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

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Abstract

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.

Section snippets

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% 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

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

Apo E isoforms in the brain

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], [69], [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

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

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]. In fibroblasts, human apo E3-containing HDLs from plasma form a complex with ABCA1,

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 receptor-dependent endocytic process

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], [208], [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

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 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

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

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