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Cholesterol and Alzheimer's disease: A still poorly understood correlation

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Cholesterol and Alzheimer's disease: A still poorly understood correlation
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  Critical Review  Cholesterol and Alzheimer’s Disease: A Still Poorly UnderstoodCorrelation Roberta Ricciarelli 1 *,  Elisa Canepa 1 , Barbara Marengo 1 , Umberto M. Marinari 1 , Giuseppe Poli 2 ,Maria A. Pronzato 1 , and Cinzia Domenicotti 1 1  Department of Experimental Medicine, University of Genoa, Genoa, Italy 2 San Luigi Hospital, University of Turin, Turin, Italy Summary A large amount of evidence suggests a pathogenic linkbetween cholesterol homeostasis dysregulation and Alzheimer’sdisease (AD). In cell culture systems, the production of amyloid- b  (A b ) is modulated by cholesterol, and studies on animal mod-els have consistently demonstrated that hypercholesterolemia isassociated with an increased deposition of cerebral A b  peptides.Consequently, a number of epidemiological studies have exam-ined the effects of cholesterol-lowering drugs (i.e., statins) in theprevention and the treatment of AD. However, while retrospec-tive studies suggested a potential benefit of statin therapy, clini-cal trials produced inconsistent results. Here, we summarize themain findings from  in vitro  and  in vivo  research where the cor-relation between cholesterol and the neurodegenerative disorderwas investigated. Recognition of this correlation could be an im-portant step forward for our understanding of AD pathogenesisand, possibly, for the development of new therapeutic strat-egies.    2012 IUBMBIUBMB  Life ,  00: 000–000, 2012Keywords  Alzheimer’s disease; cholesterol; amyloid precursor pro-tein; amyloid beta; apolipoprotein E; statins. INTRODUCTION Amyloid- b  (A b ) is a 39–42 amino acid peptide that takestwo prevalent forms in humans, A b 40  and A b 42 , although longer and shorter peptides also exist. A b  is the natural product of thecleavage of a much larger protein, the amyloid- b  precursor pro-tein (APP) ( 1 ), by proteases called  b - and  c -secretases (  2–4 ).Much attention has been focused on this peptide because muta-tions in the APP and  c -secretase genes are associated with earlyonset familial forms of Alzheimer’s disease (AD) and areknown to cause cerebral A b  accumulation. However, whilethese genetic mutations are responsible for the accumulation of A b  in familial AD, the causative factors for A b  load in sporadicforms of AD are still not known. This leads to the possibilitythat, in the absence of genetic mutations, the identification of risk factors and mechanisms by which these factors contributeto the accumulation of A b  may help in preventing the onset of this devastating disorder. Hypercholesterolemia is such a factor and has been shown by epidemiological and laboratory studiesto increase the production of A b . However, the molecular events by which cholesterol causes A b  accumulation and thereal contribution of this steroid to the pathogenesis of AD arestill poorly understood.In this review, we summarize the main findings from cellculture, animal model, observational, and clinical studies wherethe correlation between cholesterol and the neurodegenerativedisorder was investigated. CELLULAR CHOLESTEROL AND AMYLOIDOGENESIS Because of the low permeability of the blood-brain barrier toperipheral cholesterol, most of the cholesterol present in thebrain derives from  de novo  synthesis in the central nervous sys-tem (  5 ). Mature neurons are thought to reduce the cholesterolproduction and rely on glial cells, mainly astrocytes, for their cholesterol supply ( 6–8 ). The astrocytic compartment meetsneuronal cholesterol demands by secreting cholesterol–apolipo-protein E (apoE) complexes, a mechanism that may involve theactivation of the ATP-binding cassette transporter A1 (ABCA1)( 9 ). Moreover, increased levels of ABCA1 were found to lower A b  production in neuronal cultured cells ( 10 ), whereas the dele-tion of ABCA1 gene in AD mouse models was associated withgreater A b  deposits ( 11, 12 ), supporting the idea that cellular  Address correspondence to: Roberta Ricciarelli, Department of Ex-perimental Medicine, Section of General Pathology, Via L.B. Alberti,2, 16132 Genoa, Italy. Tel: +39 010 3538831. Fax: +39 010 3538836.E-mail: ricciarelli@medicina.unige.itReceived 9 August 2012; accepted 30 August 2012 ISSN 1521-6543 print/ISSN 1521-6551 onlineDOI: 10.1002/iub.1091 IUBMB  Life ,  00(00): 000–000, Month 2012  cholesterol efflux might influence A b  production. Conversely, A b peptides have been recently found to exert an inhibitory effect onboth cholesterol synthesis ( 13 ) and astrocytic ABCA1 expression( 14 ), therefore suggesting the existence of a regulatory cycle con-necting APP processing and cholesterol homeostasis.The amyloidogenic processing of APP is believed to occur at, or in close proximity to, lipid rafts, cholesterol-rich mem-brane microdomains where both  b - and  c -secretase complexesreside ( 15 ). Because the enzymatic activity of   b - and  c -secre-tases is cholesterol-dependent ( 16, 17  ), it is likely that the pro-duction of A b  reflects a biological response to the increasedcholesterol availability.Excess free cholesterol in the cell is converted into choles-teryl esters by the enzyme acyl-coenzymeA: cholesterol acyl-transferase (ACAT). Using genetic, biochemical, and metabolicapproaches, it was found that cholesteryl esters are directly cor-related with A b  production, as increasing levels of cholesterylesters enhanced A b  release in cultured cells, whereas pharmaco-logical inhibition of ACAT led to the reduction of both choles-teryl esters and A b  production ( 18, 19 ). Accordingly, the inhibi-tion of the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reduc-tase, a key enzyme in the cholesterol  de novo  synthesis,reduced both intracellular and extracellular A b  levels (  20, 21 ).Despite the multiple lines of evidence, over the last two dec-ades, indicating a role of cholesterol in the production of A b ,the molecular mechanisms involved have so far only partiallybeen uncovered. Of particular interest is the very recent obser-vation that cholesterol forms an avid complex with the A b  do-main of APP (residues 672–711), which has provided an insightinto the amyloidogenic process, implying that strategies aimedat preventing the binding of cholesterol to APP may have a pro-phylactic utility in AD (  22 ).In addition to being involved in the amyloidogenic process-ing of APP, cholesterol and its oxidation products were foundto amplify the cytotoxic effects of A b  peptides in neuronal cul-tured cells (  23–25 ). Indeed, the idea that oxysterols, a class of cholesterol oxidation derivatives, might be the link betweenaltered cholesterol metabolism and AD has been widely sup-ported, and several excellent reviews on this topic are available(  26–28 ). ANIMAL STUDIES Experimental studies performed on different animal modelshave consistently demonstrated that hypercholesterolemia isassociated with an increased deposition of cerebral A b  peptides.Sparks et al. in 1994 (  29 ) were the first to report that, comparedwith control animals, rabbits fed a cholesterol-rich diet dis-played a higher A b  immunoreactivity in hyppocampal neurons.A few years later, hypercholesterolemia was found to acceleratethe Alzheimer’s amyloid pathology in an APP/PS1 double-trans-genic mouse model (  30 ). Similarly, mice overexpressing thehuman APP carrying the K670N/M671L Swedish mutation, andfed a high-cholesterol diet, were found to enhance cerebralaccumulation of A b  (  31 ). Due to the fact that also APP trans-genic mice lacking the apoE developed hypercholesterolemia,but in this case associated with a dramatic reduction of cerebralamyloidogenesis (  32 ), it was suggested that the effects of cho-lesterol on the processing of APP may require the presence of apoE. Nevertheless, this tempting hypothesis was contradicted 1year later by experiments in mice genetically modified toexpress endogenous levels of APP and abundant human A b . Inthese animals, in fact, the diet-induced hypercholesterolemialowered the brain content of APP derivatives, including A b 40 and A b 42 , despite the high levels of apoE in the serum andbrain (  33 ).ApoE is the main cholesterol-carrier protein in the brain andis particularly involved in the transport of cholesterol fromastrocytes to neurons. The influence of apoE on  in vivo  A b  dep-osition was srcinally suggested by Strittmatter et al. in 1993(  34, 35 ) and subsequently confirmed by experimental evidencein several animal studies (  32, 36, 37  ). Although many molecular events are still to be clarified, these findings, together with thenotion that allelic variation in the apoE gene is the most influ-ential genetic risk factor for sporadic AD, have strongly sup-ported the existence of an intrinsic relationship between choles-terol homeostasis, A b  production and clearance, and apoE me-tabolism (  38 ).Over the course of several years, also a number of cognitivestudies, evaluating the influence of dietary cholesterol on mem-ory, have been performed on different animal models. Behav-ioral assessments, for example, demonstrated that AD mice feda high fat/high cholesterol diet had more spatial learningimpairment than those fed a normal diet (  39 ). In the samestudy, it was also shown that this fat-rich diet promoted athero-sclerosis in the transgenic AD animals, thus providing an addi-tional biological mechanism for the cholesterol-induced cogni-tive impairment (  39 ).In a series of elegant studies, Greenwood and Winocur (  40– 42 ) reported that rats fed a nutritionally adequate diet, but witha high cholesterol content, were impaired in a wide range of learning and memory functions. More recently, this cholesterol-induced memory impairment has been correlated with a loss of dendritic integrity, cholinergic dysfunction, inflammation (  43 ),enhanced cortical A b  and phosphorylated tau (  44 ), all indica-tions which resemble an AD-like pathology. In line with suchobservations, cholesterol-lowering drugs (i.e., statins) werefound to reduce cerebral A b  (  21, 45, 46  ), phosphorylated tau(  46  ), inflammation (  45 ), and memory deficits (  46, 47  ) in a vari-ety of animal models. Whether statins act in the brain simplyby lowering cholesterol biosynthesis or by a different mecha-nism, however, still remains an open question. EPIDEMIOLOGICAL STUDIES Although a number of epidemiological studies have shownthat hypercholesterolemia is related to an increased risk of developing AD or mild cognitive impairment (  48–50 ), other  2 RICCIARELLI ET AL.  results, which do not fit in with this conclusion, have also beenreported. In 2005, for example, Reitz et al. (  51 ) observed noeffects of cholesterol and triglyceride levels on the cognitive abil-ity of aged individuals, while other studies demonstrated thathigh levels of total cholesterol or low-density lipoprotein (LDL)-cholesterol correlated with a decreased AD (  52 ) and dementiarisk (  53 ). Such discrepancies may be explained by differences inthe assessment of cholesterol analyses, patient’s characteristics,as well as follow-up times. Several studies, in fact, consideredtotal cholesterol levels without evaluating the impact of high-den-sity lipoprotein (HDL)- and LDL-cholesterol. It should also benoted that studies finding a negative correlation between choles-terolemia and dementia were principally carried out late in thepatient’s lives, whereas studies reporting a positive correlationwere conducted on younger individuals. Furthermore, it needs tobe taken into account that when the enrolled participants are al-ready affected by AD, it might be difficult to establish if achange in cholesterol levels has an effect on the progression of the disease or,  vice versa , the AD-related changes affect thepatient’s cholesterol metabolism. Statin Therapy and AD  Together with the data obtained from animal research, someobservational studies have bolstered the hypothesis that statinsmay prevent or mitigate the course of AD.Statins are competitive inhibitors of HMG-CoA reductase,the enzyme that catalyzes the rate-limiting step in the choles-terol biosynthesis. Therefore, the direct effect of statin therapyis the reduction of circulating cholesterol and also the inhibitionof   de novo  cholesterol biosynthesis in the brain.According to a 2000 report published in  The Lancet  , individ-uals of 50 years or older who were prescribed statins had a sub-stantially lower risk of developing dementia, regardless of thepresence or absence of hyperlipidaemia. The available data,however, did not distinguish between AD and other forms of dementia (  54 ). Similarly, patients older than 60 years taking lo-vastatin or pravastatin showed a lower AD risk, compared tothe general population or patients taking other medications (  55 ).Nevertheless, although it is likely that statins affect amyloido-genesis by reducing the cerebral levels of cholesterol, the mech-anisms underlying the therapeutic benefits of statins in the brainremain unclear. For example, both lovastatin and pravastatinwere found to reduce the prevalence of AD, despite lovastatinhaving an almost 50-fold higher ability to cross the blood-brainbarrier compared to pravastatin. Interestingly, the fact that sta-tins exert a lipophilicity-independent protection against AD hasalso been recently observed in the prospective, population-basedRotterdam Study (  56  ). In addition, an observational study onpostmenopausal women with coronary heart disease reported atrend for a lower likelihood of cognitive impairment in statinusers, which was independent of plasma lipid levels (  57  ).Not all observational studies, however, lead to the conclusionthat statins protect against AD. In fact, the Cache County Study,which began in 1995 with the enrollment of 5,092 elderly resi-dents, has found no correlation between the use of statins andthe onset of dementia or AD (  58 ). Likewise, neither in the Car-diovascular Health Study (  59 ) nor in the Religious Orders Study( 60 ) was statin therapy associated with a decreased risk of de-mentia, although people taking statins appeared less likely todevelop amyloid plaques ( 60 ).Regarding the results of intervention studies, two large,randomized, controlled trials on pravastatin (PROSPER study)( 61 ) and simvastatin (MCR/BHF Heart Protection Study) ( 62 )have not confirmed a clinically demonstrable cognitive benefitof statins in the treatment of AD .  Moreover, the data publishedin 2005 by Sparks et al. ( 63 ), showing that treatment with ator-vastatin had a beneficial effect on cognition and behavior inpatients with mild to moderate AD, have not been confirmed bythe recent, randomized controlled, LEADe study ( 64 ). CONCLUSION Prompted largely by results of cellular and animal studies, theconcept of altered cholesterol homeostasis has emerged as an im-portant factor in the pathogenesis of AD. However, despite thewell-established influence of cholesterol on the amyloidogenicprocessing of APP, further investigation is needed to better understand the molecular details and the causal link, if any,between cholesterol homeostasis dysregulation and neurodegener-ation. Importantly, in epidemiological studies, methodologicalissues, including criteria for subject selection, drug dosage, dura-tion of treatment, and methods of cognitive evaluation, should bemore thoroughly considered to avoid a lack of relevant outcomesand inconsistent results. On this point, Wolozin and colleagues( 65 ) have recently concluded that the complexity of late-onsetAD pharmacological treatment might result from the cumulativeeffects of at least four different pathophysiological factors: A b accumulation, cardiovascular disease, age-associated loss of syn-aptic plasticity, and inflammation. Is it by pure chance that atleast two of these factors are influenced by cholesterol? 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