Astrocytes lipoproteins

The assembly of astrocyte lipoproteins occurs in the endoplasmic reticulum and in the Golgi. The incorporation of cholesterol in these lipoproteins is mediated by ATP-binding cassette (ABC) transporters, such as ABCAl. Indeed, the cholesterol content of astrocyte lipoprotein is associated with the level of expression of the ABCAl transporter. Apart from ABCAl, other members of the ABC transporters (ABCCl and ABCC4) have been involved in cholesterol efflux from astrocytes. The capacity of several distinct ABC transporters to regulate cholesterol export from astrocytes gives an alternative to the brain in case of defect of one of these transporters. 

In adult brain most cholesterol synthesis occurs in astrocytes. Apoprotein E (apoE) is the major apolipopro-tein of the CNS and it is secreted by astrocytes. In astrocyte cultures apoE appears in the media as cholesterol-rich particles of a size similar to peripheral HDL (5-12 nm) (Fig. 2-7). The ATP-dependent transporter ABCA1, expressed by both astrocytes and neurons, promotes the formation of the apoE-stabilized high-density lipoprotein (HDL)-sized particles from astrocytic cholesterol. 

Similarly, apolipoprotein E expression increases in neurotoxicity mediated by KA (Table 6.3) (Boschert et al., 1999). Apolipoprotein E is a major lipoprotein in the brain. It is involved in the transport, distribution, and other aspects of cholesterol homeostasis. Apolipoprotein E also plays a dominant role in the mobilization and redistribution of brain lipids in repair, growth, and maintenance of nerve cells (Mahley, 1988). The secretion of apolipoproteins E and D may be differentially regulated in cultured astrocytes. In cell culture systems this depends upon the extracellular lipid milieu (Patel et al., 1995). During neurotoxicity mediated by KA, apolipoprotein E levels increase moderately in astrocytes and apolipoprotein E mRNA increases very strongly in clusters of CA1 and CA3 pyramidal neurons. Based on hybridization in situ and immunohistochemical studies, expression of apolipoprotein E in neurons may be a part of a rescue program to counteract neurodegeneration mediated by KA (Boschert et al., 1999). 

Pitas RE, Boyles JK, Lee SH, Foss D, Mahley RW (1987) Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-con-taining lipoproteins. Biochim Biophys Acta 917 148-161. 

Apolipoprotein E (APOE) is the major lipoprotein within the CNS it is synthesized by astrocytes (Pitas et al., 1987) and by neurons under physiological and pathological conditions (Harris et al., 2004). APOE is a polymorphic 299-amino acid protein. The gene is located on chromosome 19 and has three possible alleles, s2, s3, and s4. APOE-zi is the most common (frequency in population 60-70%), followed by APOE-zA with a frequency of 15-20%, mAAPOE-z2 with a frequency of 5-10%. The three isoforms differ by single amino acid substitutions (cysteine to arginine) at two positions. APOE-e4 lacks both cysteine residues (Cys" and Cys ), while APOE-e3 and APOE-e2 contain 1 and 2 cysteine residues, respectively (Mahley and Huang, 2006). 

Pitas, R.E., Boyles, J.K., Lee, S.H., Foss, D. and Mahley, R.W. 1987. Astrocytes synthesize apoU-poprotein E and metabolize apohpoprotein E-containing lipoproteins. Biochim. Biophys. Acta 917 148-161... 

In TNCl rat astrocytes grown in Dulbecco s modified Eagle s medium + 10% fetal bovine serum, oxidised low density lipoprotein caused a dose-dependent increase in 2,7-dichlorofluorescin fluorescence, which was inhibited by pre-treatment with antioxidants, consistent with the formation of reactive oxygen species (Keller et al. 1999). 

The uptake of cholesterol-containing lipoprotein by neuronal membranes is mediated by proteins belonging to the low-density lipoprotein receptor family, especially LRPl. The journey of cholesterol from the astrocyte to the neuron is summarized in Fig. 3.7. 

FIGURE 3.7 Cholesterol flux between astrocytes and neurons. Because cholesterol cannot travel as a free solute between the astrocyte and the neuron, it is incorporated in apoE-contairang lipoproteins (inset). The journey begins in the endoplasmic reticulum of astrocytes, where cholesterol is incorporated in lipoproteins. These lipoproteins are exported via ABC transporters. In neurons, cholesterol-enriched lipoproteins are taken up by lipoprotein receptors (LRPl). Note that the astrocyte has also to fulfill its own cholesterol needs, thus a part of neosynthesized cholesterol is incorporated in astrocytic membranes. 

Fagan AM, Holtzman DM, Munson G, et al. Unique lipoproteins secreted by primary astrocytes from wild type, apoE (-/-), and human apoE transgenic mice. / Biol Chem. 1999 274(42) 30001-30007. 

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