JOURNAL OF NEUROCHEMISTRY

| 2012 | 120 | 13

doi: 10.1111/j.1471-4159.2011.07548.x

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*Department of Psychiatry, University Medicine Goettingen, Goettingen, Germany German Research Center for Neurodegenerative Diseases, DZNE Goettingen, Germany German Research Foundation Research Center for Molecular Physiology of the Brain, CMPB, Goettingen, Germany Department of Neurology, University Medicine, Goettingen, Germany MPI for Experimental Medicine, Goettingen, Germany
Read the full article Biliverdin reductase-A: a novel drug target for atorvastatin in a dog pre-clinical model of Alzheimer disease on page 135.

Alzheimers disease is the most common type of dementia in old-age. An increasing number of studies has shown that elevated serum cholesterol levels might increase the risk of Alzheimers disease (Notkola et al. 1998; Kivipelto et al. 2001). Statins lower cholesterol levels by inhibiting HMGCoA-reductase, the key enzyme of cellular cholesterol synthesis. The application of statins in animal models of Alzheimers disease resulted in reduced production of the neurotoxic peptide amyloid-beta and a benetial effect on cognitive parameters (Hartman 2005). This raised the hope that statins might be a promising drug in the treatment of Alzheimers disease. Data from epidemiologic studies and clinical trials remain conicting. Three large epidemiologic cohort studies supported the notion that statins might have a prophylactic effect and reduce the risk to develop Alzheimers disease (Cramer et al. 2008; Sparks et al. 2008; Haag et al. 2009). However, a Cochrane review published in 2009 came to the conclusion that There is good evidence from randomized clinical trials that statins given in late life to individuals at risk of vascular disease have no effect in preventing Alzheimers disease or dementia. Biologically, it seems feasible that statins could prevent dementia because of their role in cholesterol reduction and initial evidence from observational studies was very promising. Indication bias may have been a factor in these studies, however, and the evidence from subsequent randomized clinical trials has been negative (McGuinness et al. 2009). No benet could be deduced from previous clinical trials with statins in Alzheimers disease patients, according to a second Cochrane report from 2009. In the randomized,

controlled, double-blind and multicenter trial LEADe, atorvastatin was evaluated as a treatment for mild to moderate Alzheimer disease in 640 patients. Treatment was well tolerated but did not result in improved cognition or global function. Likewise, in a randomized, controlled, double-blind study of Alzheimer patients treated with 80 mg simvastatin daily for 26 weeks, a small benet in the mini mental state examination (MMSE) test was observed in the simvastatin group, however no effect could be shown in the ADAS-Cog scale (Simons et al. 2002). Consistent with this, in a recently published report by Sano et al. (2011) no benet of 40 mg Simvastatin was detected regarding cognition, global function or behavior in a randomized, double-blind and placebocontrolled trial in 406 patients with mild to moderate Alzheimers disease. So far, no primary prevention trials have been initiated with statins. Current strategies concentrate on earlier interventions such as the stage of mild cognitive impairment based on the understanding that treatment in the stage of mild to moderate Alzheimers disease might be far too late in the disease process. An ongoing, double-blind, placebocontrolled and multicenter trial with simvastatin is currently

Received October 12, 2011; accepted October 18, 2011. Address correspondence and reprint requests to Anja Schneider, MD, Memory Clinic, Department of Psychiatry and Psychotherapy, University Medicine Goettingen, Von-Siebold-Str. 5, 37075 Goettingen, Germany. E-mail: aschnei8@gwdg.de Abbreviations used: APP, amyloid precursor protein; HO-1/BVR-A, heme oxygenase-1/biliverdin reductase-A.

2011 The Authors Journal of Neurochemistry 2011 International Society for Neurochemistry, J. Neurochem. (2012) 120, 13

2 | Review

conducted for individuals suffering from amnestic mild cognitive impairment which is associated with a high risk to develop Alzheimers disease (SIMaMCI, competence network dementia, Germany). In tissue culture experiments and several animal models including mice and guinea pig, it has been shown that reduction of cholesterol results in lower activity of presenilin and beta-secretase, the two enzymes which cleave the amyloid precursor protein (APP) to release the amyloid-beta peptide (Hartman 2005) (for an overview on the pleiotropic actions of statins in Alzheimers disease see Fig. 1). Barone et al. (2012) report in this issue that statins may improve cognition independently from their cholesterol lowering effect by an antioxidant action. Previously, this group has shown that treatment of aged beagles with 80 mg atorvastatin/d over 14.5 months resulted in improved discrimination learning, while amyloid-beta concentrations in the cerebrospinal uid remained unchanged (Buttereld et al. 2011). The authors now identify heme oxygenase-1/ biliverdin reductase-A (HO-1/BVR-A) as a potential cholesterol-independent mediator of this effect. HO-1/BVR-A is a neuronally expressed enzyme which catalizes the reaction of heme to free iron, carbon monoxide and biliverdin. Biliverdin is then converted to the antioxidant bilirubin. The authors show that HO-1/BVR-A protein levels and enzyme activity were up-regulated in the parietal cortex in response to atorvastatin treatment. This was paralleled by reduced oxidative stress indices (4-hydroxy-2-nonenal and 7-ketocholesterol) which might be mediated by the increased activity of HO-1/BVR-A. These ndings might explain the protective effect observed with statins even in the absence of overt hypercholesterinemia in patients (Barone et al. 2012).

Reactive oxygen and nitrogen species are elevated prior to deposition of plaques and tangles and have therefore been widely discussed as potential mediators of neurotoxicity in Alzheimers disease as well as a potential therapeutic target. HO-1/BVR-A is the inducible form of two isoenzymes of heme-oxygenase and up-regulated under oxidative/nitrosative stress conditions and increases the production of the radical scavenger bilirubin. A reduced ability to respond to oxidative stress was described during aging and cortical HO1/BVR-A expression levels decrease during ageing and in the hippocampus of patients with Alzheimers disease or mild cognitive impairment (Abraham and Kappas 2008; Barone et al. 2011). In addition, APP can bind and inhibit HO-1/BVR-A activity (Abraham and Kappas 2008). The authors show that an up-regulation of HO-1/BVR-A protein levels and enzyme activity upon statin treatment is negatively correlated with oxidative stress markers, betasecretase 1 levels and cognitive dysfunction in aged canines. The animal model used in this study, an aged beagle hound, is especially interesting, because it is a natural model of pre-clinical Alzheimers disease and reects the age-related changes and the pathology observed in humans (Barone et al. 2012). The authors did not elucidate the mechanism how statins might regulate HO-1/BVR-A expression. The observed increase in HO-1/BVR-A expression could however be induced by the effects of statin on the transcription factor nuclear factor-like 2 (Lu et al. 2008). Nuclear factor-like 2 has previously been shown to be up-regulated by statins (Hsieh et al. 2008). Besides its antioxidative effect, HO-1/BVR-A might have an impact on other pathophysiological events in Alzheimers disease. Interestingly, HO-1/BVR-A was described to

Microglia acvaon Inammaon Oxidave stress Tau pathology

Stans Aninammatory
Reduced expression of cytokines, MHCII

Anoxidave
iNOS inhibion, reduced NO producon Reducon of free radicals

Reduced tau aggregaon

Fig. 1 Pleiotrophic actions of statins in Alzheimers disease. Statins inhibit the production of cholesterol and isoprenoids (farnesyl- and geranygeranylpyrophosphate) (orange box). APP endocytosis and amyloidogenic APP processing are impaired by low plasma membrane cholesterol. Both, b-secretase BACE and c-secretase activity, depend on membrane cholesterol and low cholesterol favors a-secretase cleavage of APP. Statins also counteract several downstream effects of Abeta: inammation, oxidative stress and tau pathology, partially by inhibition of protein isoprenylation which regulates activity of small GTPase rho, rac and ras.

B A sec ret C ase E APP

A b e t a

A bA eb t e at
a

A bA eb t e at a

Acetyl-CoA HMG-CoA Mevalonate Isopentyl-PP Ras/Rho/Rac

Oligomers

Stans

APP -secretase

Farnesyl-PP Squalen Geranylgeranyl-PP

Membrane cholesterol Stans

Cholesterol

Inhibion of Abeta producon:

Reducon of BACE/ -secretase acvity Reducon of APP endocytosis and processing

2011 The Authors Journal of Neurochemistry 2011 International Society for Neurochemistry, J. Neurochem. (2012) 120, 13

Review | 3

facilitate microglial clearance of amyloid-beta and to downregulate tau expression in a cell model (Abraham and Kappas 2008). HO-1/BVR-A expression also enhances resistance against nitrosative stress and Selley et al. reported reduced protein tyrosine nitration in APP mice treated with simvastatin (Selley 2005). Whether HO-1/BVR-A plays a crucial role in mediating antioxidant effects during aging and in Alzheimers disease remains to be established further in transgenic and knockout animal models. If this appears to be the case the regulation of HO-1/BVR-A levels can be added to the list of potentially benecial actions of statins in aging and neurodegeneration.

Conict of interest
The authors state no conict of interest.

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