Formation and function of apolipoprotein E-containing lipoproteins in the nervous system

Biochimica et Biophysica Acta 1801 (2010) 806–818

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Biochimica et Biophysica Acta j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / b b a l i p

Review

Formation and function of apolipoprotein E-containing lipoproteins in the nervous system Jean E. Vance a,⁎, Hideki Hayashi b a b

Group on Molecular and Cell Biology of Lipids and Department of Medicine, University of Alberta, Edmonton, AB, Canada Priority Organization for Innovation and Excellence, Kumamoto University, Kumamoto, Japan

a r t i c l e

i n f o

Article history: Received 23 December 2009 Received in revised form 5 February 2010 Accepted 9 February 2010 Available online 17 February 2010 Keywords: Neuron Astrocyte Apolipoprotein E Cholesterol Amyloid ß peptide Alzheimer disease

a b s t r a c t The strongest known genetic risk factor for the development of late-onset Alzheimer disease is inheritance of the apolipoprotein (apo) E4 (ε4 allele) although the mechanisms underlying this connection are still not entirely clear. In this review, we shall discuss the role of apo E in the brain, particularly in relation to Alzheimer disease. Cholesterol transport and homeostasis in the central nervous system (CNS) are separated from that in the peripheral circulation by the blood–brain barrier. However, the brain operates its own lipoprotein transport system that is mediated by high density lipoprotein-sized, apo E-containing lipoproteins that are synthesized and secreted by glial cells (primarily astrocytes). Several ATP-binding cassette (ABC) transporters are expressed in the brain, including ABCA1 and ABCG1 which play important roles in the transfer of phospholipids and cholesterol to apo E. The astrocyte-derived apo E-containing lipoproteins can bind to, and be internalized by, receptors of the low density lipoprotein receptor superfamily that are located on the surface of neurons. In addition to these receptors serving as endocytosis receptors for lipoproteins, several of these receptors also act as signaling receptors in neurons and activate pathways involved in axonal growth, as well as neuronal survival. These beneficial pathways appear to be enhanced to a greater extent by apo E3 than by apo E4. Apo E has also been implicated in the deposition of amyloid plaques since apo E3, more readily than apo E4, forms a complex with Aß peptides, and mediates the degradation of amyloid deposits. © 2010 Elsevier B.V. All rights reserved.

Alterations in the metabolism of lipids, particularly cholesterol, have been implicated in the pathogenesis of several neurodegenerative disorders including Alzheimer disease (AD), Niemann–Pick C disease (reviewed in [1]), Smith–Lemli Opitz syndrome [2], Huntington disease [3] and Parkinson's disease [4]. The mechanisms underlying the association between abnormal cholesterol metabolism and neurodegenerative diseases have not yet been clearly defined (reviewed in [5]). In this review we shall discuss the mechanisms of formation of apolipoprotein (apo) E-containing lipoproteins by glial cells and the functions of apo E in the CNS, particularly in relation to AD. 1. Cholesterol homeostasis in the brain Cholesterol is highly enriched in the brain compared to other tissues. In mammals, the brain comprises ∼ 5% of body mass, yet ∼25% Abbreviations: ABC, ATP-binding cassette; Aß, amyloid ß peptide; AD, Alzheimer disease; apo, apolipoprotein; APP, amyloid precursor protein; CNS, central nervous system; CSF, cerebrospinal fluid; HDL, high density lipoprotein; LCAT, lecithin: cholesterol acyltransferase; LDL, low density lipoprotein; LRP, LDL receptor-related protein; LXR, liver X receptor; VLDL, very low density lipoprotein ⁎ Corresponding author. 328 HMRC, University of Alberta, Edmonton, AB, Canada T6G 2S2. Tel.: + 1 780 492 7250; fax: +1 780 492 3383. E-mail address: [email protected] (J.E. Vance). 1388-1981/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.bbalip.2010.02.007

of total body cholesterol resides in the brain. The majority of sterol in the central nervous system (CNS) is unesterified cholesterol with smaller amounts of desmosterol and little cholesteryl ester. The average cholesterol concentration in most animal tissues is 2 mg/g tissue whereas in the brain the concentration of cholesterol is 15–20 mg/g tissue [6]. Although it has been widely reported that most (∼ 90%) of the cells in the brain are glial cells, while only ∼ 10% of cells in the CNS are neurons, this conclusion has been re-examined. It is now apparent that in the human brain only ∼ 50% of cells are glial cells — mainly astrocytes, oligodendrocytes and microglia [7]. The major pool of cholesterol (70–80%) in the CNS is in myelin. Oligodendrocytes – the glial cells that provide the myelin that surrounds axons and permits the transmission of electrical signals – are highly enriched in cholesterol. Correspondingly, the rate of cholesterol synthesis in the brain is highest during active myelination and declines dramatically in mature animals when myelination has been completed [6,8]. Nevertheless, cholesterol synthesis continues, primarily in glial cells, at a low rate in the brains of adult animals [9]. Of the three major classes of glial cells in the brain, microglia are a quantitatively minor (∼ 10%) class. Microglia are the primary immunocompetent and phagocytic cells of the CNS and these cells become activated in response to injury. The most abundant glial cells in the brain are the astrocytes. These cells interact with neurons but were for many years thought to play only a passive role in the brain and

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provide support for neurons. It is now evident, however, that astrocytes play a more active role in the nervous system and are required for neuronal excitability and synaptic transmission [10–13]. For example, conditioned medium isolated from astrocyte-enriched cultures enhanced synaptogenesis in CNS neurons [14,15], and the active component secreted by the astrocytes was identified as cholesterol that was contained within apo E-containing lipoproteins [16]. The half-life of cholesterol in rat brain is remarkably long: 4 to 6 months. When the rate of cholesterol synthesis in the CNS exceeds that required for maintaining constant levels of cholesterol, the excess cholesterol can be converted into 24(S)-hydroxycholesterol by the cytochrome P450-containing enzyme cholesterol 24-hydroxylase, which in mice is encoded by the Cyp46a1 gene ([17,18]; reviewed in [19]) (Fig. 1). The expression of this hydroxylase is restricted to a subset of neurons — pyramidal cells of the cortex, Purkinje cells of the cerebellum and some neurons of hippocampus and thalamus [18,20]; cholesterol 24-hydroxylase is essentially absent from astrocytes [20]. Unlike unesterified cholesterol, 24-hydroxycholesterol readily crosses the blood–brain barrier, enters the peripheral circulation, is delivered to the liver, and then is excreted into bile [18,21] (Fig. 1). 24-Hydroxycholesterol traverses a membrane bilayer, and presumably the blood–brain barrier, orders of magnitude faster than does cholesterol [22]. Targeted disruption of the Cyp46a1 gene in mice decreased the rate of cholesterol synthesis in the brain by 40%, presumably as part of a mechanism for maintaining cholesterol homeostasis since the steady state level of cholesterol in the brain was unchanged [20]. Thus, cholesterol 24-hydroxylase is responsible for at least 40% of the turnover of brain cholesterol in mice. Since this enzyme is expressed in only a limited population of neurons, less than 1% of the cells in the brain are responsible for 40% of cholesterol turnover [20]. These studies also revealed that an additional, currently unidentified, mechanism exists for the removal of excess cholesterol from the CNS. Interestingly, when cholesterol 24-hydroxylase expression was eliminated in a transgenic mouse model of AD, neither amyloid precursor protein (APP) expression, nor amyloid deposition was decreased, although lifespan of the mice was increased [23]. Most mammalian cells outside the brain acquire cholesterol from both endogenous synthesis and receptor-mediated uptake of lipoproteins – primarily low density lipoproteins (LDLs) – from the circulation [24]. In contrast, in the CNS almost no cholesterol is derived

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from plasma lipoproteins. Instead, the vast majority of cholesterol in the brain is synthesized in situ [25–28]. Several pieces of experimental evidence support this conclusion. For example, liver transplantation in humans resulted in the genotype of apo E in the plasma being that of the donor, whereas in cerebrospinal fluid (CSF) the apo E genotype was that of the recipient [29]. Moreover, elimination of the intestinal ATP-binding cassette (ABC) sterol transporters ABCG5 and ABCG8 caused the accumulation of large amounts of plant sterols in plasma whereas the CNS contained only trace amounts of these sterols [30]. The CNS, therefore, employs its own lipoprotein transport system that is separate from that of plasma, although many of the proteins that are involved in lipoprotein metabolism in the plasma, such as apolipoproteins (apos) E, A1, D and J [31,32], but not apo B [33], are also present in the brain. Moreover, lipoprotein receptors [34] and members of the ABC transporter family [35–37] are expressed in the CNS. Apo E, apo A1 and apo J in the CNS are components of lipoproteins that are the size and density of plasma high density lipoproteins (HDLs) [34,38–40]. 2. Apo E in the brain In plasma, the most abundant apolipoprotein of HDLs is apo A1. However, since the blood–brain barrier separates the CSF from plasma, the CSF contains lipoproteins whose composition is distinct from that in plasma. In CSF, the concentration of apo A1 is only 0.5% of that in plasma [34]. Apo A1 is not made within the brain but can be synthesized by endothelial cells that comprise the blood–brain barrier [41]. In addition, some apo A1 from the plasma crosses the blood–brain barrier and enters the CNS by an unidentified mechanism. The major apolipoprotein of HDL-like particles in the CNS is apo E that is made by astrocytes [42] and, to a lesser extent, by microglia [43]. In addition, small amounts of apo E are made in a few types of neurons [44–47]. The concentration of apo E in CSF is ∼5% of that in plasma [48]. Another abundant apolipoprotein in the brain is apo J (also known as clusterin); apo E and apo J are present on distinct populations of lipoprotein particles [49]. Apo E is secreted by glial cells and assembled with phospholipids and cholesterol into HDL-sized lipoprotein particles that can bind to apo E receptors on neurons. Thus, these apo E-containing lipoproteins are thought to deliver cholesterol to neurons for growth, repair and synaptogenesis [16,50–52] (Fig. 1). Apo E plays a central role in the nervous system. After nerve injury in the CNS or in the peripheral nervous system, apo E synthesis in glial cells increases by up to 150-fold [53,54], consistent with the view that apo E-containing lipoprotein particles participate in nerve repair processes. In support of this idea, in ApoE−/− mice the clearance of degenerating nerves is impaired [55]. ApoE−/− mice also have learning deficits [56–61] and develop neurofibrillary tangles [62]. In addition, apo E deficiency in neurons increases the susceptibility of the mice to ischemic injury [63], as well as ER stress after ischemia/ reperfusion [64]. Nevertheless, cholinergic parameters [65] and nerve regeneration [51,66,67] appear to be normal in ApoE−/− mice suggesting that alternative proteins can, at least partially, substitute for apo E. 3. Apo E isoforms in the brain

Fig. 1. Cholesterol transport and homeostasis in the central nervous system (CNS). Apo E is synthesized by astrocytes and is lipidated with unesterified cholesterol (chol) and phospholipids (PL) to form apo E-containing lipoproteins (LpE). The LpE bind to receptors (blue Y-shapes) on neurons thereby delivering lipids and/or initiating signaling pathways. Neurons also synthesize cholesterol and excess cholesterol is converted to 24-hydroxycholesterol which crosses the blood–brain barrier (BBB), enters the plasma and is delivered to the liver for excretion in bile.

In humans, the expression of apo E is highest in the liver but the tissue with the next highest level of apo E expression is the brain [68]. Human apo E is a 299 amino acid glycoprotein that is post-translationally sialylated (reviewed in [68–70]). Interest in understanding the role of apo E-containing lipoproteins in the CNS blossomed after the discovery in 1993 that inheritance of the ε4 allele of apo E is the strongest known genetic risk factor for the development of late-onset AD [71–73]. Humans can express 3 alternative isoforms of apo E – E2, E3 and E4 – the most common of which is apo E3. The ε4 allele frequency in the general population is 15%, but is 40% in patients with

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AD. Individuals with one ε4 allele are 3 to 4 times as likely to develop AD as those without any ε4 allele, and people with two ε4 alleles have a 12-fold higher risk of developing AD ([71]; reviewed in [74]). Moreover, the age of onset of AD symptoms is earlier in carriers of the ε4 allele than in those with the ε3 allele. On the other hand, carriers of the ε2 allele have decreased risk of developing AD [75,76]. The ε4 allele is also associated with an accelerated development and progression of several other neurodegenerative conditions such as Parkinson's disease [77], multiple sclerosis [78], head trauma [79], cerebral hemorrhage [80] and possibly stroke [81]. Brain function is differentially affected in mouse models that express human apo E4 compared to human apo E3. For example, the expression of human apo E4, rather than human apo E3, in mice impaired synaptogenesis [82], and apo E3 “knock-in” mice, that lacked endogenous apo E but expressed human apo E3, were protected, compared to mice expressing apo E4, against the age-dependent neurodegeneration that occurs in apo E knock-out mice [83]. Furthermore, memory and learning were impaired in apo E4 knock-in mice compared to apo E3 knock-in mice [84–86]. Apo E2 and apo E4 differ from apo E3 in a single amino acid: apo E3 has Cys at position 112 and Arg at position 158, whereas apo E2 has Cys at both of these positions, and apo E4 has Arg at both positions [87] (Fig. 2). A “domain interaction” has been identified between Glu-255 in the C-terminal domain of apo E4 and Arg-61 in the Nterminal domain, and this interaction is enhanced by the presence of Arg-112 in apo E4 [47,88]. Although mouse apo E is similar to human apo E4, in that it contains Arg at position 112 [89], mouse apo E lacks Arg-61 (Fig. 2). Thus, the domain interaction between Arg-61 and Glu-255 is prevented so that mouse apo E behaves functionally like human apo E3. When Thr-61 of mouse apo E was replaced with Arg, the domain interaction was introduced and the Arg-61 mouse apo E behaved like human apo E4 [90]. Interestingly, these Arg-61 mice exhibit defects in synaptic transmission. Furthermore, in astrocytes derived from the mice that expressed Arg-61-apo E, an ER stress response was activated leading to impaired astrocyte function [91]. The interaction domain of apo E4 has been proposed to promote the preferential association of apo E4 with large lipoprotein particles, such as very low density lipoproteins (i.e. VLDLs), whereas apo E3 preferentially associates with smaller particles (i.e. HDLs) [88]. Despite the strong connection between apo E isoforms and AD, the mechanisms by which apo E4 influences the onset and progression of this disease have not yet been clearly defined. One attractive hypothesis is that apo E plays a key role in the deposition and/or clearance

Fig. 2. Schematic representation of apo E isoforms in humans and rodents. Humans express 3 major isoforms of apo E: E2, E3 and E4 that differ from each other in a single amino acid. Apo E2 contains Cys at positions 112 and 158, whereas apo E3 contains Cys at position 112 and Arg at position 158. Apo E4 contains Arg at both 112 and 158. A “domain interaction” occurs between Arg-61 and Glu-225 and this occurs more readily for apo E4 than for apo E3 because the interaction is promoted by Arg-112. Rodent apo E is like human apo E4 in that it contains Arg-112. On the other hand, rodent apo E lacks Arg-61 and therefore cannot participate in domain interaction and is functionally like apo E3.

of the amyloid ß peptide (Aß) since apo E binds Aß in vivo (reviewed in [74]) (see Section 9). In support of this idea, mice that express human apo E4 develop 2.5-fold more amyloid deposits than do mice that express human apo E3 [92]. Apo J is another apolipoprotein that is abundant in the CNS and has been linked to AD. Two groups have recently performed largescale genome-wide association studies which independently identified a new single nucleotide polymorphism on the APOJ gene that was associated with AD [93–95]; both groups identified the same locus (rs11136000) on the APOJ gene. Apo J appears to function in a manner similar to apo E in lipid metabolism and transport in the CNS, although much less is known about apo J compared to apo E. Apo J has been reported to be a carrier of Aß across the blood–brain barrier [96,97] and to suppress Aß deposition in the brain [98,99]. Further studies are required to confirm the correlation between apo J and AD, and to determine the mechanism(s) by which mutations in apo J modulate Aß metabolism. 4. Generation of apo E-containing lipoproteins in the CNS Apo E expression in the brain is a highly regulated process. For example, after nerve injury apo E synthesis increases in astrocytes by as much as 150-fold [50,54,100,101]. In addition, the expression of apo E was markedly increased in cultured neurons at the level of mRNA (by 3- to 4-fold) and protein (by 4- to 10-fold), upon the addition of conditioned culture medium from an astrocytic cell line or from astrocytes isolated from Apo E−/− mice. This observation suggested that astrocytes secrete a factor that stimulates apo E expression in neurons although this factor has not yet been identified [46]. The principal cells that secrete apo E in the CNS are astrocytes; microglia also secrete small amounts of apo E [102]. Studies with chemical inhibitors indicate that protein geranylgeranylation is required for apo E secretion by mixed glial cultures [103] although the mechanism underlying this requirement is unknown. Apo E can also be synthesized in small amounts in neurons of the hippocampus and cortex, but not the cerebellum [104]. Nevertheless, apo E is expressed at low levels in hippocampal neurons only in response to excitotoxic injury [69,105]. Thus, neurons represent a quantitatively minor source of apo E in the brain. There appears to be some redundancy in the expression of apo E and apo D in the brain since in ApoE−/− mice the level of apo D, another apolipoprotein that is abundant in the brain, was increased 50-fold [106]. Apo J is also abundant in the CNS and, like apo E, is secreted by astrocytes [107,108]. Levels of apo J in the CNS are increased in response to nerve injury [109,110]. In addition, apo J levels in the brains of AD patients were shown to be higher than in control subjects. Furthermore, brain levels of apo J correlate with gene dosage of the ε4 allele [111]. In combination, these data suggest that maintenance of normal levels of apolipoproteins, such as apo E, apo J and apo D, in the CNS is important for brain function and neuronal survival. As has been proposed for the formation of plasma apo A1-containing HDLs [112–114], two poorly characterized mechanisms have been suggested for the generation of apo E-containing HDLs by glial cells: the direct secretion of lipidated apo E, and the secretion of lipidfree, or lipid-poor, apo E that is further lipidated extracellularly upon the efflux of cellular lipids. During the formation of plasma HDLs, the initial acquisition of cholesterol and phospholipids by apo A1 requires the action of the ABC transporter ABCA1 [115,116]; further lipidation of the partially-lipidated apo A1 to mature HDL is subsequently mediated by another ABC transporter, ABCG1 [35,36,117]. Thus, the nature of the extracellular acceptor for lipid efflux appears to be different for ABCA1 and ABCG1: lipid efflux mediated by ABCA1 prefers lipid-poor acceptors, whereas ABCG1 prefers lipidated acceptors such as HDLs. The role of ABC transporters in the brain is incompletely understood and it is not yet known if a parallel sequence of events

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involved in formation of plasma HDLs also operates for the formation of apoE-containing lipoproteins in the CNS. Nevertheless, ABCA1 and ABCG1 are expressed in the brain, in both neurons and glial cells [118–123], suggesting that these transporters participate in the formation of apo E-containing lipoproteins in the brain (Section 5). The nascent apo E-containing lipoproteins secreted by astrocytes are discoidal and contain little lipid — primarily unesterified cholesterol and phospholipids with essentially no cholesteryl esters [38,42, 124]. In plasma, the formation of mature, spherical HDLs requires the action of lecithin:cholesterol acyltransferase (LCAT), an enzyme that converts unesterified cholesterol to cholesteryl esters by transfer of a fatty acyl moiety from a phospholipid molecule. Although LCAT is expressed mainly in the liver, this enzyme is also expressed in the brain, primarily in astrocytes [124]. In humans, the concentration of LCAT in CSF is only 5% of that in plasma. However, glia-derived nascent apo E-containing lipoproteins are substrates for LCAT [124]. These observations indicate that LCAT might play a role in the maturation of nascent, glia-derived, apo E-containing lipoproteins in the brain. Interestingly, although phosphatidylcholine is by far the major phospholipid in plasma HDLs, most of the phospholipid in apo Eand apo J-containing lipoproteins in the CNS has been reported to be phosphatidylethanolamine [42]. The significance of this unusual phospholipid composition remains to be established. The brains of human apo E4 knock-in mice contain less apo E than do the brains of human apo E3 knock-in mice, and conditioned medium isolated from astrocytes of apo E3-expressing mice contains more apo E than does that from apo E4 knock-in mice [125]. Pulsechase experiments in astrocytes have suggested that the rate of degradation of apo E4 is greater than that of apo E3 [125]. Several studies have investigated whether or not the isoform of apo E determines how much lipid becomes associated with apo E. In primary cultures of neurons and astrocytes, the addition of recombinant human apo E isoforms promoted the efflux of cholesterol and phospholipids in an apo E isoform-specific manner and generated lipoprotein particles that were the size of HDLs. The order of potency of the apo E isoforms for lipid efflux was apo E2Napo E3Napo E4 [126]. In addition, a recent study showed that 2.5- to 3.9-fold more cholesterol and phospholipids were effluxed from rat cortical astrocytes and neurons to recombinant human apo E3 than to apo E4 [127]. Furthermore, the 22 kDa N-terminal, lipid-binding fragment of apo E3 induced more cholesterol efflux than did the same region of apo E4 [127]. A similar isoform specificity was observed for the lipidation of apo E that was synthesized endogenously by astrocytes: in astrocytes isolated from mice lacking endogenous apo E, but expressing human apo E isoforms, approximately twice as much cholesterol and phospholipid was released to apo E3 compared to apo E4 [126]. The molar ratio of cholesterol:apo E in the astrocyte-derived lipoprotein particles was 250 for apo E3 and 119 for apo E4. Since the size of the secreted particles was not affected by the isoform of the apo E these data implied that apo E4-containing lipoprotein particles contained fewer apo E molecules per particle than did the apo E3-containing particles. On the basis of these observations, the authors proposed that lipoproteins that contain apo E4 are less able to supply cholesterol to neurons than are those that contain apo E3 [126]. Overall, currently available data support the idea that more lipid is effluxed from astrocytes to apo E3 than to apo E4. 5. ABC transporters and formation of apo E-containing lipoproteins in the brain Members of the ABC transporter superfamily are key players in the regulation of formation of apo E-containing lipoproteins in the brain ([119]; reviewed in [122,128]). In plasma, the initial lipidation of apo A1 by cholesterol and phospholipids for generation of HDLs requires the action of the ABC transporter ABCA1 [115,116], followed by further lipidation in a process mediated by ABCG1 [35,36,117].

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In fibroblasts, human apo E3-containing HDLs from plasma form a complex with ABCA1, and lipid-free apo E inhibits formation of this complex [129]. The apo E-ABCA1 interaction does not appear to depend on the isoform of apo E since apo E2, apo E3 and apo E4 bind to ABCA1 with similar affinity and exhibit the same kinetics for ABCA1mediated cholesterol efflux [129]. Whether or not a parallel process operates for the formation of apo E-containing lipoproteins in the CNS is not yet clear, but both ABCA1 and ABCG1 appear to be involved in formation of apo E-containing lipoproteins by glia. The importance of ABCA1 for the lipidation of apo E in the brain is underscored by experiments performed in ABCA1 knock-out mice [130,131]. ABCA1 deficiency in mice reduced the amount of cholesterol in the CSF by 24% although the cholesterol content of the whole brain was not reduced. The apo E-containing lipoprotein particles in the CSF of Abca1−/− mice were smaller and contained less lipid than did those from Abca1+/+ mice, indicating that ABCA1 is required for the normal lipidation of apo E [130,131]. Moreover, ABCA1 deficiency reduced the size of the apo E-containing lipoproteins secreted by astrocytes and the amount of cholesterol that was effluxed to the particles [130,131]. Since some apo E-containing lipoproteins were secreted by ABCA1-deficient astrocytes it is likely that an additional mechanism, that does not require ABCA1, also exists for the lipidation of apo E. Global elimination of ABCA1 in mice markedly reduced the amount of apo E in the cortex and CSF (by 80% and 98%, respectively) although the level of apo E mRNA in the whole brain was unchanged [130]. These observations suggested that the lower amount of apo E in brains of Abca1−/− mice was due to increased degradation, rather than decreased production, of apo E. Some apparently contradictory data have been reported on whether or not ABCA1 regulates apo E secretion by astrocytes. In one study, in which the amounts of apo E in astrocyte culture medium were measured after 3 days, ABCA1 deficiency did not reduce the amount of apo E in the medium [130]. In contrast, in another study, ABCA1 deficiency reduced the amount of apo E in the culture medium of astrocytes by ∼ 50% after 6 h, and in the medium of microglia after 8 h [131]. A possible explanation for these apparently conflicting results is that after 3 days the steady state amount of apo E in the culture medium represents both newlysecreted and re-secreted [132] apo E, whereas after only 6 h the medium contains primarily newly-secreted apo E [131]. If this reasoning were correct, the large decrease in apo E in brains of ABCA1-deficient mice could be a consequence of impaired secretion of apo E by astrocytes. In a more recent study, ABCA1 expression was eliminated specifically in neurons and glia of mice, resulting in a slight reduction in cholesterol levels in the brain [123]. Motor activity and synaptic ultrastructure of the brains of the knock-out mice were altered and the number of synaptic vesicles was reduced. In summary, the experiments with ABCA1 knock-out mice demonstrate that the level of apo E in the CNS in vivo is dictated by ABCA1. Furthermore, ABCA1 is required for the production of normally-lipidated apo E by astrocytes both in vitro and in vivo. Interestingly, however, the lipidation of apo J does not depend on ABCA1 expression, consistent with the idea that apo E and apo J reside on distinct lipoprotein particles, and that apo E- and apo J-containing glial lipoproteins are assembled by independent mechanisms [131]. ABCG1 is another ABC transporter that is involved in lipid efflux to apo A1 during HDL formation in the peripheral circulation ([35, 36,117,133]; reviewed in [134]). ABCG1 and the related transporter, ABCG4, are highly expressed in astrocytes and neurons [120,121, 135,136]. ABCG4 is also highly expressed in microglia, particularly in AD brains [137]. The involvement of ABCG1 in lipid efflux from mouse cerebellar astrocytes to apolipoprotein acceptors has been investigated. Cholesterol efflux to apo A1 correlated more highly with the expression of ABCG1 than ABCA1 [120]; for example, cholesterol enrichment of cerebellar astrocytes increased the expression of ABCG1 and the efflux of cholesterol, but without increasing ABCA1 expression [120].

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Mice lacking ABCG1 and/or ABCG4 have been generated to examine the role of ABCG1 and ABCG4 in sterol metabolism in the brain [117,122,135]. Elimination of ABCG1 or ABCG4 individually did not alter the amount of cholesterol in the brain or in isolated astrocytes, but did increase the amount of the cholesterol biosynthetic intermediate, desmosterol, in the brain and astrocytes by ∼40% [135]. Although, a deficiency of neither ABCG1 nor ABCG4 independently reduced cholesterol efflux from astrocytes to HDLs, simultaneous elimination of both of these ABC transporters reduced cholesterol efflux by ∼ 30% [135]. Thus, ABCG1 and ABCG4 appear to have overlapping functions in promoting sterol efflux from astrocytes. Major unresolved questions about the function of ABCG1 in the brain include: what is the primary intracellular site of action of ABCG1? Which lipids, if any, are transported by ABCG1? Do ABCA1 and ABCG1 sequentially lipidate astrocyte-derived apo E in a process parallel to that used for HDL formation in the peripheral circulation? The expression of ABCA1 and ABCG1 in macrophages and fibroblasts is markedly increased by activation of the transcription factor LXR (liver X receptor) [138–140]. The natural ligands for LXR are oxysterols whose cellular levels generally reflect the cellular cholesterol content (reviewed in [141]). LXR exists as two isoforms, α and ß, both of which are expressed in neurons and glial cells in the brain, primarily in the hippocampus and cerebellum [142]. The expression and secretion of apo E by glial cells is enhanced by LXR agonists [120,139,143,144]. Moreover, apo E production (mRNA and protein) and secretion by astrocytes, but not neurons, are increased by 24-hydroxycholesterol, an endogenous LXR ligand in the brain [145]. As was anticipated from studies in other cell types, treatment of cerebellar astrocytes with the LXR agonist TO901317 increased the expression of ABCA1 and ABCG1, and correspondingly increased the total amount of ABCA1 protein, as well as the amount of ABCA1 on the cell surface [120]. However, the amount of radiolabeled cholesterol and cholesterol mass effluxed to apo A1 was not increased by the LXR agonist unless the cells had been loaded with cholesterol [120]. On the other hand, treatment of macrophages and fibroblasts with an LXR agonist increased the expression of ABCA1 and ABCG1 and correspondingly increased the efflux of cholesterol to apo A1 [138–140]. These observations suggest that some aspects of the requirement of ABCA1 and ABCG1 for formation of apo E-containing lipoproteins by astrocytes differ from those in the formation of plasma HDL. 6. Apo E receptors in the CNS The apo E-containing lipoproteins secreted by astrocytes can bind to, and be internalized by, receptors of the LDL receptor superfamily that are located on the cell surface of neurons [101]. For example, human LDLs can bind to, and be internalized and degraded by, primary hippocampal neurons and astrocytes [146]. In addition, apo E-containing lipoproteins isolated from rat sciatic nerves were taken up by primary neurons and Schwann cells, probably in a LDL receptordependent endocytic process [147]. Both the lipid and protein components of LDLs and HDLs that are taken up by axons of cultured sympathetic neurons are retrogradely transported into cell bodies [148]. Several receptors of the LDL receptor superfamily [for example the LDL receptor, the LDL-receptor-related protein (LRP1), the very low density lipoprotein (VLDL) receptor and the apoE receptor-2 (apo ER2)], for which apo E is a high affinity ligand, are expressed in neurons [148–153]. Many of these receptors are also present in astrocytes, microglia and oligodendrocytes [154]. However, only the LDL receptor appears to be up-regulated by cholesterol deficiency and downregulated by cholesterol enrichment [154]. In cells of the brain, lipidated, but not un-lipidated, apo E is a high affinity ligand for the LDL receptor [155]. In cells that lacked the LDL receptor, the endocytosis of astrocyte-derived apo E-containing lipoproteins was impaired, and apo E levels in the CSF of LDL receptor knock-out mice were

50% higher than in mice that expressed the LDL receptor [156]. However, in the APP mouse model of AD, lack of the LDL receptor did not significantly increase Aß accumulation in the brain [157,158]. On the other hand, in mice that over-expressed LDL receptors in the brain, apo E levels were markedly reduced (by 50–90%, depending on the level of over-expression of the LDL receptor) [159]. These observations suggest that, as in other tissues, LDL receptors in the brain endocytose apo E-containing lipoproteins. Interestingly, even a 2-fold increase in the level of expression of the LDL receptor markedly decreased amyloid plaque load in female APP mice, and decreased the associated neuroinflammation [159]. Thus, the level of expression of LDL receptors in the brain appears to be an important factor in regulating brain apo E levels as well as Aß aggregation. The LDL receptor is more highly expressed in glial cells than in neurons whereas the related receptor, LRP1, is more highly expressed in neurons than in glia [160–162]. A 3.7-fold over-expression of LRP1 in the brain modestly reduced (by 25%) the level of apo E in mouse brains but increased Aß levels [163]. It is possible that the increase in Aß was due to a direct effect of LRP1 on APP independent of the effect of LRP1 on apo E. Nevertheless, both the LDL receptor and LRP1 are able to regulate the amount of apo E in the brain. In addition to LDL receptor family members acting as receptors for the endocytosis of lipoproteins, some of these lipoprotein receptors can bind and internalize a diverse spectrum of ligands. For example, LRP1 binds more than 30 ligands including apo E, α2-macroglobulin, Aß and amyloid precursor protein, APP ([164]; reviewed in [74]). Lipid-free apo E is a relatively poor ligand for LRP1 but the affinity of the receptor for apo E is markedly enhanced when the apo E is associated with lipid [155]. LRP1 is essential for early embryonic development [165]. Moreover, adult mice that lacked LRP1 specifically in neurons had defects in synaptic transmission and motor function whereas brain morphology was normal [166,167]. Unlike the LDL receptor, LRP1 can operate as a signaling receptor in the brain [151, 152,168–171], for example, in regulating calcium signaling [172,173], long-term potentiation [174], neurite growth [52,175], brain development [176] and neuronal survival [153,177,178]. LRP1 function has also been implicated in AD. The LRP1 ligand, α2-macroglobulin, forms a complex with Aß, facilitates Aß clearance, and prevents the formation of insoluble Aß fibrils (reviewed in [74,179]). In addition, LRP1 interacts with APP and enhances the processing of APP to Aß [180, 181]. The proposal that mutations in LRP1 and α2-macroglobulin are associated with AD [182,183] remains controversial. Related receptor family members, LRP5 and LRP6, are co-receptors in the Wnt signaling pathway that regulates brain development [184–187]. Thus, receptors of the LRP family clearly play important roles in brain function. The VLDL receptor is another LDL receptor family member that is expressed in mammalian brain and in cortical neurons [188]. This receptor binds to apo E-containing lipoproteins and mediates lipoprotein uptake by neuronal growth cones, presumably as a mechanism for acquisition of lipids for membrane expansion [189–191]. The VLDL receptor, and the related apoER2 receptor which is also expressed in neurons [148,192], control neuronal survival and are key players in the Reelin signaling pathway that determines neuronal migration during brain development. This pathway is crucial for dendritic spine development and synaptic plasticity since in mice lacking both of these receptors those neuronal functions were severely impaired [193–197]. Reelin binds to the ligand-binding domain of the VLDL receptor and the apoER2 receptor [198] thereby promoting tyrosine phosphorylation of the neuronal adapter protein, Disabled-1. The binding of apo E to these LDL receptor family members reduces the Reelin-induced phosphorylation of Disabled-1 [151] and regulates microtubule function [169]. A more distantly related family member, LR11/SorLA, is a cytosolic protein that is involved in intracellular protein trafficking [199]. SorLA binds to apo E and is highly expressed in the brain, particularly in

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the hippocampus. This LDL receptor family member is predominantly expressed in neurons [200] where it was detected in cell bodies, but not distal axons [148]. SorLA is required for early development of the CNS [201] and for cellular proliferation and differentiation [199, 202,203]. Intriguingly, the levels of SorLA are significantly lower in the brains and CSF of AD patients than in brains of unaffected individuals [204,205]. Moreover, disruption of the SorLA gene in mice increases the level of the Aß peptide in the brain [206], whereas over-expression of SorLA in neurons decreases the processing of APP and the concomitant production of Aß [206]. These observations provide tantalizing indications that defects in SorLA function might be directly related to AD pathology. Thus, it will be important to understand in more detail the relationship between SorLA and AD, and to dissect further the functions of SorLA in the brain. In summary, receptors of the LDL receptor superfamily perform diverse physiological roles in the brain. Several of these family members, whose primary function was originally thought to be in the delivery of lipids via endocytosis, are now known to act as signaling receptors in the brain in response to the binding of apo E-containing lipoproteins.

7. Lipid synthesis, apo E and axonal growth Axonal extension requires a supply of lipids for membrane expansion. The dependence of axonal elongation on lipid synthesis was investigated using a novel compartmented system for culture of rodent primary neurons in which cell bodies and distal axons reside in separate compartments of 3-compartment culture dishes [207–209]. In these neuronal cultures, metabolic events occurring in distal axons can be studied independently of those in cell bodies, the rate of axonal elongation can be accurately measured, and the transport of molecules between cell bodies and distal axons can be monitored. In compartmented cultures of rat sympathetic neurons, radiolableing experiments demonstrated that phospholipids are synthesized in both cell bodies and distal axons [210] whereas cholesterol synthesis is restricted to cell bodies/proximal axons [211]. However, newlysynthesized cholesterol is efficiently transported into distal axons [150]. When neuronal cholesterol synthesis was inhibited by pravastatin the rate of axonal elongation was reduced by 50% [150]. Nevertheless, the addition of cholesterol or plasma lipoproteins to distal axons restored a normal rate of axonal growth [148,150]. Several studies indicate that apo E-containing lipoproteins stimulate axonal growth. For example, neurite extension of rabbit dorsal root ganglion neurons in vitro was increased in the presence of ß-VLDL particles that had been enriched with rabbit apo E [212]. In addition, when physiologically-relevant apo E-containing lipoproteins secreted by cultured rat astrocytes were supplied to primary cultures of rat retinal ganglion cells (neurons of the CNS), axonal elongation was enhanced in a process that was mediated by a receptor of the LDL receptor family [52]. One factor that potentially contributes to the well-established relationship between apo E isoforms and AD susceptibility is that apo E3 stimulates axonal extension whereas apo E4 either inhibits, or has no effect on, this process (reviewed in [213]). In primary cortical neurons from mice, neurite growth was increased by recombinant unlipidated E3, but decreased by apo E4 [214]. In addition, human apo E3-enriched ß-VLDLs increased neurite extension of primary neurons whereas apo E4-enriched ß-VLDLs reduced neurite growth [215]. Similarly, apo E4-enriched ß-VLDLs reduced neurite outgrowth of neuron-like Neuro2a cells and dorsal root ganglion neurons, whereas apo E3-enriched ß-VLDLs increased neurite extension [215,216]. Since ß-VLDL is a lipoprotein that is not present in the CNS, additional studies have been performed with more physiologicallyrelevant apo E-containing lipoprotein particles. However, the conclusions are essentially the same. Neurons that were grown in the

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presence of apo E3-secreting astrocytes exhibited greater neurite outgrowth than did neurons grown in the presence of apo E-deficient astrocytes, or astrocytes that secreted apo E4 [217]. Moreover, axonal growth of retinal ganglion neurons was stimulated to a greater extent by astrocyte-derived apo E3-containing lipoproteins than by apo E4-containing lipoproteins (M. Matsuo and J.E. Vance, unpublished observations). In addition, apo E4-containing HDLs from mouse CSF did not enhance neurite growth whereas apo E3-containing HDLs from CSF promoted neurite outgrowth in a process that was blocked by anti-LRP antibodies [218]. Several similar studies have also indicated that LRP1, and/or other apo E receptors, mediate the stimulatory effect of apo E-containing lipoproteins on neurite growth [52,175, 214,218–220]. Although the majority of apo E in the CNS is synthesized by glial cells, experiments on axonal growth have also been performed in apo E-expressing neuron-like cells. For example, when human apo E3 and apo E4 were expressed in Neuro2a cells, neurite growth was greater in the apo E3-expressing cells than in the apo E4-expressing cells, and the apo E3-mediated stimulation of growth was abrogated by an antibody directed against LRP [175,220]. The authors concluded that the differential effects of apo E3 and apo E4 on neurite growth were not attributable to differences in delivery of lipid from the Neuro2aderived apo E3- and apo E4-containing particles since these particles had similar lipid compositions [221]. Indeed, the apo E-containing particles secreted by the Neuro2a cells contained very little lipid (primarily phospholipid with only a trace of cholesterol – 1 mole cholesterol/ mole apo E – and no detectable neutral core lipids). Although only a few studies have been performed on axonal growth in response to apo E isoforms in vivo, mossy fiber sprouting was defective in apo E knock-out mice, and the expression of apo E3 restored normal sprouting more efficiently than did apo E4 [222]. Thus, a wide range of studies, performed in different cell types, and with different types of apo E-containing lipoprotein particles, strongly indicate that apo E3containing lipoproteins promote neurite growth whereas apo E4containing lipoproteins either do not stimulate neurite extension or are inhibitory. Uncertainty remains, however, regarding the mechanism(s) underlying the differential effects of apo E isoforms on axonal extension. One possible mechanism is that the apo E isoforms bind with different affinities to one of the LDL receptor family members on neurons, thereby differentially initiating a signaling pathway that mediates axonal growth. Another possible mechanism is that apo E3 accumulates within neurons to a greater extent than does apo E4 [223,224]. In this case, the apo E isoform-specific effects on axonal growth might be attributable to differences in the amounts of intracellular apo E which have been proposed to affect the structure of the cytoskeleton and microtubule assembly. Indeed, microtubule formation was enhanced by apo E3 in cultured neuronal cells whereas apo E4 destabilized microtubule assembly [223]. This proposal is supported by the finding that apo E3 interacts more readily than apo E4 with tau and prevents tau hyperphosphorylation which, as a result, might reduce the formation of intracellular neurofibrillary tangles (deposits of tau), a hallmark of AD disease [225]. Nevertheless, this mechanism is controversial since it would imply that apo E is present in the cytosol of neurons and that endocytosed apo E escapes from degradation in the endosomal–lysosomal system [226]. Another study found no evidence that apo E escapes from the endocytic pathway into the cytosol, and also reported that the expression of apo E in the cytosol is toxic [227].

8. Apo E and apoptosis The loss of neurons by apoptosis is a characteristic of several neurodegenerative disorders including AD. The role of apo E in promoting or preventing neuronal apoptosis has been extensively

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examined in a variety of model systems. Interestingly, when apoptosis was induced in human neuron-like cells by withdrawal of trophic factors, apo E expression increased dramatically: by 6-fold for apo E mRNA, and by 8-fold for apo E protein [228]. These observations suggested that during apoptosis apo E expression is increased as a mechanism for mediating the clearance of apoptotic bodies. Apo E-containing lipoproteins can protect neurons from apoptosis. For example, apoptosis was induced in primary cultures of rat CNS neurons (retinal ganglion cells) by withdrawal of trophic factors. However, when apo E-containing lipoproteins secreted by cultured rat astrocytes were supplied to the neurons, the apoptosis was strikingly prevented [153]. The mechanism responsible for the increased survival was investigated: a signaling pathway was initiated upon binding of the apo E-containing lipoproteins to LRP1, whereupon phospholipase Cγ1 and protein kinase Cδ were activated, and glycogen synthase kinase 3ß (a pro-apoptotic kinase) was inactivated [153,178]. In experiments in which the apo E isoforms were supplied in the form of reconstituted HDL particles [153], or in apo E-containing particles secreted by apo E3 and apo E4 knock-in mouse astrocytes [178], the protective effect was greater for apo E3 than for apo E4 [153]. The anti-apoptotic effect required that the apo E was associated with lipids but did not require cholesterol as a component of the particles. Moreover, the uptake of the lipoprotein particles by the neurons was not required for the anti-apoptotic effect [178]. Thus, the binding of apo E to LRP1 on the neuronal cell surface activates a signaling cascade that promotes neuronal survival in the absence of lipoprotein uptake. In other studies, apo E4 promoted apoptosis in a neuroblastoma cell line via a LRP-dependent pathway [229]. Furthermore, LRP1 is required for survival of primary neurons under conditions of stress (i.e. after withdrawal of trophic factors and in response to Aß-induced toxicity) [177]. In these studies, when LRP1 expression was attenuated, neuronal apoptosis increased, and the amounts of the insulin receptor and phosphorylated Akt were reduced. In addition, the extent of neuronal apoptosis was greater in brains of mice lacking LRP1 than in control mice [177]. Thus, apo E and LRP1 play key roles in neuronal survival. Numerous additional studies, in a variety of experimental systems, have indicated that apo E4 is more neurotoxic than apo E3. For example, serum from humans carrying two ε4 alleles was less antiapoptotic than was serum from carriers of the ε3 allele [230]. In addition, purified apo E4 was more toxic to neurons than was apo E3 [231,232], and apo E3 was more protective than apo E4 against oxidative stress-induced death of neuron-like cells [233]. Moreover, in rat hippocampal neurons that were incubated with medium conditioned by HEK-293 cells that expressed apo E3 or apo E4, the apo E4containing medium was neurotoxic whereas medium that contained apo E3 was not [234]. In in vivo studies, apo E3 knock-in mice were protected against age-related, and kainic acid-induced, neurodegeneration whereas apo E4 knock-in mice were not [235]. Importantly, knock-in mice that expressed both apo E3 and apo E4 exhibited the same extent of neurodegeneration as did apo E4-only mice, demonstrating that the detrimental effects of apo E4 “trumped” the beneficial effect of apo E3 [235]. The isoform-specific neurotoxic effects of apo E were also investigated under conditions of reduced cholesterol synthesis. Primary rat cortical neurons were incubated with a sublethal concentration of compactin, an inhibitor of cholesterol synthesis. Incubation of these cells with ß-VLDLs that were enriched with apo E4, but not apo E3, induced neuronal death in a process that exhibited many of the hallmarks of apoptosis [236]. Consequently, a reduced level of cholesterol synthesis in the brain, as occurs during aging, is potentially a factor that might exacerbate the neurotoxicity of apo E4. Other studies have suggested that intracellular apo E4 (but not apo E3) destabilizes lysosomal membranes in neurons thereby contributing to the reduced survival of neurons exposed to apo E4 compared to apo E3 [237]. Overall, currently available data indicate that apo E4 is neurotoxic.

9. Apo E and Aß deposition Two hallmarks of AD brains are extracellular amyloid plaques and intracellular neurofibrillary tangles. The accumulation of amyloid deposits in the brain is a central event in AD pathogenesis [238,239]. Since the steady state level of Aß in the brain reflects the balance between the production and removal of Aß, the buildup of Aß could be a consequence of either inefficient clearance or over-production of Aß, or both. Apo E has been co-localized with amyloid deposits in plaques and also in neurofibrillary tangles in the brains of AD patients [240]. In mice, the amount of apo E in the brain appears to dictate how much Aß is deposited in vivo. For example, apo E deficiency in mouse models of AD, such as the APP mice, dramatically reduces amyloid load [241,242]. Furthermore, apo E-deficient mice lack fibrillar plaques and do not develop neuronal dystrophy; a gene dosage effect was evident [241–243]. However, in brains of AD patients the levels of apo E are not markedly different from those in unaffected individuals, nor does the amount of apo E in CSF of subjects appear to depend on apo E isoform [244,245]. Although there are some conflicting data, the general consensus is that the amount of apo E in brains of apo E4 knockin mice is lower than in apo E3 knock-in mice [125,156,246,247], although apo E4 knock-in mice develop more amyloid plaques than do mice that express similar levels of apo E3 [92,248,249]. Consequently, since lower levels of apo E appear to decrease amyloid burden in mice [159,241–243] additional studies will be required to reconcile these apparently discordant findings. Interestingly, when human apo E isoforms were expressed in the APP mouse model of AD, the deposition of Aß was delayed compared to that in mice that expressed either no apo E or murine apo E [92, 242,249]. Nevertheless, the human apo E4-expressing mice produced more Aß deposits in the hippocampus than did the human apo E3expressing mice [92,235,249]. Similar observations were made when human apo E isoforms were expressed in another transgenic mouse model of AD [243]. Moreover, in in vitro studies, the toxicity of Aß peptides in human cortical neurons was enhanced by apo E4, but not apo E3 [234,250], and in Neuro2a cells, the expression of apo E3, but not apo E4, protected the cells from Aß-induced toxicity [237]. Whether or not the processing of APP and the production of Aß depend on the isoform of apo E remains controversial (reviewed in [251]). In vitro binding studies indicate that apo E promotes the clearance of Aß via a physical interaction between the two proteins. Residues 12–28 of Aß have been identified as the binding site for apo E [72,252], whereas the binding site for Aß is in the C-terminal domain of apo E, in a region that overlaps the lipid-binding site [72,253]. Although there are some contradictory data regarding the isoform specificity of the binding of apo E to Aß (reviewed in [251]), most studies have concluded that the efficiency of complex formation between apo E and Aß is in the order: apo E2Napo E3NNapo E4 [72,254,255]. Consequently, the risk of developing AD appears to be inversely correlated with the efficiency with which the apo E isoforms bind to Aß, because formation of a complex between apo E and Aß promotes the removal of Aß from the brain [92,249]. Although all three apo E isoforms increase the generation of Aß fibrils [256], apo E3 is less effective than apo E4 in stimulating this process [257,258]. In light of the ability of apo E to form a stable complex with Aß, and the isoform dependence of this binding, it has been proposed that apo E2 and apo E3, in preference to apo E4, clear Aß through endocytosis of the Aß-apo E complex via apo E receptors such as LRP1 and the VLDL receptor, both of which can bind Aß as well as Aß–apo E complexes on the neuronal surface [259,260]. The endocytosed Aß would, therefore, be expected to be delivered to the lysosomes for degradation. Thus, according to this mechanism, apo E3 would be more efficient than apo E4 in promoting Aß degradation [261]. Interestingly, elimination of the LDL receptor in an APP mouse model of AD did not alter the level of Aß suggesting either that this receptor does not

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participate directly in AD-related pathology or that compensatory mechanisms are implemented [156]. Several proteolytic enzymes that degrade Aß directly have been detected in the brain and are likely to play a role in Aß clearance, perhaps in an apo E isoform-dependent manner [261,262]. Another factor that influences the amount of Aß deposited is the extent of lipidation of the apo E. Lipid-free and lipid-bound apo E exist in different conformations [263] and the affinity of lipidated apo E for soluble Aß is greater than that of poorly-lipidated apo E. As discussed above (see Section 5), ABCA1 is required for normal lipidation of apo E in the brain. The role of apo E lipidation in amyloid deposition was, therefore, examined in three different mouse models of AD in which ABCA1 expression was eliminated [118,264,265]. In these three studies, ABCA1 deficiency reduced the amount of apo E in the brain by 75–85% but did not affect APP processing or Aß production. In two of these studies, Aß deposition was increased by ABCA1 deficiency [118,265], whereas in the other study, ABCA1 deficiency did not significantly increase amyloid deposition [264]. The observed increase in the amount of Aß was attributed to reduced degradation of Aß in response to the generation of poorly-lipidated apo E particles in the absence of ABCA1. In support of a role for ABCA1 and apo E lipidation in promoting Aß clearance in vivo, a 6-fold over-expression of ABCA1, specifically in the brains of APP mice via the PrP promoter, markedly decreased the conversion of soluble Aß to mature amyloid [266]. The increased lipidation of apo E in the ABCA1-over-expressing mice was proposed to be responsible for the decreased deposition of Aß in vivo. The role of ABCG1 in amyloid deposition was also investigated in in vitro studies and in mouse models. The expression of ABCG1 in human embryonic kidney cells that expressed APP with the Swedish mutation increased Aß production by ∼ 30% [267]. In contrast, expression of ABCG1 in Chinese hamster ovary cells that expressed APP, decreased Aß production by 64% [268]. The reasons for these apparently conflicting observations are not clear. However, in a transgenic mouse model in which ABCG1 was over-expressed 6-fold, the levels of Aß and amyloid deposition in the hippocampus and cortex were not altered [269]. Thus, over-expression of ABCG1 does not appear to markedly affect amyloid deposition in vivo. Future studies in mouse models of AD in which ABCG1 expression has been eliminated will help to clarify the role, if any, of ABCG1 in Aß deposition in an in vivo setting. The nuclear receptor LXR increases the expression of ABCA1 and ABCG1 and also increases the expression of apo E (see Section 5). Since elimination of apo E expression in mice reduced Aß deposition, the activation of LXR was, therefore, predicted to increase amyloid load. Contrary to expectations, however, in mouse models of AD, the LXR agonist TO901317 decreased Aß deposition [270–272] and preserved cognitive function [272]. Furthermore, AD neuropathology was exacerbated in mice that lacked both LXRα and LXRß [273]. These observations are consistent with the idea that the increased lipidation of apo E, rather than reduction in the amount of apo E, correlates with the decreased deposition of Aß [255,260,274]. It is appropriate to mention briefly another apolipoprotein – apo A1 – that is a component of HDL-like lipoproteins in the CNS. Similar to apo E, apo A1 binds to Aß and prevents the aggregation and toxicity of Aß in vivo [275,276]. However, in contrast to apo E deficiency, deficiency of apo A1 does not ameliorate amyloid pathology [277]. In conclusion, the mechanisms underlying the intriguing correlation between inheritance of the ε4 allele of apo E and the occurrence and progression of AD are beginning to be dissected at the molecular level. An important component of this inter-relationship is the generation of lipidated apo E-containing lipoprotein particles by astrocytes in the brain. However, the precise mechanisms by which apo E influences the deposition of Aß in the CNS still need to be clarified. Two of the most likely mechanisms that are currently being considered are (i) that apo E reduces amyloid load by altering Aß metabolism, and (ii) that apo E isoforms differentially affect neuronal

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survival and/or growth independently of effects on Aß metabolism. Consequently, further studies are required to elucidate the mechanisms that underlie the connection between apo E and AD. It will also be important to resolve the issue of whether apo E is beneficial or detrimental for AD. For example, mice that lack apo E clearly exhibit neurological deficits (Section 2). On the other hand, a low level of apo E in brains of mice dramatically reduces Aß deposition (Section 9).

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