Simvastatin improves cerebrovascular function and counters soluble amyloid-beta, inflammation and oxidative stress in aged APP mice

Cerebrovascular dysfunctions appear to contribute to Alzheimer's disease (AD) pathogenesis and the associated cognitive decline. Recently, it has been suggested that statins could be beneficial to AD patients independently from their cholesterol-lowering effects. Using 10 month-old amyloid precursor protein transgenic mice (APP mice), we sought to reverse cerebrovascular, neuronal and memory impairments with simvastatin (20 mg/kg/day, 8 weeks). Simvastatin improved reactivity of cerebral arteries, rescued the blood flow response to neuronal activation, attenuated oxidative stress and inflammation, and reduced cortical soluble amyloid-beta (A(3) levels and the number of A(3 plaque-related dystrophic neurites. However, at such an advanced stage of the pathology. it failed to reduce A(3 plaque load and normalize cholinergic and memory deficits. These findings demonstrate that low-dose simvastatin treatment in aged APP mice largely salvages cerebrovascular function and has benefits on several AD landmarks, which could explain some of the positive effects of statins reported in AD patients. (C) 2009 Elsevier Inc. All rights reserved.