells may serve a critical role in the progression of Alzheimer's disease. In the present study, it was determined whether Simvastatin inhibited the apoptosis of hippocampal cells in vitro and in vivo. The therapeutic effects of Simvastatin were evaluated in 24-month-old triple-transgenic Alzheimer's disease (3×Tg-AD) mice, and the efficacy of Simvastatin in attenuating memory and cognitive impairment was investigated. Levels of apoptosis-related gene expression in the hippocampus and hippocampal cells of experimental mice were also detected. In addition, neuron excitability was assessed in the functionally relevant brain regions in the hippocampus. The data indicated that Simvastatin significantly suppressed the apoptosis of hippocampal cells in 3×Tg-AD model mice compared with controls (P<0.01). Furthermore, treatment with Simvastatin improved the dementia status of 3×Tg-AD mice, as determined by a learning task in which mice exhibited significantly reduced attention impairment, impulsivity and compulsivity (P<0.01). In addition, results demonstrated that Simvastatin significantly inhibited hippocampal damage and significantly improved neuronal loss in hippocampal structures classically associated with attentional performance when compared with untreated mice (P<0.01). Thus, Simvastatin prevented cognitive impairment by decreasing hippocampal cell apoptosis and improving learning-memory ability. Simvastatin treatment also increased the expression of anti-apoptotic genes and decreased the expression pro-apoptotic genes (P<0.01), which may have been associated with improved motor attention and cognitive competence in 3×Tg-AD mice. Collectively, these preclinical data indicated that Simvastatin was efficient in attenuating memory lapse and hippocampal cell apoptosis in a 3×Tg-AD mouse model. Thus, Simvastatin may be useful in improving the clinical outcome of patients with Alzheimer's disease.