Cardiovascular Research Advance Access published June 30, 2014

SPOTLIGHT REVIEW

Cardiovascular Research doi:10.1093/cvr/cvu148

HDL and cholesterol handling in the brain Cecilia Vitali1, Cheryl L. Wellington 2, and Laura Calabresi1* 1

Centro E. Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita` degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy; and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada

2

Received 2 April 2014; revised 26 May 2014; accepted 2 June 2014

Cholesterol is an essential component of both the peripheral nervous system and central nervous system (CNS) of mammals. Brain cholesterol is synthesized in situ by astrocytes and oligodendrocytes and is almost completely isolated from other pools of cholesterol in the body, but a small fraction can be taken up from the circulation as 27-hydroxycholesterol, or via the scavenger receptor class B type I. Glial cells synthesize native high-density lipoprotein (HDL)-like particles, which are remodelled by enzymes and lipid transfer proteins, presumably as it occurs in plasma. The major apolipoprotein constituent of HDL in the CNS is apolipoprotein E, which is produced by astrocytes and microglia. Apolipoprotein A-I, the major protein component of plasma HDL, is not synthesized in the CNS, but can enter and become a component of CNS lipoproteins. Low HDL-C levels have been shown to be associated with cognitive impairment and various neurodegenerative diseases. On the contrary, no clear association with brain disorders has been shown in genetic HDL defects, with the exception of Tangier disease. Mutations in a wide variety of lipid handling genes can result in human diseases, often with a neuronal phenotype caused by dysfunctional intracellular lipid trafficking.

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High-density lipoproteins † Apolipoprotein E † Central nervous system † Alzheimer disease † Parkinson disease

----------------------------------------------------------------------------------------------------------------------------------------------------------This article is part of the Spotlight Issue on HDL biology: new insights in metabolism, function and translation.

1. Brain cholesterol The brain is the most cholesterol-rich organ in the body and contains almost 25% of the total amount.1 The majority (70 –80%) of this cholesterol is present in myelin, where it fulfils a critical insulating role.2 Brain cholesterol is synthesized in situ by astrocytes and oligodendrocytes and is almost completely isolated from other pools in the body.3 Cholesterol synthesis appears to be regulated by mechanisms similar to those observed outside the brain, with hydroxyl-methyl-glutaryl CoA reductase (HMGCoAR) being the most important regulatory enzyme. Brain cholesterol synthesis in both neurons and glial cells is highest during embryogenesis and childhood when myelinogenesis is maximal.4 In the adult, fully differentiated neurons progressively lose their cholesterol biosynthetic capability and rely on cholesterol-containing lipoproteins secreted by glial cells for ongoing needs for maintenance and repair of damaged membranes.4 The brain is largely separated from peripheral organs by multiple barrier systems. The core of the blood–brain barrier (BBB) are tight junctions formed by cerebrovascular endothelial cells that greatly restrict entry and egress of many blood components into the brain.5 A second barrier system, the blood –cerebrospinal fluid barrier (BCSFB), is formed by cuboidal epithelial cells of the choroid plexus as the endothelial cells within the choroid plexus are highly fenestrated.6 Of particular relevance to this review is that apoB-containing lipoproteins, including low-density lipoproteins (LDL), very low-density lipoproteins (VLDLs), and chylomicrons, are excluded from the brain by

the BBB and BCSFB. Indeed, human subjects who underwent a liver transplant exhibited the donor’s apolipoprotein E (apoE) phenotype in plasma lipoproteins, but maintained their own original phenotype in lipoproteins isolated from the CSF.7 Although cholesterol cannot cross the BBB and BCSFB, side-chain oxidized oxysterols easily traverse biological membranes and thus can also cross these barriers.3 24S-hydroxycholesterol (24S-OHC) is formed in the brain by CYP46A1, which is exclusively located in neuronal cells in the brain and in the retina,8 and can then flux 24S-OHC from the brain into the circulation.9 The plasma levels of 24S-OHC thus reflect the number of metabolically active neurons in the brain, and indeed its plasma levels are increased in neurodegenerative diseases.10 A second oxysterol, 27-hydroxycholesterol (27-OHC), has similar properties to 24S-OHC and is also able to pass the BBB.9 27-OHC is produced by all cells in the body by CYP27A1 and is quantitatively the most important oxysterol in the circulation.3 Production of 27-OHC in the brain is very low, and most of its presence in the brain and CSF reflects its extracerebral origin.9 A second possible mechanism for lipid movement between the brain and periphery is via the scavenger receptor class B type I (SR-BI), a multiligand receptor that promotes the bidirectional flux of cholesterol between lipoproteins and cellular membranes. SR-BI plays a major role in high-density lipoprotein (HDL) metabolism by mediating selective uptake of HDL cholesterol by hepatocytes.11 In the brain, SR-BI is present on the membrane of brain capillary endothelial cells, where it is reported to mediate the selective uptake of cholesterol from

* Corresponding author. Tel: +39 0250319906; fax: +39 0250319900, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected].

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Keywords

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C. Vitali et al.

plasma HDL and LDL.12 SR-BI can also allow the uptake of vitamin E13 that may play an important role in preventing oxidative stress and protecting brain cells against neurodegeneration.12,14

2. Lipoprotein synthesis and metabolism in the brain

2.1 Brain apolipoproteins 2.1.1 ApoE The major apolipoprotein constituent of HDL-like particles in the CNS is apoE. The absence of apoE has a subtle impact on brain development as apoE knock-out (KO) mice show behavioural and neurological abnormalities, and impaired synapse and dendritic arborizations especially at later ages.17 – 19 Brain and CSF apoE content and lipidation are regulated by the ABCA1 transporter,20 as shown by the reduced apoE levels detected in CSF and in brain tissue from ABCA1-deficient mice.21 ApoE is a 34 kDa glycoprotein that in humans is expressed in three different isoforms, apoE2, E3, and E4. The three isoforms are determined by three different alleles at a single genetic locus. E3 is the most common isoform in humans, E4 and E2 differ from E3 by a single amino acid substitution at residue 158 and 112 (E2: Arg158  Cys; E4: Cys112 

2.1.2 ApoJ Human apoJ is a 75 –80 kDa glycoprotein found in all biological fluids and expressed in several tissues such as testis, prostate, and brain. Its function in plasma has not been completely clarified, but it is involved in many and various biological and pathological processes, including complement inhibition, apoptosis, and cancer.32 In the CNS, apoJ is mainly synthesized by astrocytes.30 As in the whole body, apoJ in the brain is believed to have several functions. ApoJ expression is up-regulated under conditions of neuronal damage including inflammation, neurodegeneration, and senescence.23,32 ApoJ also complexes with complement components modulating the defence mechanisms in stress conditions23 and may play a role in regulating Ab clearance from the CNS33 as apoJ-containing lipoproteins can bind Ab and promote its efflux through the BBB via the interaction with LRP-2.30,33 2.1.3 ApoD ApoD, a lipocalin family member, is a 29 kDa apolipoprotein. It is a component of plasma HDL and was found in the CNS where it presumably

Table 1 Characteristics of HDL in plasma and CNS Plasma

...............................................................................

CNS

......................................................

Pre-b-HDL

HDL3

HDL2

Glial-derived HDL

CSF HDL

Size (nm)

,8.0

7.8– 8.8

8.8–13.0

8.0– 12.0

13.0–20.0

Density (g/mL)

1.125–1.25

1.125–1.21

1.063– 1.125

1.00– 1.12

1.063– 1.21

Shape Apolipoproteins

Discoidal apoA-I

Spherical apoA-I apoA-II

Spherical apoA-I apoA-II

Discoidal apoE apoJ

Spherical apoE apoA-I

Major lipids

PL/UC

PL/CE

PL/CE

PL/UC

PL/CE

.......................................................................................................................................................................................

PL: phospholipids; UC: unesterified cholesterol; CE: cholesteryl esters.

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Due to its accessibility, most investigations on the central nervous system (CNS) lipoproteins have been conducted on CSF, which is a clear, watery liquid that bathes the brain and spinal cord and is produced by the choroid plexus and, to a lesser extent, by ependymal cells that line the brain’s ventricles. CSF lipoproteins have a similar size and density to plasma HDL and they have been defined as ‘HDL-like particles’. These particles are characterized by a wide size range (10–22 nm) and various lipid–protein compositions, with a preponderance of 13–20 nm apoE/ apoA-I-containing lipoproteins (Table 1).15 Other apolipoproteins found in CSF are apoJ, apoA-II, apoA-IV, apoD, and apoH. Although apoA-I is the most important constituent of plasma HDL, it is not synthesized in the CNS.15,16 It has been demonstrated that apoA-I found in CSF is derived from blood HDL. Small HDL particles may enter the CNS via SR-BI-mediated uptake and transcytosis,12 or pathways that remain to be identified. Generally speaking, most of the CSF lipoprotein component exists at concentrations roughly 1–10% of their levels in plasma. It is important to note, however, that while CSF is in communication with the interstitial fluid (ISF) of the brain parenchyma, these two fluids are not homogenous and CSF composition therefore cannot be assumed to be representative of ISF. Very little is known about lipoprotein composition in the ISF compared with CSF, as well as how plasma-derived CSF lipoproteins gain access to the brain.

Arg). Under normal physiological conditions, neurons do not produce apoE and most of the CNS apoE is synthesized by astrocytes and microglia.22 The main function of apoE in the CNS is the lipid transport between neurons and glial cells, and apoE has key roles in the regulation of lipid metabolism in both normal and pathological conditions.22 Recent data suggest that apolipoproteins such as apoE and apoJ may be overexpressed after brain injury, acting as modulators of the inflammatory response.23 Evidence is accumulating that distinct apoE isoforms have different molecular and functional properties. The apoE 14 allele is strongly associated with the sporadic late-onset Alzheimer disease (AD).24 – 26 The mechanisms responsible for this association are not entirely known. Early data suggested that apoE may play an important role in binding b-amyloid (Ab), thus influencing its deposition in amyloid plaques.22 ApoE isoforms show different Ab-binding capacity (E2 . E3 . E4) and this ability seems to be correlated with the efficiency in promoting Ab clearance.27 – 29 Interestingly, apoE2 and E3 isoforms are more easily lipidated compared with E4, and the lipidation degree is positively associated with its affinity for soluble Ab.30 However, a recent study using microdialysis to sample the soluble apoE and Ab pools in brain ISF demonstrated that very little apoE associates with Ab in vivo, and that the mechanism by which apoE affects Ab clearance may be due to a competition between apoE and Ab for the low-density lipoprotein receptor-related protein (LRP), which regulates egress of Ab out of the brain.31

HDL and brain cholesterol

functions as a lipid transporter and as an antioxidant factor.34 Its affinity for cholesterol is low compared with other apolipoproteins, but it binds other lipids such as arachidonic acid, progesterone, and pregnenolone.34 It is synthesized by astrocytes and oligodendrocytes and, as observed for apoJ and apoE, apoD mRNA and protein levels are markedly increased in neurodegenerative diseases and after neuronal injury.35,36

2.2 Lipoprotein secretion and metabolism in the brain The mechanism underlying the formation of nascent lipoproteins in the brain is not completely understood. Among glial cells, astrocytes are responsible for the synthesis of the majority of lipoproteins found in brain tissue and CSF (Figure 1). Cultured astrocytes synthesize discoidal lipoproteins (8–12 nm) containing phospholipids, unesterified cholesterol, and apoE or apoJ.37 Several ATP-binding cassette (ABC) transporters, which are transmembrane proteins that utilize ATP hydrolysis to fuel transport of a variety of substances across biological membranes, are expressed in the CNS and are involved in apoE-containing lipoprotein secretion and lipidation (Figure 1).38 ABCA1 is expressed ubiquitously and

Page 3 of 9 interacts with lipid-free or poorly-lipidated apoE.39 ABCA1 in astrocytes is responsible for the secretion of newly lipidated nascent discoidal HDL-like particles.21 ABCA1 may also play a critical role in the removal of excess cholesterol from neurons, as shown in vitro using spherical reconstituted apoE-containing particles,40 as well as in microglia. A further incorporation of cholesterol into lipoproteins may be mediated by ABCG1 and ABCG4. ABCG1 in the CNS is expressed in microglia, oligodendrocytes, neurons, and astrocytes, whereas ABCG4 seems to be expressed preferentially in neurons.41 ABCA8 is expressed in several regions of the adult human brain with significantly higher expression in oligodendrocyte-enriched white matter compared with grey matter.42 Most of the lipoproteins found in the CSF are spherical and have different sizes than nascent discoidal HDL secreted from astrocytes, supporting the hypothesis that brain lipoproteins undergo extensive modification after secretion from glial cells,15 analogous to plasma HDL maturation (Figure 1). Less is known about CNS lipoprotein maturation compared with plasma, but many remodelling enzymes and lipid transfer proteins are expressed in the brain. Lecithin:cholesterol acyltransferase (LCAT) is the only enzyme responsible for the production of cholesteryl and oxysterol esters in plasma and other fluids;43 it is

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Figure 1 Production and interconversion of HDL particles in CNS and plasma. In brain parenchyma, ABCA1 transporter is expressed in neurons and astrocytes where it promotes the efflux of PL and UC to glia-derived apoE, thus leading to the formation of nascent lipoproteins. Moreover, discoidal apoA-I-containing HDL particles may enter the CNS via SR-BI-mediated uptake and other unknown mechanisms. Discoidal particles can further acquire PL and UC via ABCA1 and ABCG1. Maturation of discoidal particles into spherical lipoproteins likely involves the activity of LCAT, CETP, and PLTP, similar to what happens in plasma. Newly generated particles can be finally uptaken by neurons or astrocytes through the binding of apoE to LDLR family receptors. ABCA1: ATP-binding cassette transporter A1, ABCG1: ATP-binding cassette transporter G1; BBB: blood –brain barrier; CETP: cholesteryl ester transfer protein; CNS: central nervous system; EL: endothelial lipase; HL: hepatic lipase; LDLRs: LDL receptor family receptors; LCAT: lecithin:cholesterol:acyltransferase; PL: phospholipids; PLTP: phospholipid transfer protein; UC: unesterified cholesterol.

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2.3 Lipoprotein receptors 2.3.1 LRP1 The LRP1 is a large endocytic receptor first isolated in the liver, but expressed in many tissues. It binds different ligands, including apoEcontaining lipoproteins.52 In the brain, LRP1 has been found in both neurons and astrocytes, where it plays a major role in lipid homeostasis and intracellular signalling.53 LRP1 indeed interacts with the postsynaptic density protein PSD-95, a protein complex that regulates ion influx into neurons, thus modulating the neural response to excitatory molecules such as NMDA.54,55 LRP1 also plays key roles in the clearance of Ab peptides.56 As deletion of the LRP1 gene leads to the embryonic death, most of the studies on LRP1 function in the brain are performed on cells or in conditional forebrain-specific KO mice. In these models, LRP1 deletion leads to a reduction in cholesterol and triglyceride levels.57 These lipid abnormalities are associated with age-dependent structural defects in cortex and hippocampus, including synapse and dendritic spine loss and neuronal cell degeneration.58 Moreover, mice showed an abnormal behavioural phenotype with motor dysfunction and memory deficit.58 2.3.2 Low-density lipoprotein receptor The low-density lipoprotein receptor (LDLR) is the prototype member of the LDLR family that includes .10 receptors. It is localized on the outer cellular membrane of several peripheral cells and its quantitatively most relevant action is the internalization of apoB- and apoE-containing lipoproteins, thus removing cholesterol and cholesteryl esters from the circulation. The LDLR is expressed in brain capillary endothelial cells and astrocytes, where it is believed to play a role in cholesterol and Ab clearance.59 LDLR KO mice show learning and memory deficits,59 and intriguingly, cholesterol supplementation worsens the cognitive function, which may be through the accumulation of oxidative products and increased oxidative stress.60,61

2.3.3 VLDLR and ApoER2 The very low-density lipoprotein receptor (VLDLR) and the apoE receptor 2 (apoER2) are structurally very similar to the LDLR. In the periphery, VLDLR and apoER2 bind triglyceride-rich apoE-containing particles such as VLDL and intermediate density lipoproteins, but they cannot bind LDL. In the brain, both receptors are involved in reelin signalling,62 which regulates the migration of neurons from glial fibres to the developing cortical plate. As a consequence, VLDLR/apoER2 double KO mice show defects in the lamination of cerebral cortex.63 A selective deficit of either VLDLR or apoER2 leads to a subtle phenotype consisting in contextual fear conditioning and long-term potentiation deficits.64 In humans, mutations in the VLDLR are the cause of rare neurodevelopmental and psychiatric disorders, such as autosomal recessive cerebellar ataxia with mental retardation (dysequilibrium syndrome) and cerebellar hypoplasia with quadrupedal locomotion. 65

3. Low HDL and mental disorders Despite the almost total inability of circulating lipoproteins to cross the BBB and BCSFB, experimental data suggest that small HDL particles can enter the brain through transcytosis or selective uptake.12 This possibility raises the question of whether changes in plasma HDL cholesterol levels could influence brain cholesterol homeostasis and function. The relationship between HDL plasma levels and dementia has been the focus of considerable study. Although most of the studies were conducted in elderly subjects who have the presence of several dementia risk factors, low HDL-C levels are often associated with cognitive impairment.66 – 68 Data from the Whitehall II Study confirmed that, in middle-aged adults, low HDL-C was associated with impaired verbal memory and, interestingly, further reductions in HDL levels was associated with a consequent cognitive decline at 5-year follow up.69 In contrast, high HDL-C levels seem to reduce dementia risk.70 The mechanism underlying this association is not understood, but it may involve different pathogenic pathways. HDL exhibits both antioxidant and anti-inflammatory properties71 that could affect the inflammatory response in the brain. HDL-mediated reverse cholesterol transport could also reduce atherosclerotic burden in brain vessels such as the Circle of Willis, thus limiting the developing of vascular dementia. HDL also has potent beneficial effects on endothelial function72 and as the brain contains .25% of the body’s total vascular network, HDL may also affect cerebrovascular function that will in turn influence neuronal activity.73 HDL plasma levels have also been associated with other neurodegenerative diseases such as multiple sclerosis (MS).74 Patients in the acute phase MS have been reported to have lower HDL-C levels compared with those in the remission phase, and they show a higher probability of developing acute inflammatory lesions (assessed by MRI).74 – 76 The link between HDL and MS may reflect the ability of HDL to modulate the innate immune system.74,77 For example, HDL promotes the generation of M2 polarized macrophages that exhibit a reduced proinflammatory phenotype.77,78 Moreover, HDL inhibits cytokine-induced expression of adhesion molecules in endothelial cells.72 All these properties may contribute to the suppression of the immune system, thus preventing the relapses of MS. Abnormalities in HDL-C levels have been furthermore reported in patients with psychiatric disorders.79 Indeed, a reduction of CSF and serum apoA-I concentration was observed in schizophrenia patients80 and low HDL-C was observed in subjects affected by mood disorders.81

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synthesized mainly in the liver, but it is also present in brain, where it is produced by astrocytes.44 LCAT catalyses the maturation of small nascent discoidal HDL into larger spherical HDL particles.22 In humans, LCAT is found in CSF at levels corresponding to ≈5% that of plasma LCAT.22 The major activator of LCAT in the circulation is apoA-I, which is found in the CSF at only 0.3% of its levels in plasma;2 apoE may therefore act as a major activator of LCAT in the CNS.44 As glial-derived apoE-containing lipoproteins are LCAT substrates,44 LCAT likely plays a role in the maturation of apoE-containing particles in the brain. Cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP) also contribute to HDL remodelling in plasma. An active CETP enzyme has been identified in human CSF and in conditioned media from human neuroblastoma and neuroglioma cells, where it contributes to the transfer of lipids between lipoproteins.45 Whether a single-nucleotide polymorphism (SNP) in the CETP gene is associated with a lower rate of cognitive impairment is not clear, as some studies support an association but others do not.46 – 48 PLTP is expressed in cerebrovascular endothelial cells 49 and PLTP deficiency has been associated with reduced BBB integrity and increased susceptibility to oxidative stress in animal models;50 moreover, high levels of PLTP have been detected in the CSF of AD subjects,51 providing additional support for dysregulation of brain lipid homeostasis in AD. Lipoprotein shape, size, and lipid and protein composition modulate the particles’ affinity for various lipoprotein receptors that can be differentially expressed on the various cell types in the CNS, and the presence of a particular receptor on a specific cell type determines where and how the lipid transfer will occur.

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HDL and brain cholesterol

3.1 Genetic HDL defects Major causes of genetic HDL defects are mutations in three genes: APOA1, ABCA1, and LCAT.82 3.1.1 ApoA-I deficiency Several mutations in the APOA-I gene have been associated with low HDL-C levels.83 These mutations are mainly located in the central region of apoA-I, which has been shown to be responsible for LCAT activation.83 Some A-I variants are instead associated with amyloidosis and are often located in the N-terminal region of the protein.84 This pathology develops through a progressive deposition of apoA-I fragments that accumulate in various organs including the peripheral nerves. There is no evidence of an association between apoA-I deficiency and AD in humans. In AD mice, apoA-I deficiency causes a marked decrease in total plasma cholesterol levels, but does not alter total or parenchymal Ab deposition; however, it does increase cerebrovascular amyloid accumulation exacerbating the cognitive impairment.85

3.1.3 ABCA1 deficiency In humans, more than 100 mutations in ABCA1 gene have been identified, and they are related to a variable clinical phenotype.87 Functional mutations in both ABCA1 alleles cause Tangier disease (TD), characterized by very low or virtually absent HDL-C in plasma and by cholesterol esters accumulation in different tissues such as tonsils, spleen, liver, lymph nodes and, notably, peripheral nerves. The major neurological syndrome observed in TD patients is a peripheral neuropathy, which is caused by the accumulation of cholesterol esters in Schwann cells.88 Furthermore, TD patients have been reported to exhibit a syringomyelia-like syndrome, suggesting that the CNS may also be involved.88 The association between ABCA1 activity and AD is still controversial. In some isolated cases, subjects with rare ABCA1 mutations exhibited severe dementia and amyloid angiopathy. Investigations about the association of common SNPs in human ABCA1 gene and the risk of AD often led to conflicting results. ABCA12/2 mice clearly show impaired apoA-I and apoE levels in plasma and brain tissue.89 Furthermore, CNS apolipoproteins in ABCA12/2 mice are less lipidated and probably less functional in promoting Ab clearance.89,90 This hypothesis is corroborated by experiments conducted on AD mice-overexpressing ABCA1, where a reduction of amyloid burden has been observed.91

Mutations in a wide variety of lipid handling genes can result in human disease, often with a neuronal phenotype caused by dysfunctional intracellular lipid trafficking. For example, Smith –Lemli –Opitz syndrome (SLOS) is an autosomal recessive inborn error of cholesterol synthesis caused by a mutation in the enzyme 7-dehydrocholesterol reductase. SLOS is associated with a broad spectrum of effects, ranging from mild intellectual disability and behavioural problems to lethal malformations.92 The incidence of SLOS ranges between 1 in 10 000– 60 000 persons.93 Gaucher’s disease, Niemann-Pick disease, Fabry’s disease, Farber’s disease, Tay-Sach’s disease, Sandhoff’s disease, Krabbe disease, metachromatic leuokodystrophy, and Wolman’s disease are all examples of lipid storage diseases, which are inherited metabolic disorders in which the accumulation of various lipids leads to detrimental effects in many tissues including the CNS, the peripheral nervous system (PNS), liver, spleen, and bone marrow. That most lipid storage diseases can affect the nervous system indicates the narrow tolerance for dysfunctional lipid homeostasis in both the CNS and PNS. For the purposes of this review, however, we will focus our discussion on recent developments in understanding how lipid metabolism affects both common and rare neurodegenerative disease.

4.1 Alzheimer disease AD is the most common form of dementia in the elderly and is characterized by progressive memory loss. Age is the largest risk factor, as 1 in 8 persons over age 65 years and nearly 1 in 2 persons over age 85 years currently have AD. The most common genetic risk factor for late-onset AD is apoE. Inheritance of apoE4 increases AD risk and decreases AD age of onset in a gene-dose dependent manner,24,29 and accounts for 25% of heritability. ABCA1 has been shown to play key roles in apoE lipidation and Ab clearance in AD.90,91,94 Several recent genome wide association studies have shown several other genes involved in lipid metabolism to potentially contribute to AD risk. The International Genomics of Alzheimer’s Project (http:// www.alzforum.org/news/conference-coverage/pooled-gwas-revealsnew-alzheimers-genes-and-pathways, 1 April 2014) pooled genomewide association study data from four separate studies in a first-stage meta-analysis and identified nearly 12 000 loci with potential association with AD. These candidates were then tested in a new analysis including 11 000 controls and 8500 new cases, from which 20 genes reached statistical significance. Pathway analysis revealed 11 loci to be involved in four broad functional domains: ubiquitination, endocytosis, immunity, and cholesterol metabolism. ApoE, apoJ, ABCA7, and SORL1 are among the notable lipid-related genes. In addition to the requisite parenchymal amyloid plaques and neurofibrillary tangles that define AD, most of the AD patients also have significant accumulation of aggregation of Ab within cerebrovascular smooth muscle cells that lead to inflammation, oxidative stress, impaired vasorelaxation and disruption of BBB integrity.95 As capillary loss in the brains of AD subjects can be extensive, increasing attention is being directed to understanding how metabolic factors such as hypertension, cardiovascular disease, Type II diabetes mellitus, and dyslipidaemia have established detrimental effects on blood vessels and also increase the relative risk for AD. Intriguingly, many of these co-morbidities are characterized by low and/or dysfunctional HDL.73

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3.1.2 LCAT deficiency LCAT deficiency syndromes are rare genetic disorders with an autosomal recessive mode of inheritance.86 Mutations in the LCAT gene lead to an impaired (fish-eye disease, FED) or completely defective cholesterol esterification (familial LCAT deficiency, FLD).86 Since LCAT is crucial in HDL particle maturation, in LCAT-deficient subjects HDL-C levels are very low. Main clinical manifestations in FLD cases include corneal opacity, anaemia, and renal disease that eventually progresses to end-stage renal disease.86 FED cases do not have clinical manifestations of the disease except for the corneal opacity.86 To date, no neurological or psychiatric characterization of LCAT-deficient subjects has been conducted, but a reduction in LCAT activity has been observed in CSF from AD patients.16

4. Lipids and neurodegenerative disease

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4.2 Huntington disease

4.3 Parkinson disease Parkinson disease (PD) is the second most common neurodegenerative disease after AD, and like AD, aging is the largest risk factor for PD.109 PD affects 1% of persons over age 60 years and 4% of persons over 80 years. PD involves the selective loss of dopamine-producing cells in the substantia nigra, thereby disrupting communication between the substantia nigra and striatum. Thus, the clinical presentation of PD includes motor signs such as tremor, bradykinesia, stiffness, postural instability, and a shuffling gait. Depression, anxiety, and dementia are also

common in PD patients. At the neuropathological level, PD brains show accumulation of the presynaptic protein a-synuclein in neuronal perikarya (Lewy bodies) or neuronal processes (Lewy neurites) and may also exhibit accumulation of the microtubule-binding protein tau.110 Mutations in several genes including SNCA (a-synuclein), PARK2 (PD autosomal recessive, juvenile 2), PARK7 (PD autosomal recessive, early onset 7), PINK 1 (PTEN-induces putative kinase), and LRRK2 (leucine-rich repeat kinase 2) have been associated with PD, and a sequence of pathological events whereby deficits in synaptic exocytosis and endocytosis, endosomal trafficking, lysosome-mediated autophagy, and mitochondrial maintenance has been hypothesized to increase susceptibility to PD.111 The most frequently occurring mutations associated with PD risk are within GBA1 gene, which encodes lysosomal b-glucocerebrosidase, an enzyme that hydrolyses the beta-glucosidic linkage in glucocerebroside to produce the bioactive lipid ceramide. Approximately 5–10% of PD patients have heterozygous GBA1 mutations, which closely mimic idiopathic PD but may present at a younger age and is more frequently complicated by cognitive dysfunction. 112 Homozygous GBA1 mutations cause Gaucher disease, a lipid storage disorder characterized by accumulation of glucocerebroside within macrophages.113 How mutant GBA contributes to the pathogenesis of PD remains unknown and both loss of function and toxic gain of function by abnormal b-glucocerebrosidase may be important. However, both in vitro and in vivo evidence support a direct relationship between reduced glucocerebrosidase expression and a-synuclein accumulation in neurons. In cell and animal studies, decreased wild-type glucocerebrosidase leads to a-synuclein accumulation, and increased a-synuclein inhibits glucocerebrosidase function.114 – 116 In post-mortem brain tissue from symptomatic PD patients with GBA1 mutations, glucocerebrosidase and a-synuclein co-localize in Lewy bodies.117,118 A recent study of PD autopsy samples from patients with and without GBA mutations showed that glucocerebrosidase protein levels and enzyme activity were selectively reduced in the early stages of PD in brain regions with increased a-synuclein levels albeit limited inclusions, whereas GBA1 messenger RNA expression was non-selectively reduced in PD.119 The selective loss of lysosomal glucocerebrosidase was directly related to increased a-synuclein, decreased ceramide, and reduced lysosomal chaperone-mediated autophagy.

4.4 Multiple system atrophy Cytoplasmic aggregation of a-synuclein can also occur in oligodendrocytes and lead to multiple system atrophy (MSA), a progressive neurodegenerative disease characterized by parkinsonism, ataxia, and autonomic failure.120 MSA affects approximately 4 in 100 000 persons, mostly after age 65 years with an average lifespan of 7–9 years after diagnosis. Oligodendrocytes are the CNS cells responsible for producing myelin, the cholesterol, and sphingolipid-rich membrane that ensheath and insulate axons. In addition to its structural importance, myelin is also known to have a considerable capacity to undergo oxidative phosphorylation, which is hypothesized to generate ATP for use by axons.121 Therefore, decreased myelin function could contribute to axonal degeneration by several mechanisms. In vitro studies show that a-synuclein associates with lipid droplets and phospholipid bilayers, and this association triggers a conformation shift from its normally unfolded random coil state to a stable a-helix conformation.122 In MSA, case–control studies of a-synuclein solubility in autopsy samples have shown increases in SDS-soluble membrane-associated a-synuclein in affected regions that can be associated with decreased or unchanged a-synuclein levels in the soluble cytosolic fraction.123 – 128 Additionally, a comparative

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Huntington disease (HD) is an autosomal dominant neurodegenerative disorder that selectively targets medium spiny neurons of the caudate and putamen, leading to chorea, progressive cognitive decline, psychiatric problems, and progression to death 15 –20 years after clinical onset.96,97 HD is caused by expansion of a trinucleotide repeat of CAG encoding glutamine in the amino terminus of the huntingtin (htt) gene product. HD commonly manifests between age 35–45 years and is inversely related to CAG repeat length. In the normal population, the CAG repeat length is ,26, and repeats length of over 40 copies are fully penetrant. Htt is ubiquitously expressed in all tissue and has several reported roles including vesicle transport, endocytosis, transcriptional regulation protein trafficking, postsynaptic signalling, and regulation of apoptosis.98 Mutant htt affects maturation and translocation of sterol regulatory element-binding protein-2 (SREBP-2), a basic helix-loop-helix transcription factor that co-ordinates the expression of many genes involved in cholesterol metabolism.99 – 101 In cells with low cholesterol levels, SREBP-2 is activated by proteolytic cleavage that releases it from its tethered position at the nuclear envelope and endoplasmic reticulum and allows nuclear entry. Binding to SREBP-2 specific sterol regulatory element DNA sequences induces synthesis of enzymes involved in sterol biosynthesis. In turn, sterols inhibit the cleavage of SREBP-2, thus creating a negative feedback loop to constrain cellular cholesterol levels within a narrow homeostatic range.100 Expanded mutant htt interferes with SREBP-2 maturation and nuclear translocation, thereby reducing expression of several genes in the cholesterol biosynthetic pathways including HMGCoAR, Cyp51, and DHCR7.101 – 103 In cellular models expressing mutant htt including primary striatal neurons, a reduced ability to respond to cholesterol depletion compromises survival, and primary astroctyes expressing mutant htt secrete less lipidated apoE.101,104 Several HD mouse models show reduced amounts of cholesterol precursors and cholesterol metabolites including 24-OHC in proportion to CAG repeat length, further supporting a relationship between the severity of htt mutations and deficits in cholesterol metabolism.102,104 HD patients also have 24-OHC levels that are reduced proportionally to disease progression, suggesting that disease is associated with a progressive failure of CNS cholesterol metabolism.105,106 Additionally, interference with peroxisome proliferator gamma (PPARg) co-activator alpha 1 alpha (PGC1a) expression leads to reduced myelinbinding protein expression in oligodendrocytes,107 potentially exacerbating the potential for axonal damage. Wild-type htt binds nuclear receptors with established roles in lipid homeostasis including liver X receptor, PPARg, and Vitamin D receptor, and it is hypothesized that CAG expansion interferes with the ability of htt to interact with these receptors.108 Taken together, htt appears to play a role in cholesterol metabolism and dysregulation of this essential function in the presence of CAG expansion may contribute to HD onset and progression.

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HDL and brain cholesterol

study of PD and MSA brain tissue revealed distinct patterns of a-synuclein solubility between the disease groups, with MSA tissue showing a broader regional involvement and markedly more membrane-associated a-synuclein accumulation in the MSA substantia nigra compared with PD.128 Recent studies also suggest that a member of the ABC transporter family, ABCA8, may have key roles in myelin formation and pathology. ABCA8 is expressed in several regions of the adult human brain with significantly higher expression in oligodendrocyte-enriched white matter compared with grey matter.42 Additionally, ABCA8 expression is increased during aging, presumably correlated with age-associated myelination. In vitro, ABCA8 significantly stimulates sphingomyelin production in a human oligodendrocyte cell line. ABCA1 may therefore be a critical regulator of oligodendrocyte lipid metabolism. Intriguingly, ABCA8 mRNA expression is significantly increased in MSA brains compared with controls, both in affected grey matter and in affected white matter underlying the motor cortex with no significant change in an unaffected region, strongly supporting a potential role for upregulation of ABCA8 in the MSA disease process.42

5. Conclusions and perspectives

Conflict of interest: none declared.

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25. 26.

27.

References 1. Dietschy JM. Central nervous system: cholesterol turnover, brain development and neurodegeneration. Biol Chem 2009;390:287 –293. 2. Hayashi H. Lipid metabolism and glial lipoproteins in the central nervous system. Biol Pharm Bull 2011;34:453–461. 3. Bjorkhem I, Meaney S. Brain cholesterol: long secret life behind a barrier. Arterioscler Thromb Vasc Biol 2004;24:806–815. 4. Dietschy JM, Turley SD. Thematic review series: brain lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal. J Lipid Res 2004;45:1375 –1397. 5. Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 2008;57:178 – 201. 6. Lehtinen MK, Bjornsson CS, Dymecki SM, Gilbertson RJ, Holtzman DM, Monuki ES. The choroid plexus and cerebrospinal fluid: emerging roles in development, disease, and therapy. J Neurosci 2013;33:17553 –17559. 7. Linton MF, Gish R, Hubl ST, Butler E, Esquivel C, Bry WI, Boyles JK, Wardell MR, Young SG. Phenotypes of apolipoprotein B and apolipoprotein E after liver transplantation. J Clin Invest 1991;88:270 –281. 8. Liao WL, Heo GY, Dodder NG, Reem RE, Mast N, Huang S, DiPatre PL, Turko IV, Pikuleva IA. Quantification of cholesterol-metabolizing P450s CYP27A1 and CYP46A1 in neural tissues reveals a lack of enzyme-product correlations in human retina but not human brain. J Proteome Res 2011;10:241 –248. 9. Bjorkhem I. Crossing the barrier: oxysterols as cholesterol transporters and metabolic modulators in the brain. J Intern Med 2006;260:493–508. 10. Bjorkhem I, Cedazo-Minguez A, Leoni V, Meaney S. Oxysterols and neurodegenerative diseases. Mol Aspects Med 2009;30:171–179. 11. Rigotti A, Trigatti B, Babitt J, Penman M, Xu S, Krieger M. Scavenger receptor BI—a cell surface receptor for high density lipoprotein. Curr Opin Lipidol 1997;8:181 – 188. 12. Balazs Z, Panzenboeck U, Hammer A, Sovic A, Quehenberger O, Malle E, Sattler W. Uptake and transport of high-density lipoprotein (HDL) and HDL-associated alphatocopherol by an in vitro blood-brain barrier model. J Neurochem 2004;89:939 –950. 13. Goti D, Hrzenjak A, Levak-Frank S, Frank S, Der Westhuyzen DR, Malle E, Sattler W. Scavenger receptor class B, type I is expressed in porcine brain capillary endothelial cells

28. 29.

30.

31.

32. 33.

34. 35.

36. 37. 38.

Downloaded from by guest on January 17, 2017

ApoE, but not apoA-I, is produced in the CNS and incorporated in HDL particles, which are fundamental for supplying cholesterol to neurons. ApoA-I circulating with plasma HDL can enter the brain, be incorporated in CNS HDL particles, and then contribute to the protective roles of HDL in the CNS. HDL in plasma may also have effects on cerebrovascular endothelial cell function without necessarily crossing the BBB. Much remains to be learned about lipoprotein metabolism in the brain and the relationship between plasma and CNS lipoproteins. Genetic HDL disorders represent a valid tool to possibly clarify some of the open issues.

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and contributes to selective uptake of HDL-associated vitamin E. J Neurochem 2001;76: 498– 508. Thanopoulou K, Fragkouli A, Stylianopoulou F, Georgopoulos S. Scavenger receptor class B type I (SR-BI) regulates perivascular macrophages and modifies amyloid pathology in an Alzheimer mouse model. Proc Natl Acad Sci USA 2010;107:20816 –20821. Koch S, Donarski N, Goetze K, Kreckel M, Stuerenburg HJ, Buhmann C, Beisiegel U. Characterization of four lipoprotein classes in human cerebrospinal fluid. J Lipid Res 2001;42:1143 –1151. Demeester N, Castro G, Desrumaux C, De Geitere C, Fruchart JC, Santens P, Mulleners E, Engelborghs S, De Deyn PP, Vandekerckhove J, Rosseneu M, Labeur C. Characterization and functional studies of lipoproteins, lipid transfer proteins, and lecithin:cholesterol acyltransferase in CSF of normal individuals and patients with Alzheimer’s disease. J Lipid Res 2000;41:963 –974. Anderson R, Barnes JC, Bliss TV, Cain DP, Cambon K, Davies HA, Errington ML, Fellows LA, Gray RA, Hoh T, Stewart M, Large CH, Higgins GA. Behavioural, physiological and morphological analysis of a line of apolipoprotein E knockout mouse. Neuroscience 1998;85:93– 110. Krugers HJ, Mulder M, Korf J, Havekes L, de Kloet ER, Joels M. Altered synaptic plasticity in hippocampal CA1 area of apolipoprotein E deficient mice. Neuroreport 1997;8: 2505–2510. Oitzl MS, Mulder M, Lucassen PJ, Havekes LM, Grootendorst J, de Kloet ER. Severe learning deficits in apolipoprotein E-knockout mice in a water maze task. Brain Res 1997;752:189–196. Wahrle SE, Jiang H, Parsadanian M, Legleiter J, Han X, Fryer JD, Kowalewski T, Holtzman DM. ABCA1 is required for normal central nervous system ApoE levels and for lipidation of astrocyte-secreted apoE. J Biol Chem 2004;279:40987 –40993. Hirsch-Reinshagen V, Zhou S, Burgess BL, Bernier L, McIsaac SA, Chan JY, Tansley GH, Cohn JS, Hayden MR, Wellington CL. Deficiency of ABCA1 impairs apolipoprotein E metabolism in brain. J Biol Chem 2004;279:41197 –41207. Vance JE, Hayashi H. Formation and function of apolipoprotein E-containing lipoproteins in the nervous system. Biochim Biophys Acta 2010;1801:806 –818. Iwata A, Browne KD, Chen XH, Yuguchi T, Smith DH. Traumatic brain injury induces biphasic upregulation of ApoE and ApoJ protein in rats. J Neurosci Res 2005; 82:103 –114. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993;261:921 – 923. Liu CC, Kanekiyo T, Xu HX, Bu GJ. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 2013;9:106 – 118. Frisoni GB, Calabresi L, Geroldi C, Bianchetti A, D’Acquarica AL, Govoni S, Sirtori CR, Trabucchi M, Franceschini G. Apolipoprotein E epsilon 4 allele in Alzheimer’s disease and vascular dementia. Dementia 1994;5:240 – 242. Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, Patterson BW, Fagan AM, Morris JC, Mawuenyega KG, Cruchaga C, Goate AM, Bales KR, Paul SM, Bateman RJ, Holtzman DM. Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance. Sci Transl Med 2011;3:89ra57. Verghese PB, Castellano JM, Holtzman DM. Apolipoprotein E in Alzheimer’s disease and other neurological disorders. Lancet Neurol 2011;10:241 –252. Strittmatter WJ, Weisgraber KH, Huang DY, Dong LM, Salvesen GS, Pericak-Vance M, Schmechel D, Saunders AM, Goldgaber D, Roses AD. Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci USA 1993;90:8098 –8102. Fagan AM, Holtzman DM, Munson G, Mathur T, Schneider D, Chang LK, Getz GS, Reardon CA, Lukens J, Shah JA, LaDu MJ. Unique lipoproteins secreted by primary astrocytes from wild type, apoE (2/2), and human apoE transgenic mice. J Biol Chem 1999;274:30001 –30007. Verghese PB, Castellano JM, Garai K, Wang Y, Jiang H, Shah A, Bu G, Frieden C, Holtzman DM. ApoE influences amyloid-beta (Abeta) clearance despite minimal apoE/Abeta association in physiological conditions. Proc Natl Acad Sci USA 2013;110: E1807–E1816. Trougakos IP, Gonos ES. Clusterin/apolipoprotein J in human aging and cancer. Int J Biochem Cell Biol 2002;34:1430 –1448. Bell RD, Sagare AP, Friedman AE, Bedi GS, Holtzman DM, Deane R, Zlokovic BV. Transport pathways for clearance of human Alzheimer’s amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system. J Cereb Blood Flow Metab 2007;27: 909– 918. Rassart E, Bedirian A, Do Carmo S, Guinard O, Sirois J, Terrisse L, Milne R. Apolipoprotein D. Biochim Biophys Acta 2000;1482:185 – 198. Navarro A, Mendez E, Diaz C, del VE, Martinez-Pinilla E, Ordonez C, Tolivia J. Lifelong expression of apolipoprotein D in the human brainstem: correlation with reduced age-related neurodegeneration. PLoS ONE 2013;8:e77852. Navarro-Inc, Tolivia-Fernandez J. The involvement of apolipoprotein D in pathologies affecting the nervous system. Rev Neurol 2004;38:1166 – 1175. LaDu MJ, Reardon C, Van EL, Fagan AM, Bu G, Holtzman D, Getz GS. Lipoproteins in the central nervous system. Ann N Y Acad Sci 2000;903:167 –175. Kim WS, Weickert CS, Garner B. Role of ATP-binding cassette transporters in brain lipid transport and neurological disease. J Neurochem 2008;104:1145 –1166.

Page 8 of 9

62. Kim DH, Iijima H, Goto K, Sakai J, Ishii H, Kim HJ, Suzuki H, Kondo H, Saeki S, Yamamoto T. Human apolipoprotein E receptor 2. A novel lipoprotein receptor of the low density lipoprotein receptor family predominantly expressed in brain. J Biol Chem 1996;271:8373 –8380. 63. Gebhardt C, Del TD, Drakew A, Tielsch A, Herz J, Frotscher M, Deller T. Abnormal positioning of granule cells alters afferent fiber distribution in the mouse fascia dentata: morphologic evidence from reeler, apolipoprotein E receptor 2-, and very low density lipoprotein receptor knockout mice. J Comp Neurol 2002;445:278 – 292. 64. Weeber EJ, Beffert U, Jones C, Christian JM, Forster E, Sweatt JD, Herz J. Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning. J Biol Chem 2002;277:39944– 39952. 65. Ozcelik T, Akarsu N, Uz E, Caglayan S, Gulsuner S, Onat OE, Tan M, Tan U. Mutations in the very low-density lipoprotein receptor VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans. Proc Natl Acad Sci USA 2008;105:4232 – 4236. 66. van EE, de Craen AJ, Gussekloo J, Houx P, Bootsma-van der WA, Macfarlane PW, Blauw GJ, Westendorp RG. Association between high-density lipoprotein and cognitive impairment in the oldest old. Ann Neurol 2002;51:716 –721. 67. Muckle TJ, Roy JR. High-density lipoprotein cholesterol in differential diagnosis of senile dementia. Lancet 1985;1:1191 –1193. 68. Merched A, Xia Y, Visvikis S, Serot JM, Siest G. Decreased high-density lipoprotein cholesterol and serum apolipoprotein AI concentrations are highly correlated with the severity of Alzheimer’s disease. Neurobiol Aging 2000;21:27 –30. 69. Singh-Manoux A, Gimeno D, Kivimaki M, Brunner E, Marmot MG. Low HDL cholesterol is a risk factor for deficit and decline in memory in midlife: the Whitehall II study. Arterioscler Thromb Vasc Biol 2008;28:1556 –1562. 70. Reitz C, Tang MX, Schupf N, Manly JJ, Mayeux R, Luchsinger JA. Association of higher levels of high-density lipoprotein cholesterol in elderly individuals and lower risk of late-onset Alzheimer disease. Arch Neurol 2010;67:1491 – 1497. 71. Barter PJ, Nicholls S, Rye KA, Anantharamaiah GM, Navab M, Fogelman AM. Antiinflammatory properties of HDL. Circ Res 2004;95:764 –772. 72. Calabresi L, Gomaraschi M, Franceschini G. Endothelial protection by high-density lipoproteins: from bench to bedside. Arterioscler Thromb Vasc Biol 2003;23:1724 –1731. 73. Stukas S, Robert J, Wellington CL. High-density lipoproteins and cerebrovascular integrity in Alzheimer’s disease. Cell Metab 2014;19:574 –591. 74. Salemi G, Gueli MC, Vitale F, Battaglieri F, Guglielmini E, Ragonese P, Trentacosti A, Massenti MF, Savettieri G, Bono A. Blood lipids, homocysteine, stress factors, and vitamins in clinically stable multiple sclerosis patients. Lipids Health Dis 2010;9:19. 75. Weinstock-Guttman B, Zivadinov R, Mahfooz N, Carl E, Drake A, Schneider J, Teter B, Hussein S, Mehta B, Weiskopf M, Durfee J, Bergsland N, Ramanathan M. Serum lipid profiles are associated with disability and MRI outcomes in multiple sclerosis. J Neuroinflammation 2011;8:127. 76. Jamroz-Wisniewska A, Beltowski J, Stelmasiak Z, Bartosik-Psujek H. Paraoxonase 1 activity in different types of multiple sclerosis. Multiple Sclerosis 2009;15:399 –402. 77. Nobrega C, Capela C, Gorjon A, Lurdes P, Roque R, Sousa A, Ferret-Sena V, Campos E, Pedrosa R, Penin V, Sena A. Plasma lipoproteins and intrathecal immunoglobulin synthesis in multiple sclerosis. J Neurol 2011;258:202 –203. 78. Burger D, Dayer JM. High-density lipoprotein-associated apolipoprotein A-I: the missing link between infection and chronic inflammation? Autoimmun Rev 2002;1: 111– 117. 79. Mitchell AJ, Vancampfort D, Sweers K, van WR, Yu W, De HM. Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disorders—a systematic review and meta-analysis. Schizophr Bull 2013;39:306 –318. 80. Huang JT, Wang L, Prabakaran S, Wengenroth M, Lockstone HE, Koethe D, Gerth CW, Gross S, Schreiber D, Lilley K, Wayland M, Oxley D, Leweke FM, Bahn S. Independent protein-profiling studies show a decrease in apolipoprotein A1 levels in schizophrenia CSF, brain and peripheral tissues. Mol Psychiatry 2008;13:1118 –1128. 81. Lehto SM, Hintikka J, Niskanen L, Tolmunen T, Koivumaa-Honkanen H, Honkalampi K, Viinamaki H. Low HDL cholesterol associates with major depression in a sample with a 7-year history of depressive symptoms. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32:1557 –1561. 82. Oldoni F, Sinke RJ, Kuivenhoven JA. Mendelian disorders of high-density lipoprotein metabolism. Circ Res 2014;114:124 –142. 83. Sorci-Thomas MG, Thomas MJ. The effects of altered apolipoprotein A-I structure on plasma HDL concentration. Trends Cardiovasc Med 2002;12:121 – 128. 84. Obici L, Franceschini G, Calabresi L, Giorgetti S, Stoppini M, Merlini G, Bellotti V. Structure, function and amyloidogenic propensity of apolipoprotein A-I. Amyloid 2006;13: 191– 205. 85. Lefterov I, Fitz NF, Cronican AA, Fogg A, Lefterov P, Kodali R, Wetzel R, Koldamova R. Apolipoprotein A-I deficiency increases cerebral amyloid angiopathy and cognitive deficits in APP/PS1{Delta}E9 mice. J Biol Chem 2010;285:36945 – 36957. 86. Calabresi L, Simonelli S, Gomaraschi M, Franceschini G. Genetic lecithin:cholesterol acyltransferase deficiency and cardiovascular disease. Atherosclerosis 2012;222: 299– 306. 87. Singaraja RR, Brunham LR, Visscher H, Kastelein JJ, Hayden MR. Efflux and atherosclerosis: the clinical and biochemical impact of variations in the ABCA1 gene. Arterioscler Thromb Vasc Biol 2003;23:1322 – 1332. 88. Hobbs HH, Rader DJ. ABC1: connecting yellow tonsils, neuropathy, and very low HDL. J Clin Invest 1999;104:1015 –1017.

Downloaded from by guest on January 17, 2017

39. Wellington CL, Walker EK, Suarez A, Kwok A, Bissada N, Singaraja R, Yang YZ, Zhang LH, James E, Wilson JE, Francone O, McManus BM, Hayden MR. ABCA1 mRNA and protein distribution patterns predict multiple different roles and levels of regulation. Lab Invest 2002;82:273 – 283. 40. Koldamova RP, Lefterov IM, Ikonomovic MD, Skoko J, Lefterov PI, Isanski BA, DeKosky ST, Lazo JS. 22R-Hydroxycholesterol and 9-cis-retinoic acid induce ATPbinding cassette transporter A1 expression and cholesterol efflux in brain cells and decrease amyloid beta Secretion. J Biol Chem 2003;278:13244 –13256. 41. Chen J, Zhang X, Kusumo H, Costa LG, Guizzetti M. Cholesterol efflux is differentially regulated in neurons and astrocytes: implications for brain cholesterol homeostasis. Biochim Biophys Acta 2013;1831:263 –275. 42. Kim WS, Hsiao JH, Bhatia S, Glaros EN, Don AS, Tsuruoka S, Shannon WC, Halliday GM. ABCA8 stimulates sphingomyelin production in oligodendrocytes. Biochem J 2013;452:401 – 410. 43. Jonas A. Lecithin cholesterol acyltransferase. Biochim Biophys Acta 2000;1529:245 –256. 44. Hirsch-Reinshagen V, Donkin J, Stukas S, Chan J, Wilkinson A, Fan J, Parks JS, Kuivenhoven JA, Lutjohann D, Pritchard H, Wellington CL. LCAT synthesized by primary astrocytes esterifies cholesterol on glia-derived lipoproteins. J Lipid Res 2009;50:885 –893. 45. Albers JJ, Tollefson JH, Wolfbauer G, Albright RE Jr. Cholesteryl ester transfer protein in human brain. Int J Clin Lab Res 1992;21:264 –266. 46. Sanders AE, Wang C, Katz M, Derby CA, Barzilai N, Ozelius L, Lipton RB. Association of a functional polymorphism in the cholesteryl ester transfer protein (CETP) gene with memory decline and incidence of dementia. JAMA 2010;303:150 –158. 47. Johnson W, Harris SE, Collins P, Starr JM, Whalley LJ, Deary IJ. No association of CETP genotype with cognitive function or age-related cognitive change. Neurosci Lett 2007; 420:189 –192. 48. Barzilai N, Atzmon G, Schechter C, Schaefer EJ, Cupples AL, Lipton R, Cheng S, Shuldiner AR. Unique lipoprotein phenotype and genotype associated with exceptional longevity. JAMA 2003;290:2030 –2040. 49. Chirackal Manavalan AP, Kober A, Metso J, Lang I, Becker T, Hasslitzer K, Zandl M, Fanaee-Danesh E, Pippal JB, Sachdev V, Kratky D, Stefulj J, Jauhiainen M, Panzenboeck U. Phospholipid transfer protein is expressed in cerebrovascular endothelial cells and involved in high density lipoprotein biogenesis and remodeling at the blood-brain barrier. J Biol Chem 2014;289:4683 –4698. 50. Zhou T, He Q, Tong Y, Zhan R, Xu F, Fan D, Guo X, Han H, Qin S, Chui D. Phospholipid transfer protein (PLTP) deficiency impaired blood-brain barrier integrity by increasing cerebrovascular oxidative stress. Biochem Biophys Res Commun 2014;445:352 –356. 51. Vuletic S, Jin LW, Marcovina SM, Peskind ER, Moller T, Albers JJ. Widespread distribution of PLTP in human CNS: evidence for PLTP synthesis by glia and neurons, and increased levels in Alzheimer’s disease. J Lipid Res 2003;44:1113 –1123. 52. Strickland DK, Au DT, Cunfer P, Muratoglu SC. Low-density lipoprotein receptorrelated protein-1: role in the regulation of vascular integrity. Arterioscler Thromb Vasc Biol 2014;34:487 –498. 53. Pfrieger FW, Ungerer N. Cholesterol metabolism in neurons and astrocytes. Prog Lipid Res 2011;50:357 –371. 54. May P, Rohlmann A, Bock HH, Zurhove K, Marth JD, Schomburg ED, Noebels JL, Beffert U, Sweatt JD, Weeber EJ, Herz J. Neuronal LRP1 functionally associates with postsynaptic proteins and is required for normal motor function in mice. Mol Cell Biol 2004;24:8872 –8883. 55. Nakajima C, Kulik A, Frotscher M, Herz J, Schafer M, Bock HH, May P. Low density lipoprotein receptor-related protein 1 (LRP1) modulates N-methyl-D-aspartate (NMDA) receptor-dependent intracellular signaling and NMDA-induced regulation of postsynaptic protein complexes. J Biol Chem 2013;288:21909 –21923. 56. Martiskainen H, Haapasalo A, Kurkinen KM, Pihlajamaki J, Soininen H, Hiltunen M. Targeting ApoE4/ApoE receptor LRP1 in Alzheimer’s disease. Expert Opin Ther Targets 2013;17:781 –794. 57. Liu Q, Zerbinatti CV, Zhang J, Hoe HS, Wang B, Cole SL, Herz J, Muglia L, Bu G. Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1. Neuron 2007;56:66– 78. 58. Liu Q, Trotter J, Zhang J, Peters MM, Cheng H, Bao J, Han X, Weeber EJ, Bu G. Neuronal LRP1 knockout in adult mice leads to impaired brain lipid metabolism and progressive, age-dependent synapse loss and neurodegeneration. J Neurosci 2010;30:17068– 17078. 59. Castellano JM, Deane R, Gottesdiener AJ, Verghese PB, Stewart FR, West T, Paoletti AC, Kasper TR, DeMattos RB, Zlokovic BV, Holtzman DM. Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood Abeta clearance in a mouse model of beta-amyloidosis. Proc Natl Acad Sci USA 2012;109:15502 –15507. 60. Moreira EL, de OJ, Nunes JC, Santos DB, Nunes FC, Vieira DS, Ribeiro-do-Valle RM, Pamplona FA, de Bem AF, Farina M, Walz R, Prediger RD. Age-related cognitive decline in hypercholesterolemic LDL receptor knockout mice (LDLr2/2): evidence of antioxidant imbalance and increased acetylcholinesterase activity in the prefrontal cortex. J Alzheimers Dis 2012;32:495–511. 61. de Oliveira J, Hort MA, Moreira ELG, Glaser V, Ribeiro-do-Valle RM, Prediger RD, Farina M, Latini A, de Bem AF. Positive correlation between elevated plasma cholesterol levels and cognitive impairments in LdL receptor knockout mice: relevance of corticocerebral mitochondrial dysfunction and oxidative stress. Neuroscience 2011;197: 99 –106.

C. Vitali et al.

HDL and brain cholesterol

110. Dickson DW. Parkinson’s disease and parkinsonism: neuropathology. Cold Spring Harb Perspect Med 2012;2. 111. Trinh J, Farrer M. Advances in the genetics of Parkinson disease. Nat Rev Neurol 2013;9: 445– 454. 112. Beavan MS, Schapira AH. Glucocerebrosidase mutations and the pathogenesis of Parkinson disease. Ann Med 2013;45:511 –521. 113. Hruska KS, Lamarca ME, Scott CR, Sidransky E. Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA). Hum Mutat 2008;29: 567– 583. 114. Manning-Bog AB, Schule B, Langston JW. Alpha-synuclein-glucocerebrosidase interactions in pharmacological Gaucher models: a biological link between Gaucher disease and parkinsonism. Neurotoxicology 2009;30:1127 –1132. 115. Mazzulli JR, Xu YH, Sun Y, Knight AL, McLean PJ, Caldwell GA, Sidransky E, Grabowski GA, Krainc D. Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 2011;146:37 –52. 116. Yap TL, Velayati A, Sidransky E, Lee JC. Membrane-bound alpha-synuclein interacts with glucocerebrosidase and inhibits enzyme activity. Mol Genet Metab 2013;108: 56 –64. 117. Goker-Alpan O, Stubblefield BK, Giasson BI, Sidransky E. Glucocerebrosidase is present in alpha-synuclein inclusions in Lewy body disorders. Acta Neuropathol 2010; 120:641 –649. 118. Choi JH, Stubblefield B, Cookson MR, Goldin E, Velayati A, Tayebi N, Sidransky E. Aggregation of alpha-synuclein in brain samples from subjects with glucocerebrosidase mutations. Mol Genet Metab 2011;104:185 –188. 119. Murphy KE, Gysbers AM, Abbott SK, Tayebi N, Kim WS, Sidransky E, Cooper A, Garner B, Halliday GM. Reduced glucocerebrosidase is associated with increased alpha-synuclein in sporadic Parkinson’s disease. Brain 2014;137:834 –848. 120. Bleasel JM, Wong JH, Halliday GM, Kim WS. Lipid dysfunction and pathogenesis of multiple system atrophy. Acta Neuropathol Commun 2014;2:15. 121. Ravera S, Bartolucci M, Calzia D, Aluigi MG, Ramoino P, Morelli A, Panfoli I. Tricarboxylic acid cycle-sustained oxidative phosphorylation in isolated myelin vesicles. Biochimie 2013;95:1991 –1998. 122. Jo E, McLaurin J, Yip CM, St George-Hyslop P, Fraser PE. alpha-Synuclein membrane interactions and lipid specificity. J Biol Chem 2000;275:34328 –34334. 123. Duda JE, Giasson BI, Gur TL, Montine TJ, Robertson D, Biaggioni I, Hurtig HI, Stern MB, Gollomp SM, Grossman M, Lee VM, Trojanowski JQ. Immunohistochemical and biochemical studies demonstrate a distinct profile of alpha-synuclein permutations in multiple system atrophy. J Neuropathol Exp Neurol 2000;59:830–841. 124. Dickson DW, Liu W, Hardy J, Farrer M, Mehta N, Uitti R, Mark M, Zimmerman T, Golbe L, Sage J, Sima A, D’Amato C, Albin R, Gilman S, Yen SH. Widespread alterations of alpha-synuclein in multiple system atrophy. Am J Pathol 1999;155:1241 –1251. 125. Pawlyk AC, Giasson BI, Sampathu DM, Perez FA, Lim KL, Dawson VL, Dawson TM, Palmiter RD, Trojanowski JQ, Lee VM. Novel monoclonal antibodies demonstrate biochemical variation of brain parkin with age. J Biol Chem 2003;278:48120 – 48128. 126. Tong J, Wong H, Guttman M, Ang LC, Forno LS, Shimadzu M, Rajput AH, Muenter MD, Kish SJ, Hornykiewicz O, Furukawa Y. Brain alpha-synuclein accumulation in multiple system atrophy, Parkinson’s disease and progressive supranuclear palsy: a comparative investigation. Brain 2010;133:172–188. 127. Uryu K, Richter-Landsberg C, Welch W, Sun E, Goldbaum O, Norris EH, Pham CT, Yazawa I, Hilburger K, Micsenyi M, Giasson BI, Bonini NM, Lee VM, Trojanowski JQ. Convergence of heat shock protein 90 with ubiquitin in filamentous alpha-synuclein inclusions of alpha-synucleinopathies. Am J Pathol 2006;168:947–961. 128. Tu PH, Galvin JE, Baba M, Giasson B, Tomita T, Leight S, Nakajo S, Iwatsubo T, Trojanowski JQ, Lee VM. Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alpha-synuclein. Ann Neurol 1998; 44:415 –422.

Downloaded from by guest on January 17, 2017

89. Koldamova R, Staufenbiel M, Lefterov I. Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice. J Biol Chem 2005;280: 43224– 43235. 90. Hirsch-Reinshagen V, Maia LF, Burgess BL, Blain JF, Naus KE, McIsaac SA, Parkinson PF, Chan JY, Tansley GH, Hayden MR, Poirier J, Van NW, Wellington CL. The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease. J Biol Chem 2005;280:43243 –43256. 91. Wahrle SE, Jiang H, Parsadanian M, Kim J, Li A, Knoten A, Jain S, Hirsch-Reinshagen V, Wellington CL, Bales KR, Paul SM, Holtzman DM. Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease. J Clin Invest 2008; 118:671 –682. 92. Porter FD. Smith – Lemli –Opitz syndrome: pathogenesis, diagnosis and management. Eur J Hum Genet 2008;16:535 –541. 93. Yu H, Patel SB. Recent insights into the Smith – Lemli –Opitz syndrome. Clin Genet 2005; 68:383 –391. 94. Fan J, Donkin J, Wellington C. Greasing the wheels of Abeta clearance in Alzheimer’s disease: the role of lipids and apolipoprotein E. Biofactors 2009;35:239 –248. 95. Attems J, Jellinger K, Thal DR, Van NW. Review: sporadic cerebral amyloid angiopathy. Neuropathol Appl Neurobiol 2011;37:75 –93. 96. Walker FO. Huntington’s disease. Lancet 2007;369:218–228. 97. Govert F, Schneider SA. Huntington’s disease and Huntington’s disease-like syndromes: an overview. Curr Opin Neurol 2013;26:420 –427. 98. Gil JM, Rego AC. Mechanisms of neurodegeneration in Huntington’s disease. Eur J Neurosci 2008;27:2803 –2820. 99. Yokoyama C, Wang X, Briggs MR, Admon A, Wu J, Hua X, Goldstein JL, Brown MS. SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene. Cell 1993;75:187 –197. 100. Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 2002;109:1125 –1131. 101. Valenza M, Rigamonti D, Goffredo D, Zuccato C, Fenu S, Jamot L, Strand A, Tarditi A, Woodman B, Racchi M, Mariotti C, Di DS, Corsini A, Bates G, Pruss R, Olson JM, Sipione S, Tartari M, Cattaneo E. Dysfunction of the cholesterol biosynthetic pathway in Huntington’s disease. J Neurosci 2005;25:9932 – 9939. 102. Valenza M, Carroll JB, Leoni V, Bertram LN, Bjorkhem I, Singaraja RR, Di DS, Lutjohann D, Hayden MR, Cattaneo E. Cholesterol biosynthesis pathway is disturbed in YAC128 mice and is modulated by huntingtin mutation. Hum Mol Genet 2007;16: 2187 –2198. 103. Leoni V, Long JD, Mills JA, Di DS, Paulsen JS. Plasma 24S-hydroxycholesterol correlation with markers of Huntington disease progression. Neurobiol Dis 2013;55:37 –43. 104. Valenza M, Leoni V, Tarditi A, Mariotti C, Bjorkhem I, Di DS, Cattaneo E. Progressive dysfunction of the cholesterol biosynthesis pathway in the R6/2 mouse model of Huntington’s disease. Neurobiol Dis 2007;28:133 –142. 105. Markianos M, Panas M, Kalfakis N, Vassilopoulos D. Low plasma total cholesterol in patients with Huntington’s disease and first-degree relatives. Mol Genet Metab 2008; 93:341 –346. 106. Leoni V, Mariotti C, Nanetti L, Salvatore E, Squitieri F, Bentivoglio AR, Bandettini di PM, Piacentini S, Monza D, Valenza M, Cattaneo E, Di DS. Whole body cholesterol metabolism is impaired in Huntington’s disease. Neurosci Lett 2011;494:245 –249. 107. Xiang Z, Valenza M, Cui L, Leoni V, Jeong HK, Brilli E, Zhang J, Peng Q, Duan W, Reeves SA, Cattaneo E, Krainc D. Peroxisome-proliferator-activated receptor gamma coactivator 1 alpha contributes to dysmyelination in experimental models of Huntington’s disease. J Neurosci 2011;31:9544 – 9553. 108. Futter M, Diekmann H, Schoenmakers E, Sadiq O, Chatterjee K, Rubinsztein DC. Wildtype but not mutant huntingtin modulates the transcriptional activity of liver X receptors. J Med Genet 2009;46:438 –446. 109. Reeve A, Simcox E, Turnbull D. Ageing and Parkinson’s disease: why is advancing age the biggest risk factor? Ageing Res Rev 2014;14C:19– 30.

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