REVIEW ARTICLE published: 05 March 2012 PSYCHIATRY doi: 10.3389/fpsyt.2012.00017 A-subclass ATP-binding cassette in brain lipid homeostasis and neurodegeneration

Armin P.Piehler 1,2†, Mustafa Özcürümez 3† and Wolfgang E. Kaminski 4*

1 Fürst Medical Laboratory, Oslo, Norway 2 Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway 3 Bioscientia Institut für Medizinische Diagnostik GmbH, Medizinisches Versorgungszentrum Berlin, Berlin, Germany 4 Institute for Clinical Chemistry, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

Edited by: The A-subclass of ATP-binding cassette (ABC) transporters comprises 12 structurally related Silke Vogelgesang, University of members of the evolutionarily highly conserved superfamily of ABC transporters. ABCA Greifswald, Germany transporters represent a subgroup of “full-size” multispan transporters of which several Reviewed by: Michele Peters, Universitätsmedizin members have been shown to mediate the transport of a variety of physiologic lipid com- Greifswald, Germany pounds across membrane barriers.The importance of ABCA transporters in human disease Gabriele Jedlitschky, is documented by the observations that so far four members of this family (ABCA1, Universitätsmedizin Greifswald, ABCA3, ABCA4, ABCA12) have been causatively linked to monogenetic disorders includ- Germany ing familial high-density lipoprotein deficiency, neonatal surfactant deficiency, degenerative *Correspondence: Wolfgang E. Kaminski, Institute for retinopathies, and congenital keratinization disorders. Recent research also point to a signif- Clinical Chemistry, Medical Faculty icant contribution of several A-subfamily ABC transporters to neurodegenerative diseases, Mannheim, University of Heidelberg, in particular Alzheimer’s disease (AD).This review will give a summary of our current knowl- 68167 Mannheim, Germany. edge of the A-subclass of ABC transporters with a special focus on brain lipid homeostasis e-mail: [email protected] and their involvement in AD. †Armin P.Piehler and Mustafa Özcürümez have contributed equally Keywords: ATP-binding cassette transporter, Alzheimer’s disease to this work.

ABC TRANSPORTERS ABC transporters in a broad range of physiological systems is also The superfamily of ATP-binding cassette (ABC) transporters con- reflected by the fact that mutations in several ABC proteins result stitutes a large group of highly conserved, multispan transmem- in monogenetic disorders affecting diverse physiological systems brane transport proteins which can be found in all organisms (Wenzel et al., 2007). from bacteria to man (Higgins, 1992; Holland et al., 2002). In Outstanding experts in the field have recently contributed with most species, ABC transporters are abundantly represented (Lin- reviews of single members or subsets of ABC transporters covering ton and Higgins, 1998). In the , 48 functional, diverse aspects of ABC transporters and their role in health and protein-coding ABC transporter (Dean, 2005), and several disease, including brain lipid metabolism and Alzheimer’s disease ABC pseudogenes (Piehler et al., 2006, 2008)havebeenidenti- (AD; Kim et al., 2008; Mack et al., 2008; Hirsch-Reinshagen et al., fied. All ABC proteins share a common global configuration and 2009; Koldamova et al., 2010). In the present review, we focus on are composed of four specific core domains; two highly conserved the A-subfamily of ABC transporters and their role in brain lipid ABCs and two transmembrane domains (TMDs; Figure 1; Hig- transport and neurodegeneration. gins et al., 1986; Linton and Higgins, 1998). These four domains can be encoded in a single polypeptide chain, which is then called THE A-SUBCLASS OF ABC TRANSPORTERS a “full-size” transporter (Figure 1). Alternatively, two homo- or In 1994, in an effort to clone members of the ABC transporter heterodimers (“half-size” transporters), each containing one ABC superfamily, Luciani et al. (1994) identified two novel ABC trans- and one TMD, attach to form the functional transporter (Dean, porter genes, named ABC1 (ABCA1) and ABC2 (ABCA2), in close 2005). Based on phylogenetic analyses of the ABCs, human ABC proximity to each other on 9. Due to their structural transporters are divided into seven subfamilies, denoted ABC features that clearly set them apart from other ABC transporters, A–G (Dean, 2002). ABC transporters are primary active trans- Luciani et al. suggested that these transporters define a novel sub- porters using the energy from ATP-binding and -hydrolysis to group of ABC transporters, the A-subfamily of ABC transporters. translocate a wide variety of substrates including lipids, ions, Altogether, the human ABCA subfamily comprises 12 protein- sugars, peptides, amino acids, carbohydrates, vitamins, steroid coding genes, ABCA1–ABCA13, with “ABCA11” representing a hormones (Higgins, 1992; Holland et al., 2002), and xenobiotics, transcribed pseudogene (Kaminski et al.,2006; Piehler et al.,2008). such as anticancer drugs (Gottesman et al., 2002). On a subcellu- All ABCA proteins are full-size transporters (Tusnady et al., 2006). lar level, ABC transporters are located in eukaryotes in the plasma At least three characteristics define the members of the A- membrane and in the lipid membranes of the Golgi apparatus, subfamily of ABC transporters: (i) the A-subfamily contains the endosomes, multivesicular bodies, endoplasmic reticulum, perox- largest members of the ABC transporter superfamily. Accord- isomes, and mitochondria (Kaminski et al., 2006). The function of ing to their predicted primary structure, ABCA transporters

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including mutations in ABCA1 [high-density lipoprotein (HDL)- deficiency/ (TD)], ABCA3 (neonatal surfactant deficiency), ABCA4 (several forms of autosomal recessive mac- ular dystrophies), and ABCA12 (two forms of hereditary kera- tinization disorders; Kaminski et al., 2006). The phenotypes of these loss-of-function mutations have resulted in valuable infor- mation about the physiological function of ABCA transporters and identified them as lipid transporters. Over the last years, evi- dence has accumulated that members of the A-subfamily of ABC transporters are also involved in more complex diseases like ather- osclerosis (ABCA1), pediatric interstitial lung diseases (ABCA3), age-related macular degeneration (ABCA4), and AD (ABCA1, ABCA2, ABCA7; Kaminski et al., 2006).

A-SUBFAMILY ABC TRANSPORTERS IN BRAIN LIPID HOMEOSTASIS AND NEURODEGENERATION FIGURE 1 | Schematic view of an A-subclass ABC transporter. A-subclass ABC transporters are full-size transporters and consist of two ABCA1 transmembrane domains (TMD), which anchor the transporter into a lipid Molecular properties of ABCA1 membrane (L), and two ATP-binding cassettes (ABC), at which two ABCA1 is the prototypic member of the A-subfamily of ABC molecules ATP are bound and hydrolyzed to support the energy for transporters. It has been extensively studied since its identifica- substrate translocation between the inside (i) and outside (o) of a cell or compartment. A special feature of the A-subfamily members is the tion in 1994. In particular, the discovery in 1999 that mutations in unusually large, first extracellular domain (ECD) of each TMD. this ABCA subfamily transporter compromise cellular cholesterol export has attracted a lot of interest from researchers worldwide. The role of ABCA1 in cholesterol transport, HDL particle forma- are polypeptides ranging from 1543 aa (ABCA10) to 5058 aa tion and atherosclerosis has been reviewed previously (Kaminski (ABCA13) in size with a calculated molecular weight between 176 et al., 2006; Wenzel et al., 2007; Kang et al., 2010; Nagao et al., and 576 kDa (Kaminski et al., 2006). (ii) The extracellular domain 2011b), and detailed reports on the implication of ABCA1 in AD between the first and second membrane spanning helix of each and neurodegeneration have been published recently (Kim et al., predicted TMD is particularly large in this subfamily (Kaminski 2008; Hirsch-Reinshagen et al., 2009; Koldamova et al., 2010). et al., 2006). (iii) A highly hydrophobic domain in ABCA trans- The encoding ABCA1 is located on chromosome 9q31.1 porters interrupts the cytosolic linker that connects the two halves and comprises 50 exons which span 147 kb DNA. The 254 kDa pro- of an ABC transporter (Bungert et al., 2001; Vulevic et al., 2001; tein of ABCA1 consists of 2261 amino acids and displays the typical Peelman et al., 2003; Albrecht and Viturro, 2007). Most ABCA structure of a full-size ABC transporter with two ATP-bindings transporters show a broad tissue-specificity, including expression cassettes and two TMDs. ABCA1 shows a broad expression pat- in brain (Kaminski et al., 2006), beside ABCA4, which is mainly tern with highest expression levels in smooth muscle, whole blood, expressed in the eye (Allikmets et al., 1997), and ABCA13 with placenta, liver, lung, adrenal glands, fetal organs, and brain (Lang- detectable expression in only a small variety of tissues (Prades mann et al., 1999; Su et al., 2004; Kim et al., 2008). On the et al., 2002; Table 1). subcellular level, ABCA1 is present in the plasma membrane, the Table 1 lists some of the biological properties of the members Golgi compartment,and in lysosomes (Neufeld et al.,2001; Tanaka of the ABCA subfamily. et al., 2003a). Phylogenetic analyses suggest that all ABCA subfamily trans- porters have evolved from a common ancestor gene (Kaminski ABCA1 and HDL metabolism et al., 2006) and can be further divided into two subgroups. The First clues for the involvement of ABCA1 in HDL metabolism so-called “ABCA6-like” transporters comprise ABCA5, ABCA6, came from our own studies demonstrating that ABCA1 expres- ABCA8, ABCA9, and ABCA10 and represent subgroup I (Piehler sion is up-regulated by cholesterol uptake and down-regulated et al., 2002). These transporters form a compact gene cluster on during HDL-mediated cholesterol efflux in human macrophages chromosome 17q24 and are characterized by a strikingly high, (Langmann et al.,1999). The identification of mutations inABCA1 mutual amino acid sequence identity and a significantly smaller causing HDL-deficiency syndromes, including TD, confirmed the size (between 1543 aa and 1642 aa) compared to the other ABCA role of ABCA1 as a key regulator in cellular HDL metabolism proteins (Arnould et al., 2001; Piehler et al., 2002; Kaminski et al., (Bodzioch et al., 1999; Brooks-Wilson et al., 1999; Lawn et al., 2006). The remaining seven ABCA transporters (ABCA1, ABCA2, 1999; Rust et al., 1999). To date, more than 80 mutations within ABCA3, ABCA4, ABCA7, ABCA12, and ABCA13) are included in the ABCA1 gene have been described (for an overview see The subgroup II of the ABCA transporter subfamily and dispersed on Human Gene Mutation Database at http://www.hgmd.org). In TD six (Dean, 2002). patients, cholesterol accumulates in peripheral tissues like tonsils, The A-subfamily of ABC transporters has gained special focus spleen, liver, and the artery wall leading to premature atheroscle- over the last years as mutations in four members were identi- rosis and hepatosplenomegaly. This accumulation is due to an fied as the underlying causes of monogenetic diseases in humans, impaired efflux of cellular cholesterol to its extracellular acceptor

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Table 1 | Biological characteristics of A-subfamily ABC transporters.

Gene symbol Genomic Protein size Major site of expression* Expression Functionally Association (Acc. number) localization and weight in involved in with AD (Gene size)# brain tissue*

ABCA1 9q31.1 (147 kb) 2261 aa Diverse (smooth muscle, blood + Phospholipid and Inhibition of Aβ (NM_005502) 254 kDa cells, placenta, liver, lung, adrenal cholesterol transport production and glands, fetal organs and brain; amyloid forma- Langmann et al., 2003) tion ABCA2 9q34.3 (21 kb) 2436 aa Brain (Zhao et al., 2000; Kim et al., +++ Cellular cholesterol and Induction of Aβ (NM_001606) 270 kDa 2008) myelin lipid transport production ABCA3 16p13.3 (65 kb) 1704 aa Lung (Yamano et al., 2001) ++ Phosphatidylcholine and Unknown (NM_001089) 191 kDa -glycerol trafficking, surfactant production ABCA4 1p22.1 (128 kb) 2273 aa Retina (Allikmets et al., 1997)(+) N-retinylidene- Unknown (NM_000350) 256 kDa phosphatidy- ethanolamine transport in rod cells ABCA5 17q24.3 (83 kb) 1642 aa Diverse (Skeletal muscle, kidney, + Unknown Unknown (NM_018672) 187 kDa liver, placenta); (Petry et al., 2003) ABCA6 17q24.2–3 (63 kb) 1617 aa Diverse (Liver, lung, heart, and ++ Unknown Unknown (NM_080284) 184 kDa brain; Kaminski et al., 2001b) ABCA7 19p13.3 (25 kb) 2146 aa Blood (precursor) cells (Kaminski + Phospholipid transport, Inhibition of (NM_019112) 235 kDa et al., 2000; Tanaka et al., 2011b) phagocytosis Aβ-production ABCA8 17q24.2 (88 kb) 1581 aa Diverse (Heart, skeletal muscle, ++ Unknown Unknown (NM_007168) 179 kDa liver; Tsuruoka et al., 2002) ABCA9 17q24.2 (86 kb) 1624 aa Diverse (Heart, brain, and fetal ++ Unknown Unknown (NM_080283) 184 kDa tissues; Piehler et al., 2002) ABCA10 17q24.3 (97 kb) 1543 aa Diverse (Heart, brain, and ++ Unknown Unknown (NM_080282) 176 kDa gastrointestinal tract; Wenzel et al., 2003) ABCA12 2q35 (207 kb) 2595 aa Diverse (Keratinocytes, stomach; + Unknown (NM_173076) 293 kDa Annilo et al., 2002) ABCA13 7p12.3 (476 kb) 5058 aa Diverse (Trachea, testis, bone (+) Unknown Unknown (NM_152701) 576 kDa marrow, submaxillary gland, epididymus, ovary, and thymus; Prades et al., 2002; Barros et al., 2003)

#According to the Genome Reference Consortium built 37 (hg19, February 2009). *Expression information retrieved from GNF Expression Atlas 2 Data (http://biogps.org/) and the cited studies. aa, amino acids; AD, Alzheimer’s disease. apolipoprotein A-I (apoA-I),the main apolipoprotein in HDL par- that leads to stabilization and activation of the transporter. Activa- ticles, by ABCA1 leading to a lack of HDL in the patient’s plasma tion of ABCA1 triggers increased translocation of phospholipids (Bodzioch et al.,1999; Brooks-Wilson et al.,1999; Lawn et al.,1999; from the cytosolic to the exofacial leaflet of the plasma membrane Rust et al., 1999). Further studies documented that both hepatic which subsequently bends and reveals high affinity binding sites and intestinal ABCA1 contributes to HDL metabolism and that for apoA-I in so-called exovesiculated lipid domains. Membrane the liver is the predominant source of plasma HDL (Orso et al., bound apoA-I then passively accepts membrane phospholipids 2000; Basso et al., 2003; Wellington et al., 2003; Timmins et al., and cholesterol to form discoidal HDL particles (Vedhachalam 2005; Brunham et al., 2006). et al., 2007a,b, 2010; Kang et al., 2010; Nagao et al., 2011a,b). Despite extensive efforts, the molecular mechanisms by which An alternative model postulates that apoA-I is internalized after ABCA1 modulates the cellular cholesterol efflux and HDL biogen- binding to ABCA1 and the resulting apoA-I/ABCA1 complex is esis are still unclear. A current model suggests that the initial step is then targeted to late endosomes where apoA-I binds lipids. These binding of small amounts of apoA-I, the main protein component apolipoprotein–lipid complexes are subsequently released to the of HDL particles, to the large, first extracellular domain of ABCA1 extracellular space by exocytosis (Oram, 2008; Yvan-Charvet et al.,

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2010). Evidence has accumulated to suggest that both mech- amyloid load demonstrating that the poorly lipidated apoE parti- anisms of ABCA1-dependent apoA-I loading with lipids exist. cles from ABCA1-deficient glia enhance beta-amyloid deposition. However, there is still an ongoing controversy as to which one None of these studies, however, found evidence for a signifi- is the dominant mechanism in HDL biogenesis. cant contribution of Abca1 deficiency to APP processing or Aβ production in vivo strongly suggesting that Abca1 enhances amy- ABCA1 in the CNS and Alzheimer’s disease loid formation indirectly via facilitation of apoE lipidation. Con- The expression of ABCA1 in the brain was already noted by Luciani versely, ABCA1 overexpression studies revealed that robust (>6- et al. (1994) describing the identification and cloning of ABCA1 fold over endogenous expression) but not weak overexpression from embryonic mouse brain RNA. Subsequent studies reported (about 50%) of ABCA1 results in decreased amyloid deposition highest expression of ABCA1 in the brain regions of the olfac- (Hirsch-Reinshagen et al., 2007; Wahrle et al., 2008). Based on tory bulb, hippocampus, cerebellar cortex, choroid plexus, and in the findings that ABCA1 depletion results in increased amyloid germinal regions of embryonic and early postnatal brains (Fuku- deposition and ABCA1 induction shows a reciprocal effect and moto et al., 2002; Tachikawa et al., 2005). Experiments on isolated the fact that APP processing or Aβ production is not influenced brain cells showed expression of ABCA1 in neurons, astrocytes, by Abca1 depletion in vivo, the concept of the ABCA1–apoE path- microglia, and oligodendrocytes, with highest expression levels in way of Aβ clearance has been put forward. In this model, nascent neurons and microglia (Koldamova et al., 2003; Kim et al., 2006). apoE particles are secreted from astrocytes and microglia and are ABCA1 expression in brain capillary endothelial cells has also been subsequently lipidated by ABCA1 forming discoidal lipid–apoE reported (Panzenboeck et al., 2002; Ohtsuki et al., 2004). complexes. In a second step, these are further loaded with lipids Several observations led to the investigation of a potential link by ABCG1 (and likely other ABC transporters) to form spheri- between ABCA1 and apoE: (i) ABCA1 is a major regulator of HDL cal, mature apoE-containing lipid particles present in the CNS. biogenesis outside the CNS by facilitating cholesterol and phos- Finally, mature apoE–lipid particles bind Aβ and facilitate the cel- pholipid loading onto apoA-I (Kaminski et al., 2006).(ii) ApoE lular uptake and clearance of Aβ via a functional apoE-receptor is the most abundant apolipoprotein in the CNS and present (Figure 2; Hirsch-Reinshagen et al., 2009). in HDL-like particles in the cerebrospinal fluid (Hayashi, 2011). Of note, a most recent study reports that transient expression (iii) The major apoE isoforms (apoE2, apoE3, and apoE4) are of ABCA1 TD mutants in CHO cells stably expressing APP reduces highly associated with disposition to and onset of AD (Hirsch- Aβ production to a similar degree as wild-type ABCA1 but inde- Reinshagen et al., 2009). (iv) Membrane cholesterol is known to pendently of cholesterol efflux (Kim et al., 2011). These findings, regulate processing of amyloid precursor protein (APP) and gen- eration of beta-amyloid (Aβ)-fibrils (Simons et al., 1998; Puglielli et al., 2003). Initial clues for an interdependency between apoE and ABCA1 came from experiments showing that Abca1 expres- sion induced by liver X receptor (LXR) and retinoid X receptor (RXR) agonists increases efflux of cholesterol to lipid-free apoA-I and apoE3 in isolated mouse neurons, astrocytes, and microglia (Koldamova et al., 2003). Despite the fact that apoE is mainly secreted from astrocytes (Hayashi, 2011), further studies iden- tified ABCA1-dependent loading of apoE with cholesterol as a mechanism by which cholesterol is targeted to neurons (Kim et al., 2007). Importantly, ABCA1 also appears to enhance the reverse process, the removal of cholesterol from neurons. Stud- ies in ABCA1−/− mice finally documented the central role of ABCA1 in apoE lipidation and that intact ABCA1 is required for normal CNS apoE concentrations (Hirsch-Reinshagen et al., 2004; Wahrle et al., 2004). These studies demonstrated that ABCA1−/− mice had significantly reduced (about 80% reduction) apoE levels in the brain, CSF, and plasma. In addition, they revealed that the FIGURE 2 | ABC transporters in apoE lipidation and Aβ metabolism. The observed apoE reduction is specific as levels of apoJ, another major ABCA1-apoE pathway of Aβ clearance hypothesis postulates that nascent apolipoprotein in the brain, were unchanged (Hirsch-Reinshagen apoE particles secreted from glial cells are initially lipidated by ABCA1 to et al., 2004; Wahrle et al., 2004). Moreover, endogenous apoE par- form discoidal apoE-lipid particles. Further maturation and lipidation of these ticles that are secreted from ABCA1-deficient glia showed poor complexes by ABCG1 and presumably other ABC transporters finally results in mature, spherical apoE-containing lipoproteins. Both ABCA lipidation (Hirsch-Reinshagen et al., 2004; Wahrle et al., 2004). transporters and apoE have been implicated in the production, deposition, Interestingly,several independent groups were able to demonstrate and clearance of Aβ. Knock-down and overexpression studies indicate that that these poorly lipidated apoE particles enhance Aβ deposition ABCA2 promotes Aβ production which is inhibited by ABCA1 and ABCA7. in offsprings from Abca1−/− mice crossbred with four different Amyloid formation is inhibited by ABCA1, and ApoE is required for Aβ β murine models of AD (Hirsch-Reinshagen et al., 2005; Koldamova deposition. ApoE also facilitates the cellular uptake of A via apoE receptors and has a negative effect on Aβ clearance across the blood–brain barrier et al., 2005; Wahrle et al., 2005). Unexpectedly, the Abca1 null (Figure modified after Hirsch-Reinshagen et al., 2009; Hayashi, 2011). mutant offsprings exhibited increased Aβ immunoreactivity and

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which challenge the proposed model of Aβ clearance via ABCA1- and vestibular schwannomas (Wanget al.,2005; Soichi et al.,2007). lipidated apoE, rather suggest a direct effect of the ABCA1 protein However, ABCA2 has also been detected in a variety of other brain on Aβ production and amyloid formation. cells including neurons and brain endothelial cells (Ohtsuki et al., Although the molecular mechanisms by which ABCA1 impacts 2004; Broccardo et al., 2006; Kim et al., 2006; Warren et al., 2009; Aβ production and amyloid deposition is not fully understood, Shawahna et al., 2011), and other tissues outside the CNS includ- a substantial body of evidence has accumulated during the past ing monocytes, macrophages, T-cells, thyroid gland, kidney, liver, years to suggest critical roles of ABCA1 in the development of AD. thymus, heart, ovary, lung, and various tumor cells, respectively In light of this, ABCA1 may be a promising candidate for ther- (Zhao et al., 2000; Kaminski et al., 2001a; Vulevic et al., 2001; apeutical interventions aiming at the prevention and treatment Zhou et al., 2001, 2002; Ile et al., 2004; Broccardo et al., 2006). On of AD. a subcellular level, both electron microscopy and immunocolo- calization experiments indicate a localization of ABCA2 around Association studies of ABCA1 and Alzheimer’s disease lysosomes and in the Golgi apparatus (Vulevic et al., 2001; Zhou Beside these efforts to explore the functional implication of et al., 2001, 2002). Ile et al. (2004) identified a novel 5-localized ABCA1 in amyloid deposition and development of AD, 11 studies exon of ABCA2 encoding an alternative N-terminus. Using Laser have thus far investigated associations between single nucleotide scanning confocal microscopy, the authors found that this novel polymorphisms (SNP) in the ABCA1 gene and the development isoform also co-localizes with lysosome-associated proteins-1 and of AD in various populations. Among the allelic variants identi- -2 (LAMP1 and 2) and shows highest expression in peripheral fied in the ABCA1 gene, the SNPs rs2230806 (R219K), rs4149313 blood leukocytes. In addition to this alternative exon 1-transcript, (I883M), and rs2230808 (R1587K) have been most extensively ABCA2 is transcribed at least into five alternative transcripts which studied. At this point, however, the data from available association are differentially expressed in different brain regions (Piehler et al., studies are inconclusive. This sobering resume is likely the result unpublished data). of major variations in the genetic and ethnic background of the cohorts investigated and varying experimental power of the stud- ABCA2 and lipid transport in the CNS ies. The 219K allele of the coding SNP rs2230806, for example, Although the intracellular localization of ABCA2 is in agreement has been associated with both predisposition to AD (Rodriguez- with the finding that ABCA2 overexpressing HEK293 cells do Rodriguez et al., 2007; Sundar et al., 2007) and the opposite, a not stimulate cholesterol efflux to apoA-I, apoE, or apoE disks protective effect for the development of AD (Wollmer et al., 2003; (Kim et al., 2007), several observations suggest a role of ABCA2 in Katzov et al., 2004; Wang and Jia, 2007; Wavrant-De et al., 2007; brain cholesterol metabolism: (i) the putative promoter sequence Reynolds et al., 2009). Other studies were unable to identify an of ABCA2 contains multiple potential transcription factor bind- association between common ABCA1 sequence variants and AD ing sites for neural cell differentiation (Kaminski et al., 2001a). or delayed onset of AD (Li et al., 2004; Kolsch et al., 2006; Shi- (ii) ABCA2 transcription displays cholesterol–responsive regu- bata et al., 2006; Wahrle et al., 2007). Although an anti-Alzheimer lation (Kaminski et al., 2001a; Davis, Jr. et al., 2004; Davis, Jr., effect of the ABCA1 219K variant cannot be excluded at this point, 2011) and (iii) ABCA2 is coordinately expressed with other sterol- further studies that rely on stringent design and strictly defined dependent genes (Davis, Jr. et al., 2004). (iv) ABCA2 overexpres- cohorts are necessary to explore the potential association between sion in CHO cells leads to an increase in LDL receptor expression ABCA1 allelic variants and AD. and other genes involved in cholesterol metabolism (Davis, Jr. et al., 2004). (v) This results in a reduction of LDL-derived free ABCA2 cholesterol esterification and an accumulation of un-esterified Molecular properties of ABCA2 LDL-cholesterol in the endosomal/lysosomal pathway (Davis, Jr. Originally, ABCA2 was co-identified with ABCA1 in mice and et al., 2004), which is part of the processing of APP to Aβ.Arecent is the second member of the A-subfamily of ABC transporters study by Davis using N2a neuroblastoma cells, however, reported (Luciani et al., 1994). The human gene comprises 48 exons, is a decrease of the LDL receptor in response to ABCA2 overex- located on chromosome 9q34 and shows an extreme compact pression and thus a decrease in the uptake of a fluorescent LDL structure within a genomic region of only 21 kb (Kaminski et al., analog (Davis, Jr., 2011). In this work, the author also shows that 2001a; Vulevic et al., 2001; Ile et al., 2004). The ABCA2 full-length ABCA2 overexpression leads to a reduction in total,free- and ester- cDNA is 7.3 kb in size and codes for a 270 kDa protein consisting ified cholesterol levels in the neuronal cells overexpressing ABCA2 of 2436 aa (Kaminski et al., 2001a; Vulevic et al., 2001). ABCA2 (Davis, Jr., 2011). In addition, a decrease in plasma membrane is mainly expressed in brain and nervous tissues with particu- cholesterol was noted, but not in other organelles or lipid raft larly high expression in cells facilitating myelin production in the compartments. Moreover, de novo cholesterol synthesis or traf- brain (oligodendrocytes) and peripheral nerves (Schwann cells), ficking of cholesterol to the plasma membrane or the endoplasmic respectively (Luciani et al., 1994; Zhao et al., 2000; Vulevic et al., reticulum were unaffected (Davis, Jr., 2011). Together, these results 2001; Zhou et al., 2001, 2002; Langmann et al., 2003; Tanaka et al., clearly indicate a regulatory role of ABCA2 cholesterol metabolism 2003b; Su et al., 2004; Wang et al., 2005; Kim et al., 2006; Saito within the cell. et al., 2007; Wahrle et al., 2008). Based on comparison of ABCA2 Next to the studies documenting highest expression of ABCA2 expression in astrocytic tumors and oligodendrogliomas, and in in oligodendrocytes and Schwann cells, which facilitate myelina- schwannomas and healthy Schwann cells, respectively, ABCA2 has tion of neurons in the CNS and the peripheral nervous system,sev- also been proposed as a molecular marker for oligodendrogliomas eral experiments point to a role of ABCA2 in myelin lipid transport

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in addition to cholesterol homeostasis. Analysis of maturing cen- 2011). In this study, ABCA2 depletion led to a relative shift from tral and peripheral nervous tissues revealed that temporal and β-toα-secretase dependent cleavage of APP resulting in increased spatial expression of ABCA2 was closely correlated with that of levels of APPsα and a relative decrease in APPsβ production. This myelin sheath-associated proteins (Zhou et al., 2002; Tanaka et al., observation computes well with the results by Davis reporting 2003b). To date, two independent groups have reported the gen- enhanced β-secretase cleavage of APP at the alternative cleavage eration of Abca2 deficient mice. In both studies, Abca2-null mice site Glu11 (β-site; Davis, Jr., 2010) which is increasingly used phenotypically displayed reduced body weight and an obvious alternatively to the canonical Asp1 amino acid site (β-site) under distinct tremor of their limbs and were reported to be easily star- conditions of β-secretase excess (Fluhrer et al., 2002; Liu et al., tled (Mack et al., 2007; Sakai et al., 2007a). In the study by Mack 2002). As ABCA2 is a likely regulator of cellular homeostasis and and colleagues,Abca2−/− mice exhibited ultrastructurally abnor- β-secretase acts within the detergent resistant domains (DRMs) mal myelin sheathes with increased myelin sheath thickness in the of membranes (Wahrle et al., 2002; Ehehalt et al., 2003; Abad- spinal cord and a reduced periodicity of the myelin membrane Rodriguez et al., 2004; Vetrivel et al., 2004), depletion of ABCA2 both in the spinal cord and cerebrum. In contrast, no apparent may change DRM stabilization and thus the relative amount of change in total,esterified or free plasma cholesterol,or in total CNS APP processed by α- and β-secretase. Of note, Mickaki et al. also tissue lipid composition (ceramide,sphingosine,or sphingomyelin found in their study that ABCA2 depletion leads to a reduction species) were observed in the Abca2 deficient mice. Because female of APP processing by γ-secretase. This was due altered γ-secretase Abca2-null mice had a lower body weight compared to their complex formation which in turn was caused by aberrant glycosy- male littermates, the authors suggest a hormone-dependent role lation of Nicastrin, one of the components of γ-secretase (Michaki of Abca2 in neurological development (Mack et al., 2007). Sakai et al., 2011). Interestingly, the reduction of γ-secretase cleavage of et al. (2007a) observed no abnormalities in the cytoarchitectonic APP by ABCA2 depletion occurred in a substrate-selective man- or compact myelin structure in their Abca2 knock-out mice, but ner since processing of Notch, another important substrate of significant differences in lipid concentrations of both total brain γ-secretase, was unaffected (Michaki et al., 2011). tissue and myelin fractions compared to wild-type animals. From 4 to 64 weeks of age, Abca2-null mice brains exhibited an accu- Association studies of ABCA2 and Alzheimer’s disease mulation of gangliosides along with reduced sphingomyelin, and In an effort to explore a potential association between genetic an accumulation of cerebrosides and sulfatides at 64 weeks of age. variation withinABCA2 andAD,two groups reported a strong cor- Analysis of the brain of Abca2 knock-out mice revealed reduced relation between a synonymous SNP (rs908832) and early-onset sphingomyelin and a significant increase of the major ganglioside and sporadic AD in a Caucasian and a Western European popula- GM1. The latter finding is of particular interest as it has been tion, respectively (Mace et al., 2005; Wollmer et al., 2006). In one shown that raised levels of gangliosides in brain tissue induce study, however, the association was ethnicity-dependent and not beta-amyloid fibril formation (Yanagisawa, 2007). In conclusion, present in a Southern European and anAsian population (Wollmer functional studies from the past years corroborate an involvement et al., 2006). In the same study, the authors reported an associa- of ABCA2 in brain lipid metabolism. However, further work is tion of this SNP with cholesterol levels in the cerebrospinal fluid, required to define in detail the molecular involvement of ABCA2 a known determinant of AD (Wollmer et al., 2006). In contrast, in neuronal cholesterol homeostasis and myelin lipid metabolism. Minster et al. (2008) could not to confirm the observed association of rs908832 with early onset AD (EOAD) or sporadic AD. Despite ABCA2 in Alzheimer’s disease the rather limited cohort size of the EOAD cohort (137 EOAD Most recently, functional studies indicate a link between ABCA2 patients, 1006 controls), the study had a power of >90% to detect and the central molecular process in AD: beta-amyloid produc- the odd-ratios reported by Mace et al. and Wollmer et al. respec- tion. Using amplified differential gene expression, Chen et al. tively. At this point, more work is required to establish whether a (2004) showed that overexpression of ABCA2 results in upregula- clinically relevant association does exist between AD and genetic tion of genes commonly associated with oxidative stress and the ABCA2 variants. pathogenesis of AD, including seladin-1, amyloid b (A4) precur- Taken together, evidence has accumulated through the past sor protein, vimentin, LDL receptor-related protein 3, Slc23a1, and years to suggest important roles of ABCA2 in intracellular brain calsarcin-1. Using confocal microscopy, the authors showed that cholesterol homeostasis and APP processing. Although the molec- increased ABCA2 levels impact the expression of Aβ and APP,and ular basis of the interdependency of ABCA2 and cholesterol traffic that ABCA2 co-localizes with both Aβ and APP in discrete intra- and Alzheimer disease are currently not fully understood, the cellular vesicles that also stained positively for the endolysosome knowledge of altered secretase activity due to changes in ABCA2 markers LAMP1 and LAMP2 (Chen et al., 2004). Further evidence activity and cholesterol homeostasis may represent a starting point for ABCA2 as a key regulator of APP metabolism has recently been for developing therapeutical approaches to AD. provided by Davis showing that overexpression of ABCA2 in neu- ronal N2a cells increased both the transcription of APP and the ABCA7 amount of APP holoprotein, and promoted amyloidogenic pro- Molecular properties of ABCA7 cessing of APP (Davis, Jr., 2010). These findings are in line with ABCA7 is a 220 kDa A-subfamily ABC transporter that exhibits a most recent report demonstrating that knock-down/knock-out highest sequence similarity to ABCA1 (54%) and ABCA4 (49%; of ABCA2 in mammalian cells in vitro,inDrosophila melanogaster Kaminski et al., 2000, 2006; Broccardo et al., 2001). Initially, and in mice results in reduced production of Aβ (Michaki et al., ABCA7 was cloned from human macrophages (Kaminski et al.,

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2000), and shows highest expression in cells from the myelo- dependent reduction in serum total cholesterol, HDL concentra- lymphatic lineage comprising both mature and blood cell pre- tion and visceral fat (Kim et al., 2005). At this point, further work is cursors (Kaminski et al., 2000; Sasaki et al., 2003; Tanaka et al., required to establish how and to which degree ABCA7 contributes 2011b). However, expression of ABCA7 in other tissues has also to human lipid trafficking. been reported, including keratinocytes and brain (Kaminski et al., 2000; Kielar et al.,2003; Kim et al.,2006; Sakai et al.,2007a). Specif- ABCA7 in CNS lipid transport and Alzheimer’s disease ically, in situ hybridization experiments revealed the presence of Based on the notion that ABCA7 is expressed in the brain and Abca7 mRNA throughout the brain of adult mice with highest potentially functions as a lipid transporter, Chan et al. (2008) expression in the densely packed neurons of the hippocampus investigated whether ABCA7 regulates cholesterol efflux to apoE, (Kim et al., 2005), and RT-qPCR analysis of the different brain cell the major apolipoprotein in the brain, and whether it influ- types and several cell lines derived from the CNS showed highest ences beta-amyloid production. They found that overexpression of ABCA7 transcription levels in microglia (Kim et al., 2006). On the ABCA7 stimulated cholesterol efflux to discoidal apoE-lipid com- subcellular level, the localization of ABCA7 remains still unclear. plexes independent of the apoE isoform. Lipid-free apoE did not Whereas initial experiments in HEK293 cells indicated the pres- accept cholesterol suggesting that apoE disks present in the CNS ence of ABCA7 in the plasma membrane (Wang et al., 2003), a may function as acceptors for ABCA7-mediated cholesterol efflux. subsequent study could not confirm this localization by immuno- Moreover, the authors noted that ABCA7 significantly inhibited fluorescence microscopy but suggested an intracellular presence in beta-amyloid secretion from human amyloid precursor protein peritoneal mouse macrophages (Linsel-Nitschke et al., 2005). Sev- expressing cells. Using fluorogenic substrates and GFP-tagged APP eral studies have thus far reported both intracellular detection of they demonstrated that the observed inhibition was due to an ABCA7 and its localization in the plasma membrane (Ikeda et al., apparent retention of APP in a perinuclear location rather than 2003; Sasaki et al., 2003; Abe-Dohmae et al., 2004; Iwamoto et al., an inhibitory effect on α-, β-, or γ-secretase activity (Chan et al., 2006). The putative presence of ABCA7 both in the cell and on 2008). the cell surface may be explained by the observation that ABCA7 Along with the sustained efforts to elucidate the role of ABCA7 is transcribed into several alternative variants (Ikeda et al., 2003; in cellular lipid transport, evidence has accumulated during the Kaminski et al., 2006). past years that links another potential function of this transporter to neurodegenerative disease. Recent reports indicate a central The elusive function of ABCA7 role of ABCA7 in phagocytosis and the engulfment of apoptotic Despite its identification more than 10 years ago, the definite mol- cells (Iwamoto et al., 2006; Jehle et al., 2006; Tanaka et al., 2010, ecular function of ABCA7 still needs to be elucidated. Several 2011a,b). In addition to the finding that ABCA7 mRNA and pro- lines of evidence point to a role in cellular lipid transport: (i) tein is up-regulated during phagocytosis via the SREBP2 pathway ABCA7 shares highest sequence identity with ABCA1, the main (Iwamoto et al., 2006), these studies showed that knock-down molecule for cholesterol export to apoA-I to produce HDL par- of ABCA7 results in a decreased phagocytic activity (Iwamoto ticles (Kaminski et al., 2006), (ii) ABCA7 is up-regulated upon et al., 2006) and that heterozygous ABCA7+/− mice exhibit a cholesterol load of macrophages and down-regulated upon cho- defective clearance of apoptotic cells (Jehle et al., 2006). Both the lesterol efflux from these cells (Kaminski et al., 2000), (iii) the phagocytic rate and the expression of ABCA7 are increased in ABCA7 promoter contains sterol responsive elements and is regu- ABCA1-deficient fibroblasts (Bared et al., 2004; Iwamoto et al., lated by SREPBs (Iwamoto et al., 2006) and (iv) other A-subfamily 2006). In contrast, the phagocytic activity is reduced in the peri- members,of which the substrate has been identified,serve as trans- toneal cavity of ABCA7−/− mice compared to wild-type animals porters of lipids (ABCA1, ABCA3, ABCA4, ABCA12; Kaminski (Tanaka et al., 2010). These studies also indicate that apoA- et al., 2006). Results from studies investigating apoA-I mediated I and apoA-II both stabilize and increase surface ABCA7 and release of phospholipids and cholesterol by ABCA7 under different thus increases the phagocytic rate rather than contribute to lipid conditions,however,are conflicting. Whereas some reports suggest efflux from the cell. This stimulation of phagocytosis was sus- that cells overexpressing ABCA7 exhibit increased apolipoprotein- tained in ABCA1 siRNA treated J774 macrophages and in the mediated efflux of both phospholipids and cholesterol (Ikeda et al., peritoneal macrophages from ABCA1−/− mice (Tanaka et al., 2003; Abe-Dohmae et al., 2004; Hayashi et al., 2005), data from 2010). Another study by the same group also demonstrated that other experiments could not confirm that ABCA7 facilitates the statin treatment of J774 cells induces ABCA7 expression by its release of cholesterol from cells (Wang et al., 2003; Abe-Dohmae cholesterol-lowering effect and simultaneously enhances phago- et al., 2004; Linsel-Nitschke et al., 2005). The situation is compli- cytosis. This increase in phagocytic activity was abolished by cated by the observations that peritoneal macrophages treated with ABCA7 siRNA treatment of the statin stimulated cells (Tanaka ABCA7 siRNA and from heterozygous ABCA7+/− mice showed et al., 2011a). unaffected apoA-I mediated cellular cholesterol and phospholipid The finding that ABCA7 promotes Fc receptor-independent release (Linsel-Nitschke et al., 2005). Moreover, Abca7 null mice, phagocytosis is of particular interest taking into account that which have been reported to be lethal by one group (Jehle et al., human microglia cells contribute to the phagocytic removal of 2006), showed unchanged cholesterol and phospholipid efflux lev- apoptotic debris from the brain (Stolzing and Grune, 2004; Napoli els in bone marrow-derived macrophages investigated by another and Neumann, 2009) and given that among brain cells microglia group (Kim et al., 2005). Abca7 knock-out mice showed no obvi- displays highest ABCA7 expression. Based on this, it is tempt- ous phenotypic abnormalities, but surprisingly exhibited a gender ing to speculate that microglial ABCA7 has an active role in the

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Fc receptor-independent phagocytic uptake of debris and plaques et al., 2007; Cheong et al., 2007; Fitzgerald et al., 2007; Hammel generated in the process of neurodegenerative disorders. et al., 2007). Although the exact molecular contribution of ABCA3 Moreover, the recent demonstration of a T cell receptor (TCR)- to surfactant production is still unknown, an essential role of this based machinery for specific immune recognition in macrophages transporter in lipid transport, in particular in phosphatidylcholine that functions as a modulator of phagocytic capacity (Beham et al., and phosphatidylglycerol trafficking, during lamellar body for- 2011) raises the intriguing possibility of a functional link between mation has been established. Expression of ABCA3 has also been ABCA7 and the novel variable macrophages immune system. It detected in total brain tissue (Fitzgerald et al.,2007; Stahlman et al., will be most challenging to investigate whether and to which degree 2007), oligodendrocytes, neurons, astrocytes, and microglia (Kim an interdependencies exists between ABCA7 and the macrophage et al., 2006), a tissue expression pattern that is similar to that of TCR-like immunoreceptors in the pathogenesis of macrophage- ABCA2 in the developing mouse brain (Tachikawa et al., 2005). dependent neurodegenerative diseases such as multiple sclerosis Given the expression of ABCA3 in the brain and the fact that phos- and HIV dementia. phatidylcholine and phophatidylglycerol are the lipid compounds mainly affected in the ABCA3-defective lung, it appears realistic to Association studies of ABCA7 and Alzheimer’s disease assume roles of ABCA3 in the transport of these lipids in the brain. Next to functional studies, independent evidence for roles of However, studies investigating this function are currently unavail- ABCA7 in brain lipid homeostasis and neurodegeneration comes able. In detail examination of ABCA3 deficient mouse brains will from a recent genome-wide association study (GWAS) and re- help to gain further insight into a possible role of ABCA3 in brain analysis of combined GWAS datasets which identified a candidate lipid homeostasis. locus for AD in the ABCA7 gene (Jones et al., 2010; Hollingworth et al., 2011). The hot spot, which is defined by a common genetic ABCA4 variant in the ABCA7 gene (rs3764650) located in intron 13,exhib- ABCA4 is one of the best characterized A-subclass ABC trans- ited a strong association with this disease. Also a non-synonymous porters. Already in 1997 it was shown that mutations in this SNP in ABCA7 exon 32 (rs3752246) which showed the highest retina-specific transporter, also termed ABCR, cause Stargadt dis- linkage disequilibrium with rs3764650 was found to be signifi- ease. This degenerative eye-disease is characterized by progressive cantly associated with LOAD (Hollingworth et al., 2011). However, impairment of central vision early in life, presence of lipofus- as rs3752246 encodes a glycine to alanine substitution at position cin deposits in the central retina, and bilateral photoreceptor 1527 of the protein, which is regarded as a benign change, this atrophy in the macula (Allikmets et al., 1997; Molday, 2007). SNP is unlikely to be the relevant functional variant. The authors Also the rare, but more severe cone-rod dystrophy type 3 and also excluded an association between rs3764650 and the expres- type 19 have been shown to be caused by sion of ABCA7 analyzing data from two expression quantitative mutations in ABCA4 (Cremers et al., 1998; Martinez-Mir et al., trait loci (eQTL) datasets. Although these studies present com- 1998; Maugeri et al., 2000). Extensive studies of this transporter pelling evidence for an association of ABCA7 with AD, the genetic strongly suggest that ABCA4 facilitates the export of the phos- mechanisms that define a causative interrelationship still await pholipid N -retinylidenephosphatidylethanolamine, a byproduct elucidation. of the visual cycle, from the lumen to the cytoplasm of disk membranes in rod cells (Sun et al., 1999; Weng et al., 1999; Ahn OTHER A-SUBFAMILY ABC TRANSPORTERS et al., 2000; Mata et al., 2000; Beharry et al., 2004; Molday, 2007). Beside the above ABC transporters, other A-subfamily members Depletion of ABCA4 activity results in accumulation of retinoids are expressed only to a limited degree in brain and nervous tis- in disk membranes and subsequent retinal pigment epithelial sues. Anecdotic reports on potential functions of these are rare, cell death and neurodegeneration of photoreceptors, a process but mainly point to an involvement in cellular lipid metabo- that ultimately leads to severe vision loss in affected individuals lism. Future detailed studies will help to determine whether these (Weng et al., 1999; Mata et al., 2000; Molday, 2007). ABCA4 is A-subfamily transporters are implicated in brain lipid homeosta- also expressed outside the retina in rat choroid plexus epithelial sis and the pathophysiology of neurodegenerative processes. The cells and human brain capillary endothelial cells (Ohtsuki et al., following subchapter provides a brief synopsis of our current 2004; Bhongsatiern et al., 2005; Tachikawa et al., 2005) suggest- knowledge on additional members of the A-subfamily of ABC ing a role of this ABC protein in blood-cerebrospinal fluid barrier transporters. function. Because ABCA4 dysfunction leads to accumulation of retinoids in the retinal pigment epithelium, it may be worth- ABCA3 while investigating whether ABCA4 present in the choroid plexus ABCA3 is mainly expressed in the human lung alveolar type II cells is involved in the regulation of retinoid concentrations in the CNS on the limiting membrane of lamellar bodies, which represent the which are associated with motor neuron disease and AD (Maden, storage form of lung surfactant. Mutations in ABCA3 have been 2007). shown to cause fatal surfactant deficiency in full-term newborns (Shulenin et al., 2004) and are associated with milder forms of ABCA6-like transporters interstitial lung disease as well (Bullard et al., 2005; Kunig et al., Only little is known about the function of the subgroup of ABCA6- 2007; Karjalainen et al., 2008; Yokota et al., 2008). The pheno- like transporters which form a compact gene cluster located on type of surfactant deficiency caused by mutations in ABCA3 has chr 17q24.2-3. This cluster comprises the transporters ABCA5, been confirmed in ABCA3 knock-out mice by several groups (Ban ABCA6, ABCA8, ABCA9, and ABCA10, respectively. Although

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all ABCA6-like transporters are expressed at detectable levels in three entities represent hereditary dyskeratinization disorders, but the brain (Nagase et al., 1998; Arnould et al., 2001; Kaminski present with different clinical severity. Whereas et al., 2001b, 2006; Piehler et al., 2002; Tsuruoka et al., 2002; type 2 is a relatively mild form of dyskeratinization with skin Langmann et al., 2003; Wenzel et al., 2003, 2007; Kim et al., desquamation over the whole body and large, pigmented scales 2006) and it is likely that they are involved in lipid transport (Lefevre et al., 2003), HI presents with a distorting phenotype processes, their potential implication in human brain lipid home- in which the patient’s body is covered with an enormous horny ostasis and neurodegeneration remains purely speculative at this shell with deep fissures leading to water loss, electrolyte abnor- point. malities, severe infections, and mostly death within the first days Reports on ABCA5 expression and function are anecdotic and after birth (Unamuno et al., 1987; Akiyama et al., 2005; Akiyama, the sites of expression appear to be highly diverse. Interestingly, 2006). Analysis of the mutations identified in the different dysker- ABCA5 expression has been documented mainly in the context of atinization entities suggests that the severity of the phenotype epithelial malignancies including prostate cancer (Hu et al., 2007), correlates with the remaining activity of the mutated ABCA12 adenocarcinoma (Ohtsuki et al.,2007),melanomas (Heimerl et al., protein product. The molecular correlate of these dyskeratiniza- 2007), esophageal carcinoma (Huang et al., 2009), mesothelioma tion disorders is the absence or malformation of so-called lamellar (Shukla et al., 2010), and oral squamosa cell carcinoma (Cha granules (LG; Akiyama et al., 2005; Kelsell et al., 2005) which phys- et al., 2011), respectively. Other studies report high ABCA5 expres- iologically contribute to assemble the skin barrier by extruding sion in the brain, lung, heart, thyroid gland, and testis (Kubo their lipid content into the extracellular space during the ker- et al., 2005; Petry et al., 2006). Upregulation of ABCA5 in human atinization process (Wertz, 2000). Since mutations in ABCA12 brain microvascular endothelial cells derived from the blood– result in an abnormal distribution pattern of glucosylceramide, a brain barrier endothelium in response to tacrolimus treatment major lipid component of LG (Kelsell et al., 2005; Akiyama et al., has also been reported (Quezada et al., 2008). On the subcel- 2008), and ABCA12 ultrastructurally co-localizes with glucosyl- lular level, ABCA5 localizes to lysosomes and late endosomes, ceramide to LG on their way from the Golgi apparatus to the and Abca5−/− mice exhibit exophthalmos and a collapse of the cell periphery (Sakai et al., 2007b), it is realistic to assume an thyroid gland (Kubo et al., 2005). In adulthood, these animals essential role of ABCA12 in intracellular sphingolipid transport develop a -like heart and die due to car- processes (Akiyama, 2011). Of note, expression of ABCA12 has diac insufficiency (Kubo et al., 2005). Despite its expression in the also been reported in fetal brain (Annilo et al., 2002). It remains brain and its potential involvement in cholesterol metabolism (Ye to be established, however, whether ABCA12 exerts functions in et al., 2008, 2010), it appears unlikely that ABCA5 plays a cru- the regulation of the sphingolipid metabolism in the developing cial role in brain lipid homeostasis since overt abnormalities are brain. not observed in the brain of ABCA5 deficient mice (Kubo et al., 2005). ABCA13 ABCA6, ABCA9, and ABCA10 are also expressed at detectable ABCA13 is the largest known ABC transporter with a gene levels in the brain and regulated during monocyte differentiation size of 450 kb comprising 62 exons which code for a 576-kDa and cholesterol transport in human macrophages (Kaminski et al., polypeptide of 5058 aa and with an exceptionally large extra- 2001b, 2006; Piehler et al., 2002; Wenzel et al., 2003; Albrecht and cellular domain of more than 3500 aa (Prades et al., 2002; Bar- Viturro, 2007) suggesting roles of these transporters in lipid trans- ros et al., 2003). In normal tissues, highest mRNA expression port. However, definitive evidence supporting an implication of was found in human trachea, testis, bone marrow, submaxil- these highly homologous transporters in brain lipid transport is lary gland, epididymis, ovary, and thymus (Prades et al., 2002; still outstanding. Barros et al., 2003). High expression in the brain tumor cell Initial studies have indicated a role of ABCA8 in drug trans- line SNB-19 has also been reported (Prades et al., 2002). The port with a substrate specificity close to that of ABCC2 which molecular function of ABCA13 is currently unknown. Intrigu- is located at the blood–brain barrier (Tsuruoka et al., 2002). ingly, a recent report points to an association between genetic Moreover, Abca8a transcription is induced in the mouse liver variants of ABCA13 and schizophrenia, bipolar disorder, and upon acute digoxin intoxication (Wakaumi et al., 2005). A recent depression (Knight et al., 2009). In this study, the popula- study by Reppe et al. (2010) also suggests an association between tion attributable risk of the identified mutations was 2.2% for ABCA8 and bone mineral density in postmenopausal Caucasian schizophrenia and 4.0% for bipolar disorder. However, a more women. recent report failed to confirm this observation (Dwyer et al., 2011). ABCA12 ABCA12 was co-identified with ABCA13 in 2002 and mapped NON A-SUBFAMILY ABC TRANSPORTERS to the locus linked to lamellar ichthyosis on chromosome 2q34 Next to the A-subfamily ABC transporters reviewed above, several (Parmentier et al., 1999; Annilo et al., 2002). Subsequent stud- studies point to roles of ABC transporters outside this subfam- ies revealed that mutations in this transporter cause three related ily in brain lipid homeostasis and neurodegeneration (Kim et al., hereditary skin diseases: lamellar ichthyosis type 2 (Lefevre et al., 2008). ABCB1, also known as MDR1 and P-glycoprotein, is one of 2003), non-bullous congenital ichthyosiform erythroderma (Nat- the best characterized ABC transporters. It functions mainly as an suga et al., 2007; Akiyama et al., 2008) and harlequin ichthyosis exporter of amphipathic molecules such as anticancer drugs that (HI; Akiyama et al., 2005; Kelsell et al., 2005; Akiyama, 2006). All confer multidrug resistance to tumor cells (Sarkadi et al., 2006).

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Transport of lipids (phosphatidylcholine and ethanolamine,glyco- CONCLUSION sylceramide,and sphingomyelin) byABCB1 has also been reported ATP-binding cassette transporters constitute an evolutionary (van Helvoort et al., 1996). Despite its overall low expression in ancient group of large proteins which mediate the transmembrane human brain (Langmann et al., 2003), its presence and functional transport of a diverse spectrum of substrates. Specifically, the implication in the blood–brain barrier have been well documented members of the recently identified A-subfamily of ABC trans- (Cordon-Cardo et al., 1989; Tatsuta et al., 1992; Tishler et al., 1995; porters serve as key regulators of cellular lipid transport processes. Seetharaman et al., 1998; ElAli and Hermann, 2011; Vogelgesang Given that the central nervous system, next to adipose tissue, rep- et al., 2011). Importantly, recent studies indicate a central role resents the second major lipid rich area in higher organisms, it is of ABCB1 in the efflux of Aβ from the brain (Lam et al., 2001; reasonable to assume that A-subfamily ABC transporters are of Vogelgesang et al., 2004, 2011; Cirrito et al., 2005; Kuhnke et al., critical importance for the integrity of the CNS. In fact, recent 2007; Hartz et al., 2010) which is reduced by approximately 30% in evidence links A-subfamily transporters and also other members AD patients compared to healthy individuals (Mawuenyega et al., of the ABC protein family to the maintenance of brain lipid 2010). In addition to ABCB1, additional studies strongly suggest homeostasis and neurodegenerative diseases. In particular, the the involvement of the ABC proteins ABCA1,ABCC1,and ABCG2, transporters ABCA1, ABCA2, and ABCA7 are promising research respectively, in the export of Aβ (Xiong et al., 2009; Koldamova targets that bear significant therapeutic potential for the treat- et al., 2010; Krohn et al., 2011). Finally, another G-subfamily ABC ment of neurodegenerative disease. Whereas ABCA7 appears to transporter, designated ABCG1, has been implicated in the pro- inhibit Aβ production, a positive effect on Aβ production has cessing of APP to generate Aβ peptides (Sarkadi et al., 2006; Kim been reported for ABCA2. Moreover, available evidence suggests et al., 2007). Each of these transporters may represent a poten- that ABCA1 acts as a suppressor of Aβ production and deposition. tial pharmaceutical target for therapeutic interventions aiming Recent experiments involving ABCA1 inducing LXR agonists have at the reduction of Aβ accumulation and the prevention of AD shown promising,antiamyloidogenic effects and thus highlight the progression. importance of ACBA1 as a promising drug target in combatingAD.

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Kosaka, K., Michikawa, M., Molyva, and Inagaki, N. (2001). ABCA3 is evolution of respiratory distress. cord and PNS during myelination. J. D., Paraskevas, G. P., Lutjohann, a lamellar body Eur. J. Pediatr. 167, 691–693. Comp. Neurol. 451, 334–345. D., von, E. A., Hock, C., Nitsch, in human lung alveolar type II cells. Yvan-Charvet, L., Wang, N., and Tall, R. M., and Papassotiropoulos, A. FEBS Lett. 508, 221–225. A. R. (2010). Role of HDL, ABCA1, Conflict of Interest Statement: The (2006). Ethnicity-dependent genetic Yanagisawa, K. (2007). Role of gan- and ABCG1 transporters in choles- authors declare that the research was association of ABCA2 with sporadic gliosides in Alzheimer’s disease. terol efflux and immune responses. conducted in the absence of any com- Alzheimer’s disease. Am.J.Med. Biochim. Biophys. Acta 1768, Arterioscler. Thromb. Vasc. Biol. 30, mercial or financial relationships that Genet. B Neuropsychiatr. Genet. 141, 1943–1951. 139–143. could be construed as a potential con- 534–536. Ye, D., Hoekstra, M., Out, R., Meurs, Zhao, L. X., Zhou, C. J., Tanaka, A., flict of interest. Wollmer, M. A., Streffer, J. R., Lutjo- I., Kruijt, J. K., Hildebrand, R. Nakata, M., Hirabayashi, T., Amachi, hann, D., Tsolaki, M., Iakovidou, B., Van Berkel, T. J., and Van, T., Shioda, S., Ueda, K., and Ina- Received: 29 December 2011; paper pend- V., Hegi, T., Pasch, T., Jung, H. E. M. (2008). Hepatic cell-specific gaki, N. (2000). Cloning, charac- ing published: 17 January 2012; accepted: H., Bergmann, K., Nitsch, R. M., ATP-binding cassette (ABC) trans- terization and tissue distribution of 19 February 2012; published online: 05 Hock, C., and Papassotiropoulos, A. porter profiling identifies putative the rat ATP-binding cassette (ABC) March 2012. (2003). ABCA1 modulates CSF cho- novel candidates for lipid home- transporter ABC2/ABCA2. Biochem. Citation: Piehler AP, Özcürümez M lesterol levels and influences the age ostasis in mice. Atherosclerosis 196, J. 350(Pt 3), 865–872. and Kaminski WE (2012) A-subclass at onset of Alzheimer’s disease. Neu- 650–658. Zhou, C., Zhao, L., Inagaki, N., ATP-binding cassette proteins in brain robiol. Aging 24, 421–426. Ye, D., Meurs, I., Ohigashi, M., Calpe- Guan, J., Nakajo, S., Hirabayashi, T., lipid homeostasis and neurodegener- Xiong, H., Callaghan, D., Jones, A., Bai, Berdiel, L., Habets, K. L., Zhao, Y., Kikuyama, S., and Shioda, S. (2001). ation. Front. Psychiatry 3:17. doi: J., Rasquinha, I., Smith, C., Pei, K., Kubo, Y., Yamaguchi, A., Van Berkel, Atp-binding cassette transporter 10.3389/fpsyt.2012.00017 Walker, D., Lue, L. F., Stanimirovic, T. J., Nishi, T., and Van, E. M. ABC2/ABCA2 in the rat brain: This article was submitted to Frontiers in D., and Zhang, W. (2009). ABCG2 (2010). Macrophage ABCA5 defi- a novel mammalian lysosome- Neurodegeneration, a specialty of Fron- is upregulated in Alzheimer’s brain ciency influences cellular cholesterol associated membrane protein and tiers in Psychiatry. with cerebral amyloid angiopa- efflux and increases susceptibility a specific marker for oligodendro- Copyright © 2012 Piehler, Özcürümez thy and may act as a gatekeeper to atherosclerosis in female LDLr cytes but not for myelin sheaths. J. and Kaminski. This is an open-access at the blood-brain barrier for knockout mice. Biochem. Biophys. Neurosci. 21, 849–857. article distributed under the terms of Abeta(1-40) peptides. J. Neurosci. 29, Res. Commun. 395, 387–394. Zhou, C. J., Inagaki, N., Pleasure, S. the Creative Commons Attribution Non 5463–5475. Yokota, T., Matsumura, Y., Ban, N., J., Zhao, L. X., Kikuyama, S., and Commercial License, which permits non- Yamano, G., Funahashi, H., Kawanami, Matsubayashi, T., and Inagaki, Shioda, S. (2002). ATP-binding cas- commercial use, distribution, and repro- O., Zhao, L. X., Ban, N., Uchida, Y., N. (2008). Heterozygous ABCA3 sette transporter ABCA2 (ABC2) duction in other forums, provided the Morohoshi, T., Ogawa, J., Shioda, S., mutation associated with non-fatal expression in the developing spinal original authors and source are credited.

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