Lipoproteins are extracellular macromolecular complexes composed of lipids, lipid-soluble molecules and proteins. Apolipoproteins are specialized lipoprotein-associated proteins that stabilize lipoprotein particles and enable transfer of hydrophobic molecules through an aqueous environment in intravascular and extracellular space.(1) Binding of apolipoproteins to specialized lipoprotein receptors on the cell surface facilitates bi-directional transfer of lipids and lipid-soluble molecules, such as vitamins E, D, K and A, between lipoprotein particles and cells. In this capacity, apolipoproteins are essential for regulation of cellular lipid composition, lipid recycling, removal of excess lipids from the cells, maintenance of cellular anti-oxidative potential and delivery of critical structural and functional components.

Presence of some apolipoproteins on lipoprotein particles is essential for activation of enzymes involved in lipid and lipoprotein metabolism; for example, apoC-II interacts with lipoprotein lipase (LPL).(2) Furthermore, binding of apolipoproteins to the lipoprotein receptors initiates signal transduction pathways, thus regulating numerous intracellular signaling events involved in inflammation, apoptosis and other physiological and pathophysiological cellular responses.

Recent studies have shown that some apolipoproteins such as apolipoprotein E (apoE) and apoD translocate to the nucleus following cellular reuptake,(3) but mechanisms responsible for the apolipoprotein translocation to the nucleus and their functions in the nuclear compartment are largely unknown. The expansion of apolipoprotein function from their role in lipid transfer to numerous other processes suggests a much more complex role for these proteins at the cellular level.

Barriers

The brain is isolated from the systemic circulation by the blood-brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier. The barriers physically separate the brain from the fluctuations of various blood components, and transfer across these barriers requires predominantly active transfer of the molecules that enter the brain tissue.(5) Blood represents a complex system, containing large number of circulating cells, has rich protein and lipid composition and is subjected to enormous fluctuations of various components. The composition of cerebrospinal fluid (CSF) is by comparison significantly simpler, more stable and distinct from blood. Therefore, the type of apolipoproteins and composition of lipoproteins present in the brain also significantly differ from the systemic lipoproteins.

Systemic Circulation

In the systemic circulation, apoB and apoA-I are two major apolipoproteins associated with lipoprotein particles, and define two principal categories of systemic lipoproteins, apoB-containing lipoproteins (LpB) and apoAI-containing lipoproteins (LpA-I). LpB [chylomicrons; very low density lipoproteins, VLDL; intermediate density lipoproteins, IDL; low density lipoproteins, LDL; and lipoprotein(a), Lp(a)] are typically more lipid-rich than high density lipoproteins, HDL, which contain apoA-I as the major apolipoprotein, and represent a highly diverse subpopulation of systemic lipoproteins that are relatively lipid-poor compared to LpB, and contain much more varied protein cargo.(6)(7)(8) Put simply, chylomicrons transport lipids absorbed from the intestinal tract, the VLDL-LDL cascade lipoproteins transport lipids to the cells, while HDL particles are involved in bi-directional lipid transfer between lipoproteins and between lipoproteins and cells.(9)

The HDL-dependent reverse cholesterol transfer, a process that transports cholesterol from the cells to liver for recycling or excretion through bile, is of particular importance for the maintenance of cellular lipid composition.(10) Although lipid transfer has long been thought to be the main function of HDL particles, recent proteomics studies showing a very heterogeneous protein composition of HDL particles suggest a much more complex metabolic role for this lipoprotein family.(6)(7)(8)

The Brain

In contrast, under normal circumstances, the brain does not contain LpB since apoB is not expressed in the brain, and does not cross the uncompromised BBB.(11) The main HDL apolipoprotein, apoA-I, is also not expressed in the brain but it crosses the BBB and is present on the brain lipoproteins.(12) Unlike apoA-I, apoE is expressed and secreted by the brain glial cells and represents the main apolipoprotein in the brain.(13)(14)(15) Besides apoE, other major apolipoproteins expressed in the brain are apoD and apoJ.(16)(17) Other apolipoproteins are also present, but in lower concentrations (Table 1), and recent studies implicate some of these minor apolipoprotein components in pathophysiological processes and brain diseases including schizophrenia, Alzheimer’s disease (AD) and Parkinson’s disease.(18)(19)(20)(21) Expression of the brain apolipoproteins is significantly different in various brain structures and regions.

Brain Lipoprotein System

Differences in apolipoprotein composition of the brain lipoprotein particles are accompanied by a marked difference in their lipid composition. Under normal conditions, brain lipoproteins have significantly lower levels of esterified cholesterol than similar particles in plasma, and their predominant phospholipid component is phosphatidylethanolamine. The functional significance of these differences is not well understood, and our understanding of the roles of the brain apolipoprotein and lipoprotein metabolism in health and disease is currently limited.

The brain is an exceptionally lipid-rich organ. Lipids represent approximately 50% of the brain’s dry-weight, and the brain contains a quarter of the total body cholesterol.(22)(23) Unlike the rest of the body, essentially all (>99.5%) of the brain cholesterol is unesterified.(24) In humans, virtually all of the brain cholesterol is locally synthesized.(22)(25) Most cholesterol forms do not cross the BBB into the brain with the minor exception of certain oxidized forms of cholesterol.(26)(27) Although the net-flux of oxidized forms of cholesterol into the brain may be minimal, long-term effects of this process on development of neurodegenerative diseases, such as AD, cannot be neglected and may at least partially explain the increased risk of neurodegenerative diseases, including AD, in people with hypercholesterolemia.(28)(29)

In adults, the brain synthesizes on average 30 µg of cholesterol per day, (22)(30) has an average turnover rate of 0.02% and long half-life (4-6 months to 5 years).(24) Removal of cholesterol from the brain is partially performed through cholesterol oxidation by the cholesterol 24(S)-hydroxylase, an enzyme expressed by selected neurons.(31) 24(S)-hydroxycholesterol is easily transferred through the BBB into the peripheral circulation and excreted through liver into bile.(32) The blood levels of 24(S)-hydroxycholesterol depend almost entirely on the cholesterol elimination from the brain and are used as an approximate measure of cholesterol turnover in the brain.(31) This mechanism is responsible for approximately 40% of the cholesterol removal from the brain; the remaining 60% is transferred through the BBB by an unknown mechanism.(33)

Role of Brain Lipids and Lipoproteins

Lipids are critical structural and functional components of the brain tissue, and transfer of lipids within the brain tissue is essential for the maintenance of its structural and functional integrity. Normal functioning of the brain requires constant recycling of lipids, which is dependent on lipoprotein metabolism. Neurons are particularly sensitive to alterations in lipoprotein metabolism because they synthesize relatively low levels of cholesterol and other lipids, and depend largely on lipid transfer from glial cells, which are the main source of lipid and protein components of the brain lipoproteins. (34)(35)(36)(37) Furthermore, maintenance of myelin sheath, which is exceptionally lipid-rich, is dependent on normal lipoprotein metabolism.(24) It is therefore not surprising that practically all brain diseases and disorders are accompanied by alterations in lipid and lipoprotein metabolism (for examples see (38)(39)).

By size and density, brain lipoproteins secreted by astrocytes resemble HDL particles and are, therefore, typically described as HDL-like. An in vitro study suggested that microglia secrete lipoprotein particles in size similar to LDL, with size, composition and shape distinct from those secreted by astrocytes.(40) Lipoproteins are secreted in a nascent form, mature in the extracellular space by acquisition of lipid and protein components, exchange or deliver lipids to neurons, finally reaching the CSF as mature lipoprotein particles. Just as the plasma lipoproteins represent a window into millions of lipoprotein-cell interactions with the liver and peripheral tissues, so too the CSF lipoproteins represent a window into the interactions between lipoproteins and cells in the brain.

Several published studies reported the composition of different lipoprotein particles secreted by glial cells in vitro or isolated from CSF.(40)(41)(42)(43)(44)(45)(46)(47)(48)(49) Our current knowledge of the brain lipoprotein components suggests that these particles have a very complex protein composition, and that there are numerous types of the brain lipoproteins based on the apolipoproteins associated with them. However, the functional significance of these different sub-classes of brain lipoproteins is for the most part currently unknown.

Lipoproteins play a critical role in lipid recycling, which is relevant not only for lipid delivery, but also for other functions, including formation and function of synapses and neuronal repair.(37)(50)(51)(52) Published studies have shown that brain lipoproteins bind β-amyloid and that lipoprotein-bound Aβ does not form fibrils, a process that is considered a pre-requisite for formation of amyloid plaques.(53)(54)(55) Furthermore, Aβ clearance from the brain appears to be lipoprotein-dependent.(56)(57)(58) Lipoproteins also represent a transport mechanism for lipid-soluble vitamins, thus playing a role in regulation of the brain anti-oxidative potential (see, for example, (59)). In systemic circulation, lipoproteins are also involved in neutralization of lipopolysaccharide(60) and likely have a similar role in the brain during Gram-negative infections.

Much of our knowledge regarding brain lipid and lipoprotein metabolism comes from studies in various animal models. It should be noted that the lipid and lipoprotein metabolism in the human brain exhibits some significant differences compared to animal models. For example, mice do not have naturally occurring apoE isoforms, which play important differential roles in lipoprotein metabolism in human brain (see, for example, (61)). Therefore, results of in vivo studies using mouse, rat or other animal models should be interpreted with caution, as they may not have direct relevance to the human brain lipid and lipoprotein metabolism.

In summary, the brain lipoprotein system - comprised of proteins, lipids and lipoprotein receptors - is markedly different from the systemic lipoproteins and functions in a significantly different environment. It is, therefore, likely that the brain apolipoproteins have unique functions that are specific for the nervous system, as well as functions similar to those in the peripheral tissues.

Apolipoproteins In The Brain

ApoE
ApoE is the main apolipoprotein in human brain. The elegant studies by Linton and colleagues have shown that all of the brain apoE is brain-derived.(15) ApoE in the brain is expressed and secreted by glial cells, predominantly astrocytes, (12)(14)(15)(33)(62)(63) and its interaction with ABCA1 is critical for normal lipidation and function of apoE-containing lipoproteins (LpE).(64)

The expression of apoE by neurons has been controversial. ApoE is not expressed by neurons under normal physiological conditions.(65)(66) Recently published studies have shown that apoE is expressed by certain neurons in response to injury.(67)(68) It should be noted that the majority of studies regarding neuronal apoE involved transgenic mice over-expressing human apoE (for example (69)). Mouse neurons may not contain the same regulatory mechanisms for suppression of human apoE expression, supported by the fact that mouse apoE mRNA was undetectable in neurons in these transgenic mice. Only a small number of studies evaluated constitutive apoE expressed by human neurons, in which apoE expression had to be induced by toxins or severe serum starvation.(67)(70)(71)herefore, although the claims regarding neuronal apoE expression are perpetuated in the published literature, it is unlikely that neurons express apoE under normal conditions. However, apoE can enter neurons through a receptor-mediated endocytosis(72)(73) and has been shown to translocate to the nucleus of neurons when in lipidated form.(4)

ApoE plays a critical role in maintenance of the brain structural integrity and neuronal repair.(74)(75) LpE in the brain is involved in both delivery and uptake of lipids. The uptake is considered important for lipid recycling, which is a process essential for normal synaptic structure and function.(37)(51) Furthermore, lipid uptake by LpE is also involved in removing lipids from the sites of damage, which is a pre-requisite for efficient neuronal repair.(76) The ability of apoE to interact with its receptors on neuronal membrane is responsible for the uptake of lipoprotein particles and is considered to be the main mechanism for delivery of lipids to neurons.(76)(77)(78) A study by Wang and colleagues suggested that apoE-mimetics can be used in therapy of the brain injury,(79) which is in line with the known apoE functions in the brain.

Human apoE is present in three isoforms – ε2, ε3 and ε4 – with genotype combinations [APOE2/2; 2/3; 2/4; 3/3; 3/4 and 4/4) that are functionally significant both in the brain and in the rest of the organism.(80)(81)(82)(83) ApoE2 contains cysteine residues at positions 112 and 158; apoE3 contains cysteine at position 112 and arginine at position 158; apoE4 contains arginine at both positions.(84)

These sequence differences are associated with significant three-dimensional and functional consequences.(85)(86) ApoE isoforms differ in their affinity for lipids, and the composition of LpE is isoform-specific (84)(86)(87)(88). Furthermore, apoE isoforms have different affinity for apoE receptors, which are involved in lipid delivery, with apoE2 binding to the receptors with much lower affinity than apoE3 or apoE4, which have similar affinity for apoE receptor binding (idem).

In contrast, all three apoE isoforms have significantly different ability to elicit lipid efflux from neurons, with apoE4 having the weakest lipid efflux ability and apoE2 the strongest.(89) These findings suggest that apoE interactions with the ATP-binding cassette transporters ABCA1 and ABCG1, which are responsible for lipid efflux in astrocytes and neurons, are strongly apoE isoform-dependent, while apoE interactions with the receptors involved in lipid delivery show virtually no difference between the apoE3 and apoE4 isoforms. Furthermore, apoE isoform-specific interactions with other receptors, such as NMDA (N-methyl-D-aspartate) receptor, have been reported.(90)(91)

These isoform-dependent functional differences are likely relevant for the observed association of the apoE4 isoform with AD, Parkinson’s disease, multiple sclerosis, stroke, brain hemorrhage, anxiety; numerous neuromuscular diseases and other neuronal diseases and processes,(52)(92)(93)(94)(95)(96)(97)(98)(99) since reduced efflux ability may lead to a slow, yet significant, increase in the intracellular lipid levels and reduced efficiency of lipid recycling in neurons. Furthermore, apoE binding to the extracellular matrix components is isoform-specific,(100) suggesting a possibility that apoE isoform function in the extracellular space, as well as at the cellular level, may be significantly different.

Additionally, an intriguing study suggested that apoE3 and apoE4 also have different stability and/or retention in the brain tissue, since people with apoE3/4 phenotype had significantly higher levels of apoE4 than apoE3 in CSF despite similar expression levels of these two isoforms.(101) In contrast, Riddell and colleagues reported that levels of apoE4 were lower than those of apoE3 in mice expressing human apoE3/4, and that apoE4 had shorter half-life compared to apoE3 in vitro.(102)

ApoE2 has been associated with a lowered risk of AD, since the presence of at least one APOE2 allele appears to be protective against AD.(99)(103) In contrast, the presence of APOE4 is associated with an increased risk and earlier onset of AD and is still the strongest confirmed genetic risk factor in late-onset AD.(92)(104)(105)(106)ApoE plays a role of a molecular chaperone in the brain, transfers α-tocopherol, binds beta-amyloid, modulates cleavage of amyloid precursor protein, promotes proteolysis of beta-amyloid peptides, plays a role in removal of beta-amyloid from the brain, affects growth of neurons, regulates morphology of neuronal processes, affects synaptic function, and regulates numerous aspects of microtubule-associated protein tau, including its phosphorylation in neurons, and many of these functions are apoE isoform-sensitive.(107)(108)(109)(110)(111)(112)(113)(114)(115)(116)(117)(118)(119)(120)(121)(122)(123)(124)(125)(126)(127)(128)(129)(130).

Furthermore, presence of apoE4 has been associated with reduced blood flow, worse outcome of traumatic brain injury and stroke due to lower efficiency at neuronal repair, reduced brain volume, impaired memory in older subjects, altered transfer of electric potentials along axons (LTP), and greater susceptibility to neurodegeneration regardless of putative causative factors, suggesting that apoE isoforms have differential effects on many brain processes.(52)(91)(131)(132)(133)(134)(135)(136)(137)(138)

Among other confirmed or suspected roles of apoE, its function in repair of neurons appears to be of particular importance. Studies have shown that levels of apoE levels significantly increase following neuronal injury in vivo. (139)(140)(141)(142) ApoE-/- mice have insufficient recovery from neuronal injury(143) and an infusion of apoE ameliorated neuronal damage following cerebral ischemia, neurodegeneration and cognitive impairment in apoE-/- mice.(144)(145)

Despite the observed differences in apoE3/3 vs. apoE4-positive subjects in various physiological and pathophysiological processes, a study by Levi and colleagues suggests that the impact of an unfavorable APOE genotype can be overcome or attenuated by an enriched, challenging environment.(146)These findings are supported by observations that early and prolonged education, as well as regular physical, mental and social activity, significantly reduce the impact of the APOEε4 genetic risk factor on neurological diseases and disorders (for example (147)(148)(149)). In contrast, lack of education, sedentary lifestyle, unchallenging mental and impoverished social environments increase risks of neurological disorders in all people (idem), and likely even more so in those with apoE4.

ApoA-I
ApoA-I in the brain is derived from the systemic circulation(12)(62) and represents a significant apolipoprotein component of the brain lipoproteins. Some studies have shown that apoA-I is expressed and secreted by the endothelial cells comprising the BBB. ApoA-I mRNA has been reported in the spinal cord in animal models but it is unclear whether the same is true in humans.(150)(151)

Compared to plasma, apoA-I levels in the brain are very low (approximate values of 0.2-0.4 mg/dl in CSF vs. 120-160 mg/dl in plasma; 152, 153). Despite the low levels of apoA-I in the brain, its ability to interact with the ATP-binding cassette transporters, ABCA1 and ABCG1, in the brain is likely significant for normal functioning of brain cells.

These ATP transporters are involved in apolipoprotein lipidation and recycling of lipids within the brain tissue. Specific knockdown of the ABCA1 expression in the brain was associated with a compensatory increase in apoA-I in the brain in vivo, and the mice had significantly reduced synapse number, as well as disturbed synapse structure and function.(154) Mauch and colleagues suggested that recycling of cholesterol in the brain is critical for the synapse development and function.(51) In vivo studies confirmed the functional relevance of the brain ABCA1-dependent lipid efflux for normal brain function.(64)(154)

Given the fact that apoE interacts with the ABC transporters in the brain,(155)(156) the role of apoA-I in the brain is likely more complex than providing an additional ligand to these receptors. A new study by Wang and colleagues suggested that CSF levels of apoA-I are decreased in patients with Parkinson’s disease,(157) and a study by Huang and colleagues has shown decreased apoA-I levels in the brain, as well as in the periphery, in patients with schizophrenia.(158) A recent in vivo study suggested that an apoA-I mimetic peptide improved cognitive function and reduced amyloid burden in an AD mouse model, as combination treatment with the peptide and statins significantly reduced inflammation in the brain of these mice, while statin alone did not have such effect.(159) These findings suggest that apoA-I has specific physiological functions in the brain. Although mice lacking apoA-I have been engineered,(160) the CNS phenotypic characteristics have not been reported.

ApoD
ApoD is a member of the lipocalin family and is considered to be an atypical apolipoprotein due to a relative lack of α-helices.(161) It binds multiple hydrophobic molecules including arachidonic acid and steroid hormones.(161)(162) In humans, expression of apoD is low in neonates, and increases during development and under oxidative stress.(163) Although the highest levels of apoD expression are in glial cells (astrocytes, oligodendrocytes and microglia), neurons also express apoD.(163)(164)(165)(166) Neuronal injury significantly increases apoD expression in both central and peripheral neurons.(167)(168)(169) ApoD functions are likely tissue-specific, since its association with different ligands is tissue-dependent.

Physiological functions of apoD are still poorly understood but published studies have shown that it has transfer and proteolytic activity, regulates signal transduction and protects against oxidative stress.(170)(171) ApoD is considered neuroprotective and is most likely involved in tissue repair.(167)(172)(173) Interestingly, in vivo studies in Drosophila have shown that apoD homolog knock-out in glial cells is associated with reduced lifespan and decreased stress resistance, with the opposite results in the overexpression model.(174)(175) These findings have been confirmed in a mouse model, showing that apoD deficiency is associated with an increased level of the brain lipid peroxidation, reduced learning and locomotor abilities.(171)

Increased ApoD has been reported with stroke,(173) traumatic brain injury,(168) neurodegenerative diseases such as AD,(176) demyelinating diseases such as multiple sclerosis and chronic inflammatory demyelinating polyneuropathy,(177) viral encephalopathy(172) and in psychiatric diseases including schizophrenia and bipolar disorder.(178) Published studies reported increased levels of apoD mRNA and protein in AD,(176) and an association of apoD levels with the extent of the disease (Braak stage) and apoE genotype.(179) In AD, apoD levels were reportedly positively associated with neurofibrillary tangles (idem). Its relationship with amyloid plaques is unclear, since some studies reported no correlation,(179) while others reported that they correlate with compact, but not with diffuse, amyloid plaques.(180) These findings, combined with the known apoD functions, suggest that the observed increased levels of apoD in various brain disorders may be associated with an attempt to repair damaged neurons.

ApoJ (clusterin)
ApoJ is nearly ubiquitously expressed and is one of the more abundant apolipoproteins in the brain. ApoJ functions as a multi-talented molecular chaperone, and has many different functions in the periphery including lipid transfer, cell survival, tissue remodeling, cell-cell and cell-matrix interactions, and inhibition of complement activation.(181)(182) Although clusterin is considered a secreted protein, alternative splicing creates specific apoJ isoforms found in cytoplasmic and nuclear compartments.(183)(184)

ApoJ is expressed in the brain by both glial cells and a subset of neurons.(165)(185)(186) Through its role in cell survival (see section below on apolipoprotein-receptor interactions) apoJ plays a significant role in neuroprotection, and different apoJ forms can either promote or protect against apoptosis, depending on their intra- or extracellular localization.(182)(184)(187)(188) Retrotranslocation of apoJ has been reportedly induced by stress.(189) The intracellular forms have been found to play a role in DNA repair, transcription and organization of microtubules.(184)(190)(191)(192)(193) Neurons expressing apoJ have higher resistance to apoptosis.(194)

Probably the best researched correlation between apoJ and brain disorders is its relationship with AD. ApoJ mRNA is elevated in AD.(183) ApoJ binds Aβ peptides, preventing formation of fibrils, and is involved in its clearance from the brain.(55)(122)(129)(195)(196) Given these known apoJ functions, it is not surprising it plays an important role in processes protecting the brain against development of AD.(197) ApoJ genetic variants have been associated with an increased risk of AD, suggesting that structural alterations in those variants significantly affect its function in the brain and reduce its ability to protect the brain from pathophysiological processes involved in development of AD.(198)

ApoJ also plays an important role in other neurological disorders. For example, brain injury increases apoJ expression in vivo,(142)(199) and increased apoJ expression by astrocytes is associated with better survival following an ischemic injury in vivo.(200) An interesting study by Dati and colleagues has shown that recombinant human apoJ significantly accelerated remyelination and motor-evoked potentials of damaged nerves in peripheral neuropathy, suggesting strong neuronal regeneration effects in vivo.(201) ApoJ has also been reported to associate with α-synuclein, therefore playing a role in Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy.(202)

ApoL
ApoL proteins are involved in regulation of apoptosis and immune response(203). ApoL proteins are encoded by six genes and multiple splice-isoforms.(204) All six genes are expressed in the brain; apoL1 and apoL2 are expressed in the frontal cortex neurons.(204)(205) It should be noted that of the six apoL proteins, only apoL1 contains signal peptide and is secreted outside of the cell, while the other apoL proteins are intracellular. (206) ApoL1 is associated with HDL in plasma and therefore fulfils the requirements for classification as an apolipoprotein.(207)(208) ApoL1 gene polymorphisms affect concentration of triglycerides in plasma(209) and apoL1 has specific role in protection against trypanosome infection.(210)

Elevated apoL levels and differential expression of APOL have been found in several neuropsychiatric diseases.(205)(211) For example, significant increases in apoL1, apoL2 and apoL4 expression have been shown in schizophrenia, while apoL2 is significantly increased in bipolar affective disorder.(205) Studies suggested that specific APOL single nucleotide polymorphisms are associated with an increased risk for development of schizophrenia.(18)(212) ApoL2 mRNA levels were reportedly also increased in prefrontal cortex of persons abusing drugs.(213) The mechanisms responsible for the observed correlations between apoL and psychiatric diseases are currently unknown. Interestingly, patients with schizophrenia have significantly different lipid composition of the cell membrane, not only in the brain but in peripheral cells as well, suggesting a systemic dysregulation of lipid and lipoprotein metabolism, and a possible role of apoL1 in pathophysiology of schizophrenia.(214)(215)

Apolipoprotein-receptor Interactions

Apolipoprotein interactions with receptors play a role not only in lipid transfer between lipoprotein particles and cells, but also initiate signal transduction cascades. For example, binding of apoE to its receptors, APOE2 or VLDLR, on neuronal membrane regulates phosphorylation of Disabled-1 (Dab1), activates the phosphatidylinositol (PI3K)-Akt pathway, reduces activity of glycogen synthase kinase 3β (GSK3β) and reduces phosphorylation of microtubule-associated protein tau.(126)(216)(217)(218) ApoA-I binding to ABCA1 transporters recruits Janus kinase 2 (JAK2), leading to binding of a transcription factor STAT3 (signal transducer and transcription activator 3), phosphorylation and translocation of activated STAT3 to the nucleus where it regulates transcription of numerous genes.(219)(220) A recent study has shown that apolipoprotein binding to ABCA1 activates the RhoA signaling.(221)

The ability of apolipoproteins to activate signal transduction in cells containing relevant receptors is functionally significant, although not necessarily completely separated from their lipid transfer functions since binding of apolipoproteins to specific receptors is often dependent on their lipidation status. Binding of LpE to the LDL receptor-related protein (LRP) protects neurons from apoptosis through a signal transduction pathway involving protein kinase Cδ (PKCδ) and GSK3β, while lipid-free apoE does not exert the same protection.(222) Lipid-poor apoA-I binds to ABCA1, while lipidated apoA-I binds with higher affinity to ABCG1.(223)(224) Binding of apoJ to megalin is also dependent on apoJ lipidation status, since binding affinity for megalin significantly increased after apoJ lipidation.(225)

Therefore, lipid components of apoJ-containing particles play a significant role in apoJ’s ability to induce cell survival through the PI3K-Akt-Bad-cytochrome c pathway (225)(226). These known interactions between apolipoproteins and receptors most likely represent only a subset of their physiological roles in the brain, and require further investigation.

PLTP – The “Other” Extracellular Lipid Transfer Protein in the Brain

Phospholipid transfer protein (PLTP) is not considered to be an apolipoprotein despite its association with lipoprotein particles and its role in lipid transfer. It instead belongs to a family of proteins involved in transfer of lipids and lipopolysaccharides that includes cholesteryl ester transfer protein (CETP), bactericidal permeability-increasing protein (BPI) and lipopolysaccharide-binding protein (LBP).(227) Its α-helix/β-sheet structure somewhat resembles apoD. PLTP is likely the only extracellular lipid transfer protein in the brain besides apolipoproteins, since CETP is most probably not expressed in the brain under normal circumstances. The vast majority of the brain cholesterol is in the unesterified form, and accumulation of the esterified form is associated with brain disorders,(224)(228) suggesting that CETP has no functional role in the healthy brain.

Known PLTP functions include transfer of different classes of phospholipids, unesterified cholesterol and α-tocopherol between different lipoprotein particles, and between lipoproteins and cells.(229)(230)(231)(232)(233) PLTP is critical for maintenance of the tissue levels of α-tocopherol including the brain.(232)(234) An interesting case study reported an association between a specific mutation in PLTP gene and ataxia due to low levels of α-tocopherol,(235) suggesting that the role of PLTP in regulation of the brain anti-oxidative potential needs to be further explored. PLTP plays a significant role in lipid efflux through its interaction with ABCA1 (231) and its binding to ABCA1 activates JAK2 in a manner similar to apoA-I.(219)(220)

PLTP is nearly ubiquitously expressed and is highly expressed in the brain. (236) Brain PLTP is differentially expressed by various brain regions and it is secreted by all types of the brain cells (idem). PLTP levels are altered in neurodegenerative, demyelinating and inflammatory diseases, and it is down-regulated in Down syndrome.(236)(237)(238) PLTP activity in CSF may be a good marker of neuronal cell death. It likely has predictive value in multiple sclerosis and probably in other inflammatory diseases of the brain, since PLTP activity levels are significantly decreased in active inflammatory brain diseases and recover in the remission phase.(238)

A large proportion of the brain PLTP is associated with the apoE-containing lipoproteins but a significant proportion is apoE-free (idem). PLTP regulates apoE expression in astrocytes and there is a high correlation between these two proteins in CSF (idem). PLTP also reduces phosphorylation of tau through binding to insulin receptor and insulin-like growth factor 1 receptor on neuronal membrane, activating the PI3K-Akt pathway and increasing levels of the inactive form of GSK3β.(239) Although it is currently considered a secreted protein, we have shown that it re-enters the cell and translocates to the nucleus.(240)

Conclusions

Although our knowledge of lipid transfer mechanisms within the brain and the roles of lipid transfer proteins in the brain in health and disease significantly increased in the last two decades, it is still limited. Lipoprotein and apolipoprotein functions in the brain encompass more than lipid transfer, and include regulation of cell signaling pathways and other intracellular functions.

Published studies show a strong relationship between the brain lipid and lipoprotein metabolism and neurodegenerative, demyelinating, inflammatory and psychiatric diseases. These findings indicate that the brain lipid and lipoprotein metabolism plays a major role in the development of brain diseases. Given the exceptional importance of lipids in the brain structure and function, more research is needed to understand physiological and pathophysiological relevance of the apolipoprotein- and lipoprotein-dependent functions in human brain.

In summary:
Lipoprotein metabolism is important for the brain structure and function; Alterations in the brain lipid and lipoprotein metabolism could cause and likely contribute to development of numerous brain disorders; Better understanding of lipoprotein metabolism in the brain is critical for future preventive and therapeutic approaches to brain diseases.

Acknowledgments

The author thanks Dr. John J. Albers for critical reading of the manuscript.

This article is dedicated to the memory of Dr. John “Jack” F. Oram, a brilliant scientist, an inspiring colleague and a wonderful friend, who recently lost a long and courageous battle with lung cancer. Jack dedicated his life to science, and – among many noteworthy achievements – his work and his stubborn belief that cellular lipid efflux is a receptor-mediated process led to the discovery of ATP-binding cassette A1 (ABCA1) and its role in lipid efflux and cell signaling.