Cholesterol homeostasis: a key to prevent or slow down neurodegeneration.

0.98 MB·English

by  Anchisi, Laura

REVIEWARTICLE
published:04January2013
doi:10.3389/fphys.2012.00486
Cholesterol homeostasis: a key to prevent or slow down
neurodegeneration
LauraAnchisi1,2,SandraDessì4,AlessandraPani3 andAntonellaMandas4*
1ChildNeuropsychiatryUnit,AziendaSanitariaLocale(ASL)n◦5,Oristano,Italy
2DepartmentofClinicalandExperimentalMedicineandPharmacology,UniversityofMessina,Messina,Italy
3DepartmentofBiomedicalSciences,UniversityofCagliari,Monserrato,Cagliari,Italy
4DepartmentofMedicineSciences,UniversityofCagliari,Monserrato,Cagliari,Italy
Editedby: Neurodegeneration, a common feature for many brain disorders, has severe
RaquelMarin,UniversidaddeLa consequences on the mental and physical health of an individual. Typically human
Laguna,Spain neurodegenerative diseases are devastating illnesses that predominantly affect elderly
Reviewedby: people, progress slowly, and lead to disability and premature death; however they
GiuseppeAstarita,Georgetown
may occur at all ages. Despite extensive research and investments, current therapeutic
University,USA
EnricoDainese,Universityof interventions against these disorders treat solely the symptoms. Therefore, since the
Teramo,Italy underlying mechanisms of damage to neurons are similar, in spite of etiology and
*Correspondence: background heterogeneous, it will be of interest to identify possible trigger point of
AntonellaMandas,Departmentof neurodegenerationenablingdevelopmentofdrugsand/orpreventionstrategiesthattarget
MedicineSciences,Universityof
many disorders simultaneously. Among the factors that have been identified so far to
Cagliari,SS554bivioSestu,
Monserrato,Cagliari09042,Italy. cause neurodegeneration, failures in cholesterol homeostasis are indubitably the best
e-mail:[email protected] investigated. The aim of this review is to critically discuss some of the main results
reported in the recent years in this field mainly focusing on the mechanisms that,
by recovering perturbations of cholesterol homeostasis in neuronal cells, may correct
clinicallyrelevant features occurring in different neurodegenerative disorders and, in this
regard,alsodebatethecurrentpotentialtherapeuticinterventions.
Keywords:neurodegenerativedisorders,neuronalmembranes,cholesterolhomeostasis,cholesterolesterification,
drugtargets
INTRODUCTION:NEURODEGENERATIONAND Christie, 2008). Cholesterol is a multifaceted molecule, which
CHOLESTEROL servesasessentialmembranecomponent,ascofactorforsignaling
Progressivelossofstructureorfunctionofneurons,neurodegen- moleculesandasprecursorforsteroidhormones.Inthecentral
eration, (Bartzokis, 2004) is a common feature for many neu- nervoussystem(CNS),itisrequiredforbraingrowthandmyeli-
rodegenerative diseases such as Alzheimer’s disease (AD) (Pani nationofaxonsinthedevelopingbrainandforcontinued axon
etal.,2009a,b),Parkinson’sdisease(PD)(Asher,2011),multiple growthandsynapseremodeling inthematurebrain(Koudinov
sclerosis (MS) (Luessi et al., 2012), amyotrophic lateral sclero- andKoudinova,2003;Dietschy,2009).CholesterolintheCNShas
sis (ALS) (Pratt et al., 2012) and prion disorders (PrD) (Pani alsoanimportantroleinpromotingphaseseparationwithinneu-
et al., 2009a,b). Neurodegeneration may also occur in response ronmembranesleadingtolaterallyorganizedregionscalledlipid
to stroke, and head andspinal cord trauma (Thompson,2008). rafts (Brownand London, 1998). These regions areenriched in
Typically these diseases affect older people, however, also autis- unesterified(free)cholesterol(FC)andotherspecificlipidcom-
tic spectrum disorders (ASD), which includes autism, attention pounds (sphingolipids, plasmenylethanolamine, anionic phos-
deficit disorder (ADD), attention deficit hyperactivity disorder pholipids,plasmalogens,andarachidonicacidcontainingphos-
(ADHD), Asperger syndrome and other disorders that affect pholipids) (Simons and Ehehalt, 2002; Korade and Kenworthy,
children, are thought to be caused by abnormalities in brain 2008).Lipidraftsallowalateralseparationofthemembranelead-
function orstructure ofprobablegenetic origin(Johnsonet al., ingtofunctionallydistinctregionsofthemembrane.Somelipid
2007). Although majoradvances havebeen madein the under- raftsareneededinordertoexportproteinsoutofthecell,others
standingneurodegeneration, itspathophysiologyisnotyet fully are used to anchor specific proteins in the membrane and keep
understood and treatment that can prevent or slow down neu- proteinclusterstogether.Thus,theyareproteinandlipidfluctuat-
rodegenerative disorders is still lacking. Therefore, there is an ingmicrodomainsimportantforproteintraffickingandsorting,
urgent need to identify possible triggers of neurodegeneration forcellsignaling,andformanifoldcellularprocesses.Reduction
inordertodevelopeffectivetreatmentand/orpreventionstrate- ofcellularcholesterol leadsto disruptionofraftfunctions (Bari
giesthatcouldamelioratemanydiseasessimultaneously.Among et al., 2005; Murai, 2012). Finally, it is also important to men-
the factors that until now have been identified as affecting the tion the role of cholesterol in the synthesis of neurosteroids.
neurodegeneration development, failures in cholesterol home- Thesecompoundsactasallostericmodulatorsofneurotransmit-
ostasisareindubitablythemostwell-known(Ansteyetal.,2008; ter receptors and are synthesized, especially in myelinating glial
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Anchisietal. Propercholesterollevelsinneuronalmembrane
cells,fromcholesterolorsteroidalprecursors(MellonandGriffin, The above discussed organization of cholesterol highlights the
2002;Kimotoetal.,2006).Onthebasisoftheaboveinformation, importance of cholesterol’s unique molecular structure in pro-
it can deduce that, changes into one or more of the integrated moting the formationofthe liquid-orderedphase.Inthis spirit
sets of homeostatic mechanisms that finely regulate cholesterol it seems obvious that cholesterol molecules do not function
contentinneurons,couldadverselyaffectthenormalbrainfunc- alonebutthey dosoinaco-operativemanner,highlighting the
tions leading to neurodegeneration; a better understanding of importance of understanding collective orderingphenomena in
severalmolecularmechanismsofcholesterolinvolvementinthis PMs. All these structural and functional roles of cholesterol in
process might thus represent a useful tool to identify biomark- PMs,implythatevenminorchangesinneuronalPMcholesterol
ersforneurologicdisordersaswellastargetsforpharmacological concentrationscanleadtoneurodegeneration.
interventions. Here we review some of the main results on the
subjectareareportedinrecentyearswiththeaimtoprovideplau- FREECHOLESTEROLINTHECENTRALNERVOUSSYSTEM
sible explanations of how alterations in brain and blood lipid Human CNS contains over 23% of the total body cholesterol
metabolismcontributetoneurodegeneration.Amajorfocuswill while accounting for only 2% of the total body mass. Because
beonthemechanismsthat,byrestoringcholesterolhomeostasis thebrain’scholesterolmetabolismisalmostexclusivelysegregated
perturbations in neuronal cells, may improve clinically relevant fromtheperipheralcirculationbythebloodbrainbarrier(BBB),
featuresfoundtobepresentindifferentmajorneurodegenerative cholesterolmetabolisminbrainisdifferentfromthatinperiph-
diseases. ery.IntheadultbrainitismainlyintheFCformandonlytrace
amountofesterifiedcholesterol(CE)arepresent.Nearly95%of
CHOLESTEROLINNEURONALPLASMAMEMBRANE this FC is synthesized de novo from acetate, predominantly in
The plasma membrane (PM) consists of both lipids and pro- theendoplasmicreticulum(ER)ofglialcells—astrocytesand,to
teins, its fundamental structure being the phospholipid bilayer, alesserextent,oligodendrocytes—withonlysmallamountssyn-
whichformsastablebarrierbetweentwoaqueouscompartments thesizedinneurons(DietschyandTurley,2004;Dietschy,2009).
inside and the outside of the cells. Cholesterol is a ubiquitous FCpool inadulthumanbrain(about490mg/kg) isdistributed
component of all PMs, including those of neurons, where it among three different compartments: (1) myelin membranes
determines their permeability, fluidity, and mechanical proper- (2) neuron PMs and (3) glial cells. Myelin membranes account
ties. InthePMs,cholesterol initsfreeformhasthetendencyto for 70–80% of FC (about 380mg/kg), whereas the remaining
formregularlydistributedlateralstructuresgivingrisetothefor- 110mg/kgpresumablyresidesinthemembranesofcellularele-
mationof highlyordered nano-scalemembranedomainscalled ments: about 11mg/kg in neurons (∼10% of brain cells), and
lipid rafts (Simons and Ehehalt, 2002; Korade and Kenworthy, about99mg/kg in different types of glial cells and vascularele-
2008) which have important roles in numerous cellular func- ments (Jiménez-López et al., 2010). The specificity of lipids,
tions. Despitemanystudies,however,howcholesterol isunique mainly FC and their patterns of accumulation during develop-
inpromotingtheformationoflipidraftsandwhatemergesfrom ment (Dietschy and Turley, 2004; Dietschy, 2009), contributes
the interactions of it with other lipids still remain unresolved to thedirect andpermissiverolesthat thesecompoundsplayin
questions. It has shown that lipid rafts generally contain 3–5- signal transduction as well as in both activation and deactiva-
foldtheamountofcholesterolfoundinthesurroundingbilayer tionofraftresidentproteinsinvolvedinmultiplebrainfunctions
(Pike, 2003); this cholesterol enrichment seems to be necessary (GeorgeandWu,2012).Thehumanbrainincreasesdramatically
toholdraftstogetherandtomodulateraft-dependentcellfunc- insizeandcomplexityinthefirstyearoflife(Blümletal.,2012),
tions,havingsterolsextraordinaryorderingcapacity.Inneuronal andsynthesisoflipidcomponentsincreaseinproportionto the
PMs, FC, due to its structure and the saturation of the hydro- progressiveincreaseofbrainvolume(DietschyandTurley,2004).
carbonchains,preferentiallyinteractswithphosphatidylcholines Frombirthtoadolescence,thereisa4-foldincreaseinthevolume
and sphingolipids such as sphingomyelin; its small head-group ofthehumanbrain;thisincreasehoweverisnotuniform:there
andtherigidringstructurepreventalmostalldirectsterol-sterol is differential growth between subcortical and cortical regions,
contactshelpingcholesteroltoavoidtheexposureofhydrophobic andbetweendifferentregionsofcortex.Whereasthereisarapid
membraneregionstowaterwhichwouldgiverisetoaveryunfa- increaseinsynaptogenesisaroundthetimeofbirthforallcorti-
vorablecontribution to the free energy. The cholesterol biosyn- calareasstudied,themostrapidburstofsynapseformationand
theticpathwayshowsasystematicremovalofmethylgroupsfrom the peak density of synapses occur at different ages in different
thesteroidring.Eachremovalstepoptimizessterolpropertiesin areas (Johnson, 2001). For example, prefrontal cortex is one of
termsoforderingandcondensingeffects(Aittoniemietal.,2006). the last regions of the brainto reach maturation, in this region
Analysisofthemolecularorientationshaverevealedthatcholes- ofbrainsynaptogenesis startsbetween 3and4months, andthe
terol,especiallyathigherconcentrations,clearlypromotesoppo- density ofsynapsesincreasesslowlyand doesnotreach itspeak
site configurationsresulting inasandwiching-likepattern—two until after the first year. The prefrontal cortex is the part of the
cholesterol moleculessandwich a phospholipid.This configura- frontal lobes lying just behind the forehead and is responsible
tion is found to be more likely for saturated than unsaturated forcognitive analysisandabstractthought, andthemoderation
lipids in agreement with cholesterol’s higher tendency to order of “correct” behavior in social situations. Although some con-
andcondensesaturatedthanunsaturatedlipids,andthismayat troversy, the consensus is that brain structures have the overall
leastinpartexplainwhytheliquid-orderedphaseisnotobserved appearance of those in the adult by 2 years of age, and that all
atsmallcholesterolconcentrations(Martinez-Searaetal.,2010). themainwhitematterfibertractscanbeobservedby3yearsof
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Anchisietal. Propercholesterollevelsinneuronalmembrane
age(Matsuzawaetal.,2001;Pausetal.,2001).Insomereports,it and in spinal cords of ALS patients (Cutler et al., 2002). In
issuggested thatafterarapidincreaseingreymatter(predomi- animal models it has been found that brain CE accumulation
nantlycomposedofneuroncellbodiesandunmyelinatedaxons), and increased activity of the esterifying enzyme, acyl coenzyme
brain volume up to ∼4 years of age, there is then a prolonged A(CoA): cholesterol acyltransferase (ACAT1) precedethe clini-
period of slight decline that extends into adult years (Johnson, cal phenotype (Posse de Chaves and Narayanaswami, 2008); in
2001). Arolefor lossofwhite matter inneurodegeneration has addition, exposure of cultured hippocampal neurons to neuro-
beenpreviouslyreported(Bartzokis,2004),however,whetherthe toxic components (i.e., amyloid β-peptide, Aβ) and of cultured
decline in brain volume is associated with loss of white matter motorneuronstooxidativeinsults,producesadiscreteaccumu-
remains unknown (Matsuzawa et al., 2001). It is important to lationofintracellularCE(Cutleretal.,2002).Worthyofmention,
remember the white matter is so called because the high con- stearoyl-CoA desaturase (SCD), an ER enzyme that catalyzes
centration of myelin which is constituted of about 70–85% of the biosynthesis ofmonounsaturated fatty acids(MUFAs)from
lipids,mainlycerebroside,cholesterol, andphosphatidylcholine. saturatedfattyacidshasbeenrecentlyshowntohavearoleinpro-
As cholesterol is an essential component of myelin in white vidingoptimalsubstrateforcholesterolesterification(Patonand
matter, not surprisingly, the size of the sterol pool in the CNS Ntambi,2009).Thisisparticularlyimportantinlightoftherecent
increases(ordecreases)inaproportionalmannertowhitemat- study by Astarita et al. (2011) that suggests that cholesterol/CE
tervolume(DietschyandTurley,2004).Humanssynthesizehigh homeostasis (SCD-ACAT) is altered in AD. Although it is still
ratesofcholesterolafterbirthmainlyinoligodendrocytes,asthe unclearifelevatedlevelsinCEaretheresultofcelldeathprocess
CNSmaturesandmyelinproductiondecreasestoverylowlevels, or if they directly contribute to neurogegeneration, abnormal-
CNScholesterol poolreachesaconstantvalue.Insummary,the ities in CE metabolism appear to be another characteristic of
majority of brain cholesterol is accumulated between neonatal neurodegenerativediseases.
period and adolescence when neurons become surrounded by
specializedPMstermedmyelin(DietschyandTurley,2004).After FCANDNEURODEGENERATION
myelination, the metabolism ofcholesterol inthe adultbrainis Growing evidence indicates that membrane lipid rafts are
characterizedbyaverylowturnoverandminimallosses(Morell involved in the generation of Aβ and PrPsc amyloidogenic-
and Jurevics, 1996). However, recent results indicate that both peptidesfromamyloidprecursorprotein(APP)andcellularprion
cholesterolsynthesisanddegradationareactiveintheadultbrain protein (PrPc), (deposition of which in brain parenchyma and
aswellandthatalterationsinthesemechanismsprofoundlyinflu- vessel walls are the major pathological feature of AD and PrD,
encehigher-orderbrainfunctions(Martinetal.,2010;Orthand respectively), possibly through the creation of a favorable lipid
Bellosta,2012). environment (Figures1 and 2) (Pani et al., 2011). It has been
reportedthat,whenAPPandPrPcmoleculesoccupyalipidraft
CEANDESTERIFICATIONINTHECNS region of the membrane, they are more accessible to and, thus,
Asalreadyreported, cholesterol, inadultbrain,ismainlyinthe preferentially cleaved by amyloidogenic enzymes (i.e., raft resi-
freeform,whileonlytraceamountsofCEarepresent.However, dentβ-secretaseorBACE1). Ontheotherhand,whenAPPand
asignificantportion(upto5%)oftotalcholesterolisfoundtobe PrPc molecules are outside rafts, they appear to be preferen-
esterifiedinthedevelopingbrain.ItfollowsthattheCEconcen- tiallycleavedbynon-amyloidogenicnon-raftresidentα-secretase
trationinthebrainfallsbetweenveryearlystageofdevelopment (ADAM 10) (Simons and Ikonen, 1997). It has been thus sug-
and late stages of adulthood (Husuf, 1992). Interestingly, a fast gestedthatAPPandPrPcinthebrainarepresentintwocellular
and temporary risein the concentration ofCE occursat atime pools:one,outsiderafts,wherethesetwoproteinsareprocessed
that corresponds to the onset of myelinogenesis. This transient inanormalway;theother,insidetherafts,whereabnormalcleav-
increase appears to be a universal phenomenon, because it has age takes place (Simons and Ikonen, 1997). If it is so, it can
beenfoundinallmammalianbrainsthathavebeenstudiedsofar. be assumed that compartmentalization of membrane proteins
Inparticular,(Yusufetal.,1981)reportedthatinhumanstheCE depends by spatial distribution of the lipid raft microdomains
concentrationsinthethreemainpartsofbrain,forebrain,cere- whichinturnisregulated bythelevelsofFCandthereforethat
bellum,andbrainstem,werehighestat13–15weeksandrapidly maintenanceofcholesterolhomeostasisisessentialforneurons.If
fellduringgrowth.TransientrisesinCEconcentrationswerealso cholesterollevelsarehigherorlowerthanthephysiologicalrange;
seenaroundbirthintheforebrainandfewmonthsafterbirthin several metabolic pathways of compensation can be activated
thecerebellum,aperiodcoincidingwiththeonsetofactivemyeli- thatifcontinuedforlongperiodscanleadtoneurodegeneration
nationintherespectivebrainareas.Thus,theincreaseintheCE throughdifferentmechanisms.
inthedevelopinghumanforebrainappearstobegovernedbytwo
events, one representing brain growth and the other represent- CEANDNEURODEGENERATION
ingtheactivephaseofmyelination,supportingtheideaofaclose A significant amount of genetic, biochemical, and pharma-
associationbetweenCEandtheprocessofmyelination. cological data highlighted that modifications in cholesterol
Beside during physiologic development, changes in CE esterification and trafficking are associated with Aβ and PrPsc
metabolismhavebeenreportedinmanydifferentneurologicdis- biogenesis (Puglielli et al., 2001; Hutter-Paier et al., 2004;
ordersincludingAD,ALS,MS,andPrD.Inparticular,anincrease Bhattacharyya and Kovacs, 2010; Huttunen et al., 2010; Pani
inCEconcentrationhasbeenfoundinAD(Pugliellietal.,2001), et al.,2007a,b,c,2011;Orrùet al.,2010a,b,c).Moreover,several
MS (Machtoub et al., 2011) and PrD brains (Pani et al., 2011) studiesinvariouscellandanimalmodelsofADevidencedthat,
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Anchisietal. Propercholesterollevelsinneuronalmembrane
FIGURE1|Alzheimer’sdisease(AD).ADisaprogressiveneurologic diagnosethediseaseinautopsy.Aβpeptidesarefragmentsfromalarger
diseaseofthebrainleadingtotheirreversiblelossofneuronsandthelossof proteincalledamyloidprecursorprotein(APP),atransmembraneproteinthat
intellectualabilities,includingmemory,andreasoning,whichbecomesevere penetratesthroughtheneuron’smembrane.Theyaregeneratedinthe
enoughtoimpedesocialoroccupationalfunctioning.Althoughscientistsare amyloidogenicpathway(B)ofAPPprocessingbysequentialproteolysisby
stilltryingtofullyunderstandthecause/sofAD,theformationofamyloidβ β-(BACE1)andγ-secretases.Inthealternativenon-amyloidogenicAPP
(Aβ)proteinpositiveneuriticplaquesisconsideredoneofthemostimportant processingpathway(A),α-secretasecleaveswithintheAβpeptideregion
characteristicofADsomuchsothatAβdepositioninthebrainisusedto andpreventsAβgeneration.
geneticorpharmacologicalinhibitionofACATactivitymarkedly (PBMCs)fromADpatientsandfromsheepwithnaturalscrapie
suppressesAβgeneration.Inhibition,byRNAi-induceddecrease (Pani et al., 2007a,b,c, 2009a,b). It has been shown that about
of ACAT expression, or by ACAT inhibitors (i.e., CP-113,818 85% of AD patients displayed significantly higher PBMCs-CE
and avasimibe), of cholesterol esterification prevents Aβ gener- levels than cognitively normal age-matched controls. Of note
ation and its deposition in cell cultures, and markedly reduced is that parallel analysis in AD first-grade relatives revealed that
neuritic plaques in AD murine models. More recently, Bryleva up to 30% of them exhibited a peripheral cholesterol pattern
et al. (2010) by using a combined mousegenetic and biochem- similar to that of AD patients. Interestingly, higher CE pool
ical approach, showed that ablation of ACAT1 gene in triple was also observed in skin fibroblasts of healthy sheep with a
transgenic(3XTg-AD)miceleadedtomorethan60%reduction scrapie susceptible prion genotype compared to sheep carrying
in full-length humanAPP and its proteolytic fragments, and to ascrapie-resistantpriongenotype(Panietal.,2007a).Inagree-
an improvement in cognitive deficit. Microarray studies during mentwithfindingsofearlyACAT1activationinmousebrainsof
disease progression of different mouse strain-prion strain com- experimental scrapie(Hwanget al., 2009), and in brainsof AD
binations revealed that ACAT1 expression gene was activated (Pani et al., 2011), we also found increased ACAT1 expression
as early as 10 weeks post prion infection. At advanced stages in both skin fibroblasts and PBMCs from AD patients (Pani
of the disease (18–22 weeks after infection), only the ACAT- etal.,2009a,b)andinskinfibroblastsfromscrapie-affected and
encoding gene—out of all the genes involved in cholesterol scrapie-susceptible sheep (Pani et al., 2007a).
synthesis, trafficking, andprocessingexamined—wasconstantly
up-regulated(Hwangetal.,2009).Changesincholesterolesteri- EVIDENCEFORALTEREDLIPIDHOMEOSTASISINAUTISTIC
ficationsimilartothatobservedininsultedbrainswereobserved SPECTRUMDISORDERS(ASD)
by us in peripheral cells. In particular, increased CE levels were Nowadays, more and more researchers talk about ASD as
foundinskinfibroblastsandperipheralbloodmononuclearcells neurodegenerativedisorders(Hagerman,2006).Thisisbasedon
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Anchisietal. Propercholesterollevelsinneuronalmembrane
FIGURE2|Thepriondiseases (PrD). PrDare alarge group of related composed mainlyor entirely of an abnormal conformation of a
neurodegenerative conditions, which affect both animalsand humans. host-encoded glycoprotein calledtheprionprotein (PrPc).Thereplicationof
Included areCreutzfeldt–Jakob disease andGerstmann-Strãussler-Scheinker prionsimpliesthetransformation ofthenormalversionofthisproteinPrPc
in humans, bovine spongiform encephalopathy, or “madcow disease” in into amisfolded form (PrPsc).Anincreased concentration of PrPcatthe
cattle, chronicwastingdiseaseinmuledeerandelk,andscrapie insheep. membrane leads to astructural transition toward abnormal intermolecular
Prion diseases are unique inthat they canbe inherited, can occur beta sheet. Thisdimerization could well bethe initial step onthe pathway
sporadically, orcan be infectious. The infectious agent inthe PrDis of the conversion into PrPSc.
theidentificationinsomeautisticchildrenofpathophysiological levelsinPBMCsfromchildrenwithsporadicautism.Inaddition,
featuressuchason-goingsystemicandCNSredoxabnormalities since, many studies have outlined the dimensionality of autism
and inflammation, and the evidence of brain volume and neu- inregardtoitscomorbiditywithotherneurodevelopmentaldis-
ronloss.Geneticalterations,prenatalexposuretovirusesand/or orders such as ADHD we also determined CE levels in PBMCs
toxinsmaternalandfetalimmuneinteractions(Takahashietal., fromchildrenaffectedbyADHD.Thisisthemostcommonpsy-
2001;Nicolsonetal.,2007),andotherasyetundeterminedcauses chiatric disorder in children, affecting about 3–5% of children
may contribute independently or synergistically to the develop- globally(Spencer et al., 1999) and is characterized primarilyby
mentofautism.Recently,evidencehasbeenreportedsupporting the co-existence of attention problems and hyperactivity, with
aroleforcholesterol alsointhepathogenesisofthesedisorders. symptomsstartingbeforesevenyearsofage(Waschbuschetal.,
Three mechanisms working in concert have been hypothesized 2002; Wilens et al., 2002). In about 30–50% of those individ-
to explain how low cholesterol levels may contribute to spo- uals diagnosed in childhood, symptoms persist into adulthood
radicASD(LeeandTierney,2011):(1)impairedsonichedgehog (Kuhneetal.,1997).Inamannersimilartothatobservedinthe
(SHH) signaling molecules which are involved in the regula- AD patients, both autistic and ADHD children unveiled higher
tion of organogenesis including the organization of the brain. CEslevelsincytoplasmoftheirPBMCscomparedtothatofage-
During embryonic development, SHH is covalently modified matchedcontrolchildren(Anchisietal.,2013).Theseresultslead
with both palmitate and cholesterol and secreted as part of a ustohypothesizethatincreasedintracellularCElevelsinPBMCs
lipoproteincomplexthatregulatesbrainmorphogenesisthrough might represent a peripheral preclinical and clinical marker of
thepatched/smoothenedsignalingsystem(2)alterationsinmem- neurodegenerationbothinoldandyoungaffectedsubjects.The
branelipidraftstructureandproteinfunctionresultinginabnor- above-mentionedobservationsleavelittledoubtthatcholesterol
malsynapticplasticity, and(3)impairedneurosteroidsynthesis. esterification is involved in neurodegeneration and suggest that
Starting from these considerations, and from the notion that CEs and ACAT, beside biomarkers, might become important
many scientists consider AD “nothing more than autism in the therapeutic targets in treating several neurodegenerative disor-
elderly,”wethoughtthatitmightbeinterestingtodetermineCE ders. Thus the last part of the review is aimed at providing
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Anchisietal. Propercholesterollevelsinneuronalmembrane
informationontheresearchinthefield,whichmayhelptounder- certain AD patients present a moderate, yet significant, reduc-
stand the molecular mechanism/s underlying the link between tioninmembranecholesterol (Abad-Rodriguezetal.,2004).As
changes in cholesterol esterification and neurodegenerative pointedoutabove,inneurons,cholesterolinmainlylocatedatthe
processes. PMsandmembraneenvironmentisoffundamentalimportance
inregulatingmembraneproteindegradationandinmodulating
EVIDENCETHATLOWANDNOTHIGHNEURONAL protein/peptide fibrillization. Actually, cholesterol is crucial for
MEMBRANECHOLESTEROLLEVELSCONTRIBUTETO the myelin as well as for the synapse. Mutant mice lacking the
NEURODEGENERATION abilitytosynthesizecholesterolhadseverelydisturbedmyelinin
Inspiteoftheintenseresearchcarriedoutinrecenttimes,therole theirbrains,andexhibitedataxia(un-coordinatedmusclemove-
ofcholesterolasariskfactorforneurodegenerationremainscon- ments)andtremorindicatingthatcholesterolisanindispensable
troversialanditisstilldebatedifhighorlowneuronalmembrane componentofmyelinmembranesthatcontributeproperproduc-
cholesterol levels are involved in neurodegenerative disorders. tion ofthe myelin sheath and their function in synapses (Saher
In AD, the high cholesterol model assumes that higher FC lev- et al., 2005). All these findings call for a reconsideration of the
els in neuronal membrane may exert harmful effects (Simons highcholesterolmodel,andsuggestthatlowratherthanhighlev-
et al., 1998) and implies that lowering CNS cholesterol would elsofcholesterolinneuronalmembranescouldbedetrimentalfor
bebeneficial to neuronalfunction. Indeed, thereisalargebody cellsandmightalsopromoteneuronaldegeneration.However,it
of evidence suggesting that increased levels of PM cholesterol hasbeendemonstratedthatformodelcelllinestheoverallcholes-
promotetheamyloidogenicprocessingofAPPandtherebycon- terol content canchange from 2 to 4-fold atdifferent phases of
tribute to the key series of molecular proteolytic events widely cell growth(Canselletal.,1997;Takahashietal.,2007).Thus,a
believed to underpin the etiology of AD. A number of genes full understanding of the in vivo dynamic variability of choles-
involved in cholesterol homeostasis havebeen identified assus- terolandlipidraftcontentinplasmaororganellemembranesas
ceptibility loci for sporadic or late-onset AD and cholesterol afunctionofcellularphysiologicalstateisstilllacking.
and other specific lipids have been also shown to enhance the
propensity of Aβ to form neurotoxic aggregates (Beel et al., MOLECULARMECHANISMSLINKINGCHOLESTEROL
2010). It has been proposed that high membrane cholesterol ESTERIFICATIONTONEURODEGENERATION
by increasing co-clustering of lipid rafts induces co-localization Taking into account the above and data obtained in our labo-
of APP-BACE1 (Simons et al., 1998; Wolozin et al., 2000); this ratory,amodeldescribingsomemechanismslinkingcholesterol
in turn may influence APP processing as well as its location esterificationtoneuronaldegenerationcouldtentatively bepro-
cleavage stimulating the amyloidogenic pathway that leads to posed (Figures3 and 4). It is well known that cells and tissues,
increased Aβ production. On the contrary, the low membrane includingbrain, areprotected from the accumulationof poten-
cholesterol model envisages a protective role of relatively high tially toxic FC excess by ACAT1–mediated esterification and by
amountsofmembranecholesterolassumingthatAPPislocated cholesterol efflux (Tabas, 2002), ACAT activity being allosteri-
innon-raftmembranedomains(LedesmaandDotti,2006,2012). cally activated by the presence of high FC levels in ER (Chang
High membrane cholesterol would maintain APP and BACE1 et al., 2001). Cellular cholesterol undergoes a continuous cycle
separated into different membrane domains thus reducing Aβ of esterification and ester hydrolysis; net breakdownof CE tak-
generation (Ledesma and Dotti, 2006, 2012; Pani et al., 2011). ing place when ER–FC levels decline. The enzyme responsible
Theideathathighcholesterollevelsmightberesponsibleforneu- for the degradation of CE is neutral cholesterol ester hydrolase
rodegeneration was mainly supported by findings that cultured (nCEH). Under physiological conditions intracellular CE levels
human hippocampal neurons and neuroblastoma cells express- in brains are very low and generally do not exceed the nCEH
ing the amyloidogenic Swedish mutation of APP, treated with capacitytore-hydrolizeCEtoFCandtorecycleFCbacktoPM
statins,thewell-knowninhibitorsofcholesterolsynthesis,exhib- (PaniandDessì,2003).Inneurons,ifinexcess,apartofER–FCis
ited reduced Aβ production and inflammatory response to Aβ convertedtoCEbyACAT1locatedattheERandstoredascyto-
aggregates and increased α-secretase activity (Höglund et al., plasmic lipid droplets, another part leaves the brain (Dietschy,
2006).Statintreatment alsocontributedto maintaincholesterol 2009).FCdoesnotacrosstheBBB,thereforebeforetoexitCNS,it
distributioninthecellmembraneandnormalfunctionofmem- isconvertedinto24S-hydroxycholesterol(24S-OHC)andinthis
braneproteins while delaying APP cleavageand Aβ production form moves from neurons via the ATP-binding cassette trans-
(Höglund et al., 2006). Decreased Aβ production has also been porterA1(ABCA1)pathway,throughcerebrospinalfluid(CSF),
showninguineapigstreatedwithhighdosesofstatins(Ledesma cross the BBB, and is released into the systemic venous circu-
and Dotti, 2005). However, several new data raise doubts on lation. The fate of the 24S-OHC once it reaches the circulation
thebeneficialeffects ofstatinsinneurodegenerationandonthe hasnotyet beendefined. Anaccuratemethod basedonisotope
notion that high cholesterol in neuronal membranes is associ- dilution-massspectrometry showedthatinbloodcompartment
ated with brain dysfunction. This includes the finding of the 24S-OHCismainlyassociatedwithHDLandLDL(Babikerand
increase of amyloid production and presence of neurodegener- Diczfalusy,1998),suggesting thatsteady-state plasma24S-OHC
ation in female mice treated with statins able to cross BBB, the levelsfollowsthemetabolicfateofcholesterol inHDLandLDL
evidence that defective cholesterol metabolism and trafficking (i.e., uptake by the liver). Since most of the circulating 24S-
are present in the familial forms of a number of neurodegen- OHC arises from brain cholesterol, its levels are considered a
erative diseases and the observation that the hippocampus of measureofcholesterol turnoverinthe CNS(Orth andBellosta,
FrontiersinPhysiology|MembranePhysiologyandBiophysics January2013|Volume3|Article486|6
Anchisietal. Propercholesterollevelsinneuronalmembrane
FIGURE3|Cholesterolhomeostasis(steadystate).Differentlyfromthe subsequentmetabolismandtraffickingtootherintracellularsites.Neurons
mosttissuesthattakeupcholesterolfromcirculatingplasmalipoproteins keepconstanttheircholesterolconcentrationsthroughthesamehomeostatic
throughtheclassicmechanismofthelowdensitylipoproteinreceptor(LDLR), mechanismsregulatingtheintracellularcholesterolmetabolisminperipheral
duetotheBBB,braindoesnothavedirectaccesstocholesterolcarriedby tissues:cholesterolsynthesizedintheER,aswellasthatreleasedbyApo
plasmalipoproteinsandtherefore,itmeetsitscholesterolneedsthroughde E—containinglipoproteincatabolism,movestoPMs,inpart,byinteracting
novosynthesismainlyinglialcells,withonlyasmallamountofcholesterol withCav-1.OncethecapacityofPMsandothercompartmentstoabsorb
synthesizedinneurons.Glialcellspackageneo-synthesizedcholesterolinto cholesterolisexceeded,cholesterolistransportedbacktotheER,where,ina
ApoE—containinglipoproteinparticles,whichinturnaresecretedintotheCSF smallpartitisesterifiedbyACATandaccumulatedaslipiddroplets.Thelarge
throughtheATP-bindingcassettetransporter1(ABCA1).ApoE-containing partofexcesscholesterol,however,isconvertedinto24S-OHC,crossesthe
lipoproteinsarethentakenupbyneuronsandFCreleasedistransportedfor BBB,enterstheplasma,andisdeliveredtotheliverforexcretionintobile.
2012).CellsintheCNSsynthesizealloftheirowncholesterolin thetransportofcholesterolbetweensubcellularmembranesand
the ER from acetyl CoA through the mevalonate pathway. The PMsandeventuallyitsexchange withApoE and/orABCA1 for
rate-limiting step of the mevalonate pathway is the conversion efflux.Thesefindingsimplythatanimbalanceofoneormoreof
ofhydroxyl-methyl-glutaryl-CoA(HMG-CoA)tomevalonateby thesefinelyregulatedhomeostaticmechanismscapableofcausing
HMG-CoAreductase.Boththeseandseveralotherenzymesthat evenmodestchanges inER–FCpool, maycontribute to serious
function in later steps of cholesterol synthesis are integral ER andsometimesfatalconditions.Inthisway,itisplausibletosup-
membrane proteins. In the ER, FC levels fluctuate much more posethat, ifareduction inthetransport ofcholesterol between
thanthatinPMsandareconsideredthemajorregulatorsofthe ERandPMsoccursasaconsequenceofgeneticand/orenviron-
cellularcholesterolhomeostaticmachinery.Oncesynthesized,FC mental factors, ER–FC in neurons may increase. This increase
leavestheER,therebyhelpingtomaintainlowERsterolcontent activates ACAT1 leading to abnormal CE accumulation while
andisrapidlytargeted to PMswhere, dependingonthetypeof membrane cholesterol and its distribution in raft-domains are
CNScellsisutilized formembraneturnoverandaxonalgrowth reduced. If this altered transport persists over time the conse-
orbecomeavailableforextracellularapoproteinE(ApoE)accep- quences will be: rafts disassembly, demyelination, alterations in
tors (astrocytes) (Dietschy, 2009; Orth and Bellosta, 2012). In synapsisformationand function (neurodegenerative disorders).
summary, the ER, where many critical enzymatic reactions of Consideringthatcaveolin-1(Cav-1)isacholesterol-bindingpro-
cholesterol metabolism take place, is relatively cholesterol poor, tein that delivers newly synthesized cholesterol at the ER to the
thusmaintenanceofcellularcholesterolhomeostasisnecessitates PMs (Smart et al., 1996), the fact that embryonic fibroblasts
www.frontiersin.org January2013|Volume3|Article486|7
Anchisietal. Propercholesterollevelsinneuronalmembrane
FIGURE4|Cholesterol homeostasis (neurodegenerative disorders). the consequences may be: rafts disassembly, demyelination, alterations
An imbalance of one or more of finely regulated homeostatic in synapse formation and function, in other words, neurodegeneration.
mechanisms that lead to even modest changes in ER-FC pool in Beside ACAT1 activation, an increase in ER cholesterol pool of neurons
neurons can cause a serious and sometimes fatal neurologic disorder. may also activate the CYP46A1 thereby enhancing the levels of
Namely, if a reduction in the transport of cholesterol between ER and circulating 24S-OHC. This is an oxygenated derivative of cholesterol able
PM occurs as a consequence of genetic and/or environmental factors, to cause lipoprotein oxidation (ox-LP). With a mechanism similar to that
neuronal ER-FC increases. This increase may cause the activation described for atherosclerosis, o×-Lp might be recognized by scavenger
of ACAT1 leading to an increased CE synthesis while reducing the receptors (SR) on the surface of white blood cells, which in turn may
distribution of FC in raft-domains. If these alterations persist over time be engorged with CE and become foam cells.
and peritoneal macrophages from Cav-1 null mice were found 2009), this elevation was even more pronounced in CSF of
enriched inCEsbutdepleted ofFCmembranescomparedwith moderatecognitivedecline—mildorearlystageofADinwhich
theirwild-typecounterparts(Changetal.,2006),supportsthese an increase of 24S-OHC was also consistently observed in the
conclusions. Signs of premature neuronal aging and degenera- plasma compartment. In plasma, 24S-OHC is mainly present
tion,increasedAβ,decreasedcerebrovascularvolumeandreduc- in HDL and LDL in its esterified form (24S-OHCE). At this
tioninsynapseswerealsoobservedinbrainsofyoungCav-1null point, it should be mentioned that 24S-OHC is an oxygenated
micecomparedtoyoungWTmice(Headetal.,2010).Verylow derivative of cholesterol and consequently a potential inducer
mRNAlevelsofCav-1andparticularlynCEHwerefoundbyusin of LDL oxidation. In agreement increased levels of circulating
skinfibroblastsandinPBMCsfrompatientswithAD(Panietal., oxidized LDL (ox-LDL) were found in patients with neuro-
2009a,b).Interestingly,neuron-targetedre-expressionofCav-1in logic disorders (Ehnholm, 2009). With a mechanism similar
Cav-1nullneuronsinvitrodecreasedAβexpression(Headetal., to that described for atherosclerosis, ox-LDL might be recog-
2010). nized byscavengerreceptors(SR)onthesurfaceofwhiteblood
Beside ACAT1 activation, an increase in ER cholesterol pool cells, which in turn may be engorged with CE. Such a sce-
of neurons may activate the enzyme cholesterol 24-hydroxylase nariomayhelp toexplainwhysubjectswithneurologicaldisor-
(CYP46A1)therebyenhancingproductionof24S-OHC(Shafaati dersfrequentlypresentanaccumulationofCE intheirPBMCs.
et al., 2007). The oxysterol is then secreted into CSF, and According to this model, progressive FC accumulation in ER
through the BBB, delivered into the circulation. Really, ele- membraneswouldintensifyACAT1dysfunctionleadingtoneu-
vatedCSF-24S-OHCconcentrationshavebeenfoundinpatients rodegeneration. Finally, efflux pathways may also be inhibited
with AD compared to age-matched controls (Prasanthi et al., by conversion of cholesterol into oxysterols. This information
FrontiersinPhysiology|MembranePhysiologyandBiophysics January2013|Volume3|Article486|8
Anchisietal. Propercholesterollevelsinneuronalmembrane
indicatesthatbraincholesterolalterationsduringneurodegener- currently notmarketed and moreresearch isneeded to develop
ation involve dynamic modifications in cholesterol homeostatic safe and effective inhibitors for human use. In 2008, a study
networks,whicharereflectedinperipheraltissues,therefore,the used the mammalian target of rapamycin (mTOR) inhibitor,
useoftherapeuticstrategies,aimedatre-establishingrightcholes- rapamycin, to treat learning disabilities associated with a dis-
terol membrane amounts and their differential distribution in easecalled tuberoussclerosiscomplex(TSC)inmice(Ehninger
lipid rafts, would contribute to successful treatment/prevention et al., 2008). This is a rare genetic disorder that causes brain
ofneurodegenerativedisorders. tumors, seizures, learning disabilities, skin lesions, and kid-
ney tumors. In humans, half of TSC patients are autistic.
CEASDRUGTARGETFORPREVENTIONAND/OR The results showed that rapamycin was able to reverse mental
TREATMENTOFNEURODEGENERATION retardation in TSC mice raising the possibility that this drug
Inpreviousstudieswehavefoundthatcelltreatmentswithcom- may be effective in the treatment of mental disorders asso-
binationsofvariouscholesterolinterferingdrugsshowedsynergic ciated with autism (Ehninger et al., 2008). In 2010, Galvan
anti-prioneffects,apparentlybyrestoringcholesterolhomeosta- and her team published a research showing that rapamycin
sis in infected cells (Orrù et al., 2010c) The lysosomotropic also improves learning and memory deficits and reduces brain
drugs quinacrine and chlorpromazine, which, in addition to lesions and Aβ levels, in a mouse model of AD, suggesting
several other effects (Dohura et al., 2000) respectively deter- that rapamycin may have an another exciting use: to fight AD
mine cell cholesterol redistribution (Klingenstein et al., 2006) (Spilman et al., 2010). Rapamycin added to diet late in life
and activation of cholesterol biosynthesis (Fernø et al., 2006), was also able to extend lifespan in a mice model of aging
transportation and efflux (Vik-Mo et al., 2009), reduced up (Harrison et al., 2009). If these results continue to be repeated
to 10-fold their EC50 against PrPsc when associated with a and pilot studies demonstrate that treatment works and is safe,
CE inhibitor (Varghese et al., 2005), or with the cholesterol- rapamycin, which is already approved for other indications,
traffickingmodulatorssuchasprogesteroneorverapamil(Butler couldbeutilized—soonerthanexpected—to preventbehavioral
etal.,1992;Debryetal.,1997).CElevelsdirectlycorrelatewith symptoms in autistic children and in AD patients as well as
Aβ production (Bhattacharyya and Kovacs, 2010), as already to improve health to the end of life. At this point it will be
mentioned, in fact, experiments in cellular and animal mod- crucial to understand how rapamycin exerts its positive effect
els of AD showed dramatic reduction of Aβ generation and on the brain. It has been suggested that the drug operates
deposition upon inhibition of ACAT. Interestingly, a report on in preventing behavioral symptoms in autism and AD and in
Aβ-positive neurons of autopsied brain tissue from AD patient extending lifespan through a combination of anti-neoplastic
not only showed the presence of lipid droplets in neurons, but effects and effects on cellular stress resistance and response to
also showed a positive correlation between Aβ levels and lipid nutrient dynamics. In a study that has just been published, it
droplets(Gomez-RamosandAsuncionMoran,2007).Although, has been shown that the levels of three major monoamines
at present, it is not possible to form a complete picture of (norepinephrine,dopamineand5-hydroxytryptamine)andtheir
the functionally relevant causal relations, ACAT1 has becom- metabolites (3,4-dihydroxyphenylacetic acid, homovanillic acid,
ing an excellent potential drug target for neurodegeneration. and 5-hydroxyindolacetic acid) were significantly increased in
Inhibition of ACAT1 reduces the intracellular CE and storage, midbrain of rapamycin-treated mice compared to controls.
leaves more FC available for the membrane compartment and The Authors suggest that oral administration of rapamycin,
causesa decrease inAβ production(Bhattacharyya and Kovacs, enhances learning and memory in young adults, maintains
2010). memory in old C57BL/6J mice, and has concomitant anxi-
TheknowledgeofthecriticalroleplayedbyACATinthefor- olytic and antidepressant-like effects, possibly by stimulating
mation of CE-enriched cells (foam cells), the accumulation of major monoamine pathways in brain (Halloran et al., 2012).
which has an integral part into the development of atheroma, Studies conducted to evaluate the effect of rapamycin in the
led to the discoveryofseveralinhibitorsofthis enzyme(Chang human coronary artery smooth muscle cell (VSMC) showed
et al., 2009). Theoretically, inhibition of ACAT, by blocking the that besides its effect as mTOR inhibitor, rapamycin amelio-
esterification of cholesterol, could prevent the transformation ratedimbalanceofintracellularcholesterolhomeostasisinduced
of macrophages into foam cells and slow the progression of by inflammatory cytokines. In particular, in VSMCs, the drug
atherosclerosis. In some animal models, ACAT inhibitors were reducedlipiddropletsaccumulationandCEcontentinducedby
remarkably effective in reducing the formation of atheromas IL-1 and increased intracellular cholesterol efflux by upregulat-
(Bocan et al., 1993; Kusunoki et al., 2001), however, no indi- ingABCA1andABCG1geneexpression.Similarresultswerealso
cation of whether this effect was due to a reduction in the obtainedinourlaboratoriesinperipheralcellsfromADpatients
number of cells or to the extent of CE enrichment or to both (Pani et al., 2009a; Mulas et al., 2011). When everolimus, the
was reported. On the contrary, some studies involving geneti- 40-O-(2-hydroxyethyl)derivativeofsirolimus,wasaddedtocul-
callyengineeredmicehavesuggestedthattheinhibitionofACAT1 turedfibroblastsobtainedbyskinbiopsyfromADpatients,asig-
may promote atherosclerosis (Perrey et al., 2001). In addition, nificantreductionofCEaccumulationwasobserved(Panietal.,
recent clinical trials of ACAT inhibitors in humans failed to 2009a). In prion-infected N2a cells, Nile red and filipin stain-
show a therapeutic efficacy and this prompted researchers to ingofintracellularlipidsrevealschangesbothinthecontentand
pronounce the imminent death of ACAT inhibitors as a viable distributionofmostintracellularlipids;cell treatments withCE
anti-atherosclerotic therapy (Farese, 2006). ACAT inhibitors are modulators,showedmarkedanti-prionactivity.Themostpotent
www.frontiersin.org January2013|Volume3|Article486|9
Anchisietal. Propercholesterollevelsinneuronalmembrane
anti-prionic effect was obtained with everolimus that drasti- CONCLUSION
cally inhibited cholesterol esterification. Anti-prion effect also Inthisreviewwepresentevidencethatpreexistentand/orinduced
hadverapamil,acalcium-blockingdrugthatinhibitscholesterol modifications of cholesterol homeostasis may create a mem-
trafficking from the PM to the ER, and progesterone, a brane lipid environment favorable to the initiation/progression
sterol hormone that affects cholesterol trafficking both from ofneurodegeneration,andthereforethatpharmacologicretrieval
the PM and lysosomes (Orrù et al., 2010c). These results ofthesemodificationsmayrepresentasuccessfulwaytohamper
suggest that inhibitors of cholesterol esterification by restor- neuronal degeneration. Evenif there is still much to be learned
ing cholesterol homeostasis may represent a more successful aboutthephysiologicfunctionofcholesterolesterificationandits
therapeutic approach than drug treatments lowering choles- precise role in polarized cells such as neurons, CE and ACAT1
terol content per se (i.e., statins). Notably, our data also appear to be suitable targets for anti-neurodegeneration drug
point to CE accumulation in peripheral cells as an easy- development. In this context, drugs able to reduce the rate of
to-detect hallmark associated with neurodegenerative disor- cholesterol esterification, suchasACATinhibitors, progesterone
ders and/or indicative of increased susceptibility to develop andrapamycininparticular,areemergingasthebestsuited for
disease. thispurpose.
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