Statins more than cholesterol lowering agents in Alzheimer disease: their pleiotropic functions as potential therapeutic targets

Abstract

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.

Keywords: Alzheimer disease; Biliverdin reductase; Cognition; Heme oxygenase; Oxidative stress; Statin.

Figure 1. Schematic representation of atorvastatin-induced HO/BVR-A system-dependent neuroprotective effects in the brain

Alzheimer disease (AD) is characterized by an increase of beta amyloid production (Aβ) following beta (BACE1) and gamma secretase (γ-secretase)-dependent cleavage of amyloid precursor protein (APP). Accumulation of Aβ oligomers is responsible for the observed increased oxidative stress levels in the brain. In order to counteract increased oxidative stress levels, cells promote the up-regulation of the heme oxygenase-1/biliverdin reductase-A (HO-1/BVR-A) system that is one of the earliest events in the adaptive response to stress. The HO-1/BVR-A system reduces the intracellular levels of pro-oxidant heme and generates equimolar amounts of the free radical scavengers biliverdin/bilirubin as well as the pleiotropic gaseous neuromodulator carbon monoxide (CO) and ferrous iron [Fe(II)]. Atorvastatin administration was able to increases (i) HO-1 protein levels and (ii) both BVR-A protein levels and activity (increased bilirubin (BR) production). Either BVR-A and BR possesses antioxidant features responsible of the reduction of oxidative stress, as demonstrated by the negative correlations found between oxidative stress biomarkers levels and (i) BVR-A protein levels or (ii) BVR activity in the brain [147]. Furthermore the up-regulation of the HO-1/BVR-A system is associated with an improvement of cognitive functions (learning) following atorvastatin treatment [147]. Finally, BVR-A protein levels and activity were significantly associated with decreased BACE1 protein levels suggesting a role for BVR-A in Aβ production [147]. All these effects contribute to the neuroprotective role of the HO-1/BVR-A system in the brain. Arrows, stimulation; dotted lines, inhibition.