Review - Part of the Special Issue: Alzheimer's Disease - Amyloid, Tau and BeyondStatins more than cholesterol lowering agents in Alzheimer disease: Their pleiotropic functions as potential therapeutic targets

Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by severe cognitive impairment, inability to perform activities of daily living and mood changes. Statins, long known to be beneficial in conditions where dyslipidemia occurs by lowering serum cholesterol levels, also have been proposed for use in neurodegenerative conditions, including AD. However, it is not clear that the purported effectiveness of statins in neurodegenerative disorders is directly related to cholesterol-lowering effects of these agents; rather, the pleiotropic functions of statins likely play critical roles. The aim of this review is to provide an overview on the new discoveries about the effects of statin therapy on the oxidative and nitrosative stress levels as well as on the modulation of the heme oxygenase/biliverdin reductase (HO/BVR) system in the brain. We propose a novel mechanism of action for atorvastatin which, through the activation of HO/BVR-A system, may contribute to the neuroprotective effects thus suggesting a potential therapeutic role in AD and potentially accounting for the observation of decreased AD incidence with persons on statin.

Statins have been proposed to modulate several cellular pathways having neuroprotective or neurotoxic effects independent on their ability to lower cholesterol, but, rather, dependent on the kind of statin used. Atorvastatin treatment promoted a decrease of oxidative and nitrosative stress levels in the brain of a dog model of AD. These effects were mediated by an increased activity of the HO-1/BVR-A system having the anti-oxidant and anti-nitrosative bilirubin as end-product. In addition, increased BVR-A activation was negatively associated with BACE-1 protein levels. Thus, atorvastatin may have a neuroprotective role in the progression of AD by modulating the HO-1/BVR-A system.