Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ReviewFormation and function of apolipoprotein E-containing lipoproteins in the nervous system
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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