Major Apolipoproteins in the Brain
Cholesterol is a key structural component of the brain, and cholesterol transport and distribution within the central nervous system (CNS) is mediated by a lipid metabolic cycle that includes generation of apolipoproteins as lipid carriers, lipidation by cholesterol and phospholipid transporters, enzyme remodeling of these particles and their receptor-mediated uptake and turnover in cells. It is becoming increasingly appreciated that Alzheimer’s Disease (AD) patients often have comorbid conditions such as cardiovascular disease, type II diabetes mellitus, or hypertension, each of which can greatly affect lipoprotein metabolism, especially at the vessel wall and thereby possibly contribute to AD pathogenesis. Here we review the known biology of lipids and lipoproteins in the CNS and discuss how alterations in lipid metabolism may impact AD pathogenesis. Apolipoprotein E (
2. Lipid and lipoprotein metabolism in the CNS
2.1. General biology and function of lipids and lipoproteins in the CNS
The brain is the most cholesterol-rich organ in the body, with an average cholesterol content of 15-20 mg/g wet weight compared to 2 mg/g for peripheral tissues in the adult mouse . The majority of the brain’s sterol content is located in free cholesterol, 70-80% of which is in myelin. Cholesterol, sphingomyelin and phospholipids form the major structural components of cellular membranes, with cholesterol, phosphatidylcholine and phosphatidylethanolamine being the most abundant lipids in synaptic vesicles . Many lipids also participate in important signaling pathways in the brain, with lipid-mediated second messengers derived from sphingomyelin and phosphatidylinositol, activation of G- protein coupled receptors and nuclear receptor activation being particularly important [1, 3].
|• Lipid transport
• Aβ homeostasis
• BBB integrity
• Cerebrovascular health
• Innate immune response
• Reelin signaling
|• Involved in Aβ metabolism: deposition, transport across the BBB, clearance through ISF and the CSF pathways, and enzymatic degradation
• Regulation of inflammation
• ApoE4, the most established AD genetic risk factor, is associated with:
|1. Impaired Aβ degradation and clearance
2. Increased tau phosphorylation and formation of NFT
3. Ineffective lipid transport
4. Impaired synaptic integrity
5. Reduced ability to suppress inflammation
• Choroid plexus epithelial cells
|• Golgi chaperone
• Inflammatory response
• Complement regulation
• Cell Cycle regulation
• Reelin signaling
|• Third most highly associated susceptibility locus for AD.
• Potentially involved in Aβ sequestration, degradation and clearance
||• Not produced in the brain||• Reverse cholesterol transport
• Vascular endothelial health
|• AD comorbidities such as type II diabetes and hypercholesterolemia lead to apoA-I dysfunction
• Reduction of CAA, neuroinflammation, and oxidative stress in mouse models of AD
As lipids are insoluble in aqueous environments, neutral lipids are transported through bodily fluids on lipoprotein particles consisting of amphipathic apolipoproteins that surround and stabilize their lipid cargo. The general structure of mature spherical lipoproteins consists of a core of neutral cholesterol ester and triglycerides surrounded by amphipathic free cholesterol and phospholipids at the exposed surface, all of which are encapsulated by apolipoproteins . Four major lipoprotein classes, defined by their buoyant density, are found in the circulation: high density lipoproteins (HDL), low density lipoproteins (LDL), very low density lipoproteins (VLDL) and chylomicrons. While LDL, VLDL and chylomicrons are triglyceride rich, HDL is triglyceride poor, and the HDL-like lipoprotein species found within the CNS contain even less triglyceride than plasma HDL. As apolipoprotein B (apoB), the major apolipoprotein of chylomicrons, VLDL, and LDL, is not found in the CNS, lipoprotein metabolism in the brain and cerebrospinal fluid (CSF) is based entirely on a lipoprotein class that most resembles plasma HDL with respect to size, shape, and density [4-11]. In rodents, astrocytes secrete apoE-containing lipoproteins that are primarily composed of phospholipids (~6 µg/ml) and cholesterol (~13 µg/ml), 0-18% of which is found in the esterified form. These nascent lipoprotein particles are discoidal, ranging from 9-17 nm in diameter with a density of 1.00-1.12 g/ml [7, 10]. Clusterin, also known as apolipoprotein J (apoJ), is also produced by astrocytes but is secreted virtually free of lipids [7, 10, 12]. Conversely, whereas lipoprotein particles found in CSF are of a similar diameter (11-20 nm) and density (1.063-1.12 g/ml) to those secreted by astrocytes, they are distinguished by their spherical shape and a greater proportion of phospholipids and cholesterol, with approximately 70% of cholesterol found as cholesterol esters [5, 7, 8, 10, 13]. ApoE and apolipoprotein A-I (apoA-I) are the major apolipoproteins present in CSF by mass, with apolipoproteins A-II, A-IV, D, CI, CIII, and clusterin also present to a lesser extent [5, 8-11]. In the healthy CNS, lipoproteins regulate the transport, delivery and distribution of lipids. In addition, lipoproteins are also thought to regulate many functions in the CNS including inflammation, oxidative stress, vascular tone, cerebral blood flow, and blood brain barrier (BBB) integrity (Table 1) .
2.2. Apolipoproteins present in the CNS
ApoE is present at 2-10 µg/ml in human and mouse CSF [8, 13, 15, 16] and at 10-50 ng/ml in interstitial fluid (ISF) from both wild-type mice as well as in targeted replacement mice that express human apoE . ApoE is the most abundant apolipoprotein expressed within the brain, where it is synthesized and secreted by astrocytes and, to a lesser extent, microglia . Secreted apoE particles are lipid-rich, containing equal amounts of apoE and lipid, and carry cholesterol secreted by astrocytes [10, 18]. Indeed, lipidation of apoE is essential for its stability and function [19-21]. Humans express three
Brain tissue has one of the highest concentrations of clusterin, which is expressed in astrocytes, epithelial cells of the choroid plexus, and selected neuronal subsets . As a result, clusterin is present in CSF at concentrations of 4-6.5 µg/ml in healthy human adults . In humans, due to the presence of three alternative mRNA start sites, the clusterin gene
Unlike apoE and clusterin, apoA-I is not expressed in either murine or human brain [28-31], suggesting that its presence in the CNS reflects transport across the BBB and/or the blood-CSF-barrier (BCSFB) following its production from hepatocytes and enterocytes. Although
In addition to apoE, clusterin, and apoA-I, other apolipoproteins are also detected in the CNS, including apoD, apoC-I, apoC-III, apoA-II, and apoA-IV [8, 9, 11], each of which is detected in human CSF [5, 8-11]. It has been shown that apoD, an apolipoprotein with antioxidant and anti-inflammatory properties, is produced in neuroglial cells, pia mater cells, and perivascular cells in the human brain [34, 35].
2.3. Cholesterol and Phospholipid Transporters
Lipid-poor apolipoproteins receive cholesterol and phospholipids from membrane bound transporters that are part of the ABC transporter family. The ubiquitously expressed transporter ABCA1 mediates the transfer of cellular cholesterol and phospholipids from cellular membranes to lipid-poor apolipoprotein acceptors including apoA-I and apoE [36- 39], a process that is essential for the production of both plasma and CSF HDL. HDL plays a critical role in the regulation of lipid homeostasis, and is particularly important for cells such as macrophages and microglia that form part of the innate immune system. ABCA1 activity in these phagocytic cells is exquisitely sensitive to cholesterol accumulation, and by catalyzing efflux of excess cholesterol and phospholipids to apoA-I and apoE acceptors, ABCA1 activity helps to maintain intracellular cholesterol balance. In humans, mutations that block ABCA1 function cause Tangier Disease, which is characterized by a 95% loss of plasma HDL cholesterol and apoA-I levels due to rapid catabolism of lipid-poor apoA-I by the kidney. ABCA1-dependent lipidation of CNS apoE is also critical for its stability as both total body and brain-specific loss of ABCA1 in mice leads to a significant 60-80% reduction of brain and CSF apoE [20, 21, 30]. Whether ABCA1 also regulates apoE levels in the brain of Tangier Disease patients is not known. Notably, Wahrle et al. did not observe significant differences in CSF apoE levels between control subjects versus those with ten different
Highly homologous to ABCA1, ABCA7 is also abundantly expressed in microglia, oligodendrocytes, neurons, and astrocytes in both humans  and mice [42, 43]. Although the potential for ABCA7 to act as a cholesterol and/or phospholipid transporter in the CNS is unknown, when overexpressed in human embryonic kidney cells, ABCA7 can mediate the transfer of phospholipids and sphingomyelin, but not cholesterol, to lipid-poor apoA-I and apoE . The relative contribution of ABCA7 to the
Following initial lipidation, nascent HDL lipoproteins can receive additional lipids from the cholesterol transporters ABCG1 and ABCG4 , which are abundantly expressed in grey and white matter of the brain . Unlike ABCG4, whose expression appears to be restricted to neurons, astrocytes, and the retina, ABCG1 is widely expressed throughout the body and is found in the liver, intestine, lungs, kidney and spleen in addition to neurons, astrocytes, microglia, and choroid plexus epithelial cells [47, 48]. In addition to lipid efflux activity, ABCG1 and ABCG4 are also believed to regulate intracellular transport of cholesterol and sterols and vesicle trafficking in the brain [47, 48].
2.4. Enzymes involved in lipoprotein metabolism
Many enzymes involved in lipoprotein metabolism are found in CSF, although for most, their CNS expression patterns and functional roles have not been explored to the same extent as in the periphery. For example, lecithin cholesterol acyltransferase (LCAT), phospholipid transfer protein (PLTP), and cholesteryl ester transfer protein (CETP) are all detectable in brain tissue and CSF [13, 49-53] and, as they have established roles in plasma lipoprotein metabolism, it is of interest to understand whether they function similarly in the brain.
In plasma, LCAT is the enzyme responsible for generating the cholesterol ester core characteristic of mature circulating lipoproteins, including HDL. As the more hydrophobic cholesterol esters migrate to the core of the lipoprotein particle, the discoidal nascent particle takes on its mature spherical shape. LCAT-mediated esterification of cholesterol serves not only to generate mature HDL particles, but also to maintain the downward cholesterol gradient between the cell and the lipoprotein particle, enabling further cholesterol efflux . LCAT is present in human CSF at levels corresponding to 2.2-2.5% of that in serum and migrates with γ-like lipoproteins [13, 49]. In mice, LCAT is secreted mainly by astrocytes, can be activated by both apoA-I and apoE, and esterifies free cholesterol contained on glial-derived apoE-containing lipoproteins . LCAT may therefore play a role in maturation of discoidal lipoprotein particles secreted from glia to the spherical particles that circulate in CSF by catalyzing the cholesterol esterification of immature CNS lipoprotein particles [5, 7, 56].
PLTP is another enzyme intimately involved in the maturation and turnover of lipoprotein particles within the circulation and CNS. PLTP’s primary activity involves the transfer of phospholipids between HDL particles, thus modulating HDL size and composition, and transferring lipids between apoB-containing lipoproprotein particles and HDL . Within the CNS, PLTP is highly expressed by neurons, astrocytes, microglia, oligodendrocytes, BBB endothelial cells, choroid plexus ependymal cells and can be found both in brain tissue and CSF in human and animals [57-61]. Within CSF, PLTP is associated with apoE-containing lipoproteins where it actively participates in phospholipid transport [13, 62, 63] with activity corresponding to 15% of plasma levels in humans  and 23% of plasma levels in rabbits . Functionally, PLTP has been reported to regulate apoE expression and secretion by astrocytes  and participate in neuronal cell signalling .
In plasma, CETP catalyses the bi-directional transfer of cholesterol esters from HDL in exchange for triglycerides from VLDL and LDL, thereby reducing circulating HDL concentration and increasing its size . CETP can potentially diffuse through the BCSFB and enter the brain from plasma. However, it is not clear whether CETP is produced in the brain. Yamada et al. reported CETP-like immunoreactivity in astrocytes in healthy human brain . Albers et al. have suggested that CETP is locally produced in the brain, as they were able to detect CETP in human CSF samples at concentrations higher than what would be expected from simple diffusion of proteins across the BCSFB . However, Demeester et al. were unable to detect CETP in human CSF and CETP mRNA in the human brain . A few other studies have also not detected CETP mRNA in the CNS of rabbits and cynomolgus monkeys [59, 67]. Undoubtedly, more research on the production and the role of CETP in the CNS of healthy individuals is needed.
2.5. Receptors involved in lipoprotein uptake and turnover
Lipoprotein uptake and delivery of lipids into target cells of the CNS is regulated by the low density lipoprotein receptor (LDLR) family . The four major apoE receptors in the CNS are LDLR, lipoprotein receptor related protein-1 (LRP1), very low density lipoprotein receptor (VLDLR), and apolipoprotein E receptor 2 (apoER2) . Of these, LDLR is the only receptor that has apoE as its only known ligand in the CNS . LDLR and LRP1 levels are inversely correlated with brain apoE levels as deletion or overexpression of these receptors in mice increases or decreases brain apoE levels, respectively [70-73]. VLDLR and apoER2 also serve as essential receptors for the neuromodulatory ligand Reelin, which is involved in long term potentiation, learning and memory [74-76]. Like apoE, clusterin can also bind to VLDLR and apoER2 to regulate Reelin signaling (Table 1) . LDLR, LRP1, VLDLR and apoER2 are all expressed on neurons, which have a high LRP1:LDLR ratio. LRP1 and LDLR are also found on astrocytes, which have a low LRP1:LDLR ratio, and LRP1 and VLDLR are found on microglia [78-81]. Solubilized forms of these receptors, generated via ectodomain shedding or splice variants lacking the transmembrane domain, possibly contribute to negative feedback and inhibition of lipoprotein uptake . Of note, the lipoprotein related protein 2 (LRP2), also known as megalin, and the neuronal sortilin- related receptor (SORL1 receptor) are also additional apoE receptors expressed in the CNS [83, 84].
3. Alterations to lipids and lipoproteins in Alzheimer’s disease
The neuropathology of AD is defined by the presence of amyloid plaques and neurofibrillary tangles (NTFs), which are composed of deposited amyloid-beta (Aβ) peptides and filamentous hyperphosphorylated tau, respectively . In addition to parenchymal amyloid plaques, most AD patients also have accumulation of amyloid in cerebral blood vessels, known as cerebral amyloid angiopathy (CAA) [14, 86]. Furthermore, neuronal degeneration and dysfunction, the brains of AD patients are often marked by significant signs of chronic inflammation, oxidative stress and vascular dysfunction. Not surprisingly, apolipoproteins, the lipids they carry, and the transporters responsible for their lipidation may be intimately involved in each step of the disease. In particular, the interrelationship between cerebrovascular dysfunction and AD is increasingly appreciated. Epidemiological, clinical, neuropathological and pathophysiological evidence shows that several cardiovascular risk factors also increase AD risk, including age, sex, hypertension, dyslipidemia, and type II diabetes [87-90]. Dementia progresses more rapidly in patients with cerebral infarcts [90- 93] and infarction and other forms of brain injury may potentiate AD pathophysiology [94- 96]. Importantly, many of these cardiovascular risk factors include aspects of dysfunctional lipid and lipoprotein metabolism, which likely occurs at the vessel wall. However, compared to the wealth of knowledge about lipid and lipoprotein physiology in large peripheral vessels, little is known about the mechanisms by which vascular risk factors for AD may impair the function of cerebral vessels. Importantly, BBB dysfunction may contribute to inflammatory processes in the CNS, where exacerbated inflammatory responses or failure to resolve inflammatory reactions are increasingly recognized to play important roles in AD pathogenesis .
3.1. Changes in brain lipid composition and their direct effects in AD
One often overlooked neuropathological observation initially reported by Alois Alzheimer is the presence of adipose inclusions in the brain, which Alzheimer defined as “extraordinarily strong accumulation of lipoid material in the ganglion cells, glia and vascular wall cells, and the particularly numerous fibril-forming glia cells in the cortex and, indeed, in the entire central nervous system” . Almost all major classes of lipids have some correlation with AD pathogenesis . A recent review by Kosicek and Hecimovic reported that the
Changes to CNS lipid composition can also influence the production of Aβ peptides. As the generation of these peptides involves several lipid-associated steps, including intracellular trafficking and inter-membrane proteolytic cleavage, it is not surprising that, in addition to genetic changes that alter Aβ production, there are also indirect, lipid- dependent changes that can affect production of Aβ. Aβ peptides are derived via sequential proteolytic processing of the amyloid precursor protein (APP) by β-secretase and γ- secretase. This leads to liberation of Aβ peptides 38-46 amino acids in length into the extracellular space [106-108]. Of these, Aβ40 and Aβ42 are quantitatively the most important for amyloid deposition . In healthy brains, the vast majority of APP is processed by α-secretase, followed by γ-secretase cleavage, which prevents toxic Aβ peptide generation . All of the enzymes involved in APP processing are transmembrane proteins, raising the hypothesis that the lipid composition and lipid organization in the membrane may affect Aβ production . Numerous
The production of Aβ peptides is not unique to AD pathology, but a constitutive process that is a product of normal cell metabolism throughout life, confirmed by its secretion from primary cells in culture and its presence in the plasma and CSF of healthy individuals [108, 116, 117]. Therefore, it is possible that disrupted Aβ homeostasis, either via increased production or impaired degradation and clearance, leads to its net accumulation in the brain, triggering subsequent neurotoxicity. Aβ production is clearly enhanced in cases of familial early onset AD (<60 years of age), which account for 2-3% of the AD population . In contrast to familial early-onset AD cases, the vast majority of AD subjects who develop cognitive impairment in late life have no genetically-determined net increase in Aβ production. For these late-onset AD patients, who account for up to 99% of the AD population , aging, environmental factors, or other genetic-related impairments in Aβ degradation and clearance are thought to lead to the net accumulation of Aβ within the CNS [120-122].
3.2. Apolipoproteins and AD pathogenesis
Of the apolipoproteins present in the CNS,
In addition to modulating Aβ, apoE may also be involved in tau phosphorylation. In neurons, hyperphosphorylation of the microtubule-associated protein tau by kinases, including GSK-3β and CDK5, causes the dissociation and aggregation of tau to ultimately form neurofibrillary tangles . Under conditions of stress or injury, neurons have been reported to synthesize and process apoE4 to produce neurotoxic C-terminal fragments. Release of these fragments into the neuronal cytosol has been reported to enhance tau phosphorylation and formation of NFT-like structures [139, 140].
ApoE4 has additional deleterious consequences. Compared to apoE3, apoE4 is less effective at mediating cholesterol transport in the brain; human knock-in
ApoE plays an integral role in inflammatory processes in the brain. Inflammation of the brain’s glial supporting cells, known as neuroinflammation, is a prominent feature AD  and contributes to neuronal damage. In response to Aβ or lipopolysaccharide (LPS), LRP1-mediated glial cell activation increases apoE, which can limit the inflammatory response by signaling though LDL receptors to suppress c-Jun N-terminal kinase signaling [145, 146]. There is also evidence that isoform-specific apoE modulation of the innate immune response can modulate Aβ deposition . Consistent with apoE having an anti- inflammatory role,
According to the AlzGene database,
Although the specific mechanisms by which an individual SNP in
A mechanistic involvement of clusterin in AD pathology is also supported by
Although apoA-I is relatively abundant in CSF and brain tissue, the physiological roles of apoA-I containing lipoprotein particles in the CNS, their potential influence on AD risk and pathology, and whether they affect AD pathogenesis through actions from one or both sides of the BBB remains unknown . The most established data regarding apoA-I and AD are human epidemiological studies examining the interaction between serum apoA-I and HDL-cholesterol levels with AD risk (Table 1). At mid-life, high serum apoA-I levels resulted in a significantly lower risk (hazard ratio (HR) 0.25) of dementia later in life,  while high levels of serum HDL cholesterol (> 55 mg/dL) in cognitively normal elderly was associated with a significantly reduced risk (HR 0.4) of AD even after adjusting for
Although questions remain about the importance of apoA-I to AD in humans, studies in preclinical AD mouse models support a role for apoA-I in removing amyloid selectively from the cerebral vasculature, leading to reduced neuroinflammation and maintenance of cognitive function (Table 1). Specifically, genetic loss of
Although the roles of other CNS apolipoproteins in AD pathogenesis are not as extensively studied, apoD, apoC-I, apoA-IV, and apoC-III may play a role. The most significant change due to aging is observed in gene expression levels of
3.3. Cholesterol and phospholipid transporters in AD
There is a growing body of pre-clinical and clinical evidence that supports the involvement of ABCA1, and recently ABCA7, in the pathogenesis of AD . In mice, ABCA1-mediated lipidation of apoE correlates with a net increase in Aβ clearance . For example, total body deficiency of
The association of
In contrast to ABCA1, numerous independent GWAS have identified associations between multiple
Despite high expression in the brain, ABCG1 does not appear to have a marked role in AD pathogenesis, as ABCG1 overexpression in AD mice does not significantly change Aβ or amyloid burden . Although a recent GWAS study reported that
3.4. LCAT, PLTP and CETP in AD
Although better characterized with respect to their involvement in atherosclerosis, research is emerging regarding the potential role of the lipoprotein modifying enzymes LCAT, PLTP and CETP in AD [53, 65, 247]. One early study in a small group of symptomatic AD patients suggested that CSF LCAT activity was reduced by 50% compared to cognitively normal age-matched controls , raising the possibility that aging may influence LCAT activity or LCAT activity may influence AD pathogenesis. Stukas et al. recently tested this hypothesis in mice and found that the abundance and activity of LCAT in liver, cortex and plasma is unaltered by aging or the presence of amyloid deposits . Furthermore, total loss of
PLTP may also be involved in the pathogenesis of AD. Intriguingly, whereas PLTP synthesis by neurons and glia is increased in the early stages of AD , its levels, and more importantly, its activity are reduced in brain tissue and CSF of AD patients in later stages [57, 63]. In mice, deletion of
Another enzyme that plays a central role in lipid homeostasis that can potentially affect dementia outcome is CETP. As reduced CETP activity in humans is associated with reduced cardiovascular disease risk, the functions of CETP in atherosclerosis and the potential of CETP inhibitors for cardiovascular disease have been of intense interest . The
3.5. ApoE receptors
APP endocytosis is regulated by several members of the lipoprotein receptor family leading to increased or reduced Aβ generation . These receptors are also critical for Aβ clearance. LRP1 can bind Aβ directly or bind apoE-associated Aβ to internalize and transport soluble Aβ across the BBB to plasma for eventual degradation, or mediate degradation within cell lysosomes [262-266].
4. Conclusions and future directions
ApoE is the major apolipoprotein produced within the CNS and is intimately involved in the risk, progression, and pathogenesis of AD. Allelic differences in
In the cardiovascular field, many preclinical and clinical studies have endeavored to increase the net concentration of circulating HDL to protect against cardiovascular disease. Many of these studies may also have implications for CNS function. However, as some of these approaches, such as the inhibition of CETP, have failed to meet their primary endpoints for cardiovascular disease despite significantly increasing HDL cholesterol levels, the lipoprotein field is now deeply invested in understanding the functional complexities of HDL. Therapeutic interventions aimed at increasing the function of HDL particles and their cargo may be of much greater importance than increasing its net levels, in both the peripheral and CNS compartments. Given the complexity of the HDL proteome and lipidome, it will be critical to divest the same details in the CNS to allow for therapeutic development targeting lipoprotein species.
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