Astrocytes and Microglia Respond to Estrogen with Increased apoE mRNAin Vivoandin Vitro

Stone, David J.; Rozovsky, Irina; Morgan, Todd E.; Anderson, Christopher P.; Hajian, Hagop; Finch, Caleb E.

doi:10.1006/exnr.1996.6360

Cited by 234 publications

(156 citation statements)

References 23 publications

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“…Unlike apoE in plasma lipoproteins that is present in the same particle along with several other apoproteins, apoE in the CNS is initially secreted predominantly by astrocytes in unique HDL-like particles that contain apoE as the sole apoprotein constituent LaDu et al, 1998). Glia (astrocytes and microglia) are cells in the CNS that produce the majority of apoE (Boyles et al, 1985;LaDu et al, 1998;Nakai et al, 1996;Pitas et al, 1987a;Stone et al, 1997), with astrocytes appearing to produce the preponderance of this protein. It has been demonstrated that astrocytes secrete apoE in nascent HDL-like lipoprotein particles, which contain cholesterol and phospholipid but lack a cholesteryl-ester core (DeMattos et al, 2001b;Fagan et al, 1999;LaDu et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Production and characterization of astrocyte-derived human apolipoprotein E isoforms from immortalized astrocytes and their interactions with amyloid-β

Morikawa

Fryer

Sullivan

et al. 2005

Neurobiology of Disease

119

127

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The apolipoprotein E (apoE) genotype is an important genetic risk factor for Alzheimer's disease (AD). In the central nervous system (CNS), most apoE is produced by astrocytes and is present in unique high-density lipoprotein (HDL)-like particles that have distinct properties from apoE derived from other sources. To develop an efficient system to produce astrocyte-derived apoE in large quantities, we produced and characterized immortalized cell lines from primary astrocyte cultures derived from human APOE knock-in mice. APOE2, APOE3, and APOE4 expressing cell lines were established that secrete apoE in HDL-like particles at similar levels, cholesterol composition, and size as those produced by primary astrocytes. In physiological buffers, astrocyte-secreted apoE3 and E4 associated equally well with amyloid-B. Under the same conditions, only a small fraction of AB formed sodium dodecyl sulfate (SDS)-stable complexes with apoE (E3 N E4). These immortalized astrocytes will be useful for studying mechanisms underlying the isoform-specific effects of apoE in the CNS. D 2004 Elsevier Inc. All rights reserved.

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Section: Introductionmentioning

confidence: 99%

Production and characterization of astrocyte-derived human apolipoprotein E isoforms from immortalized astrocytes and their interactions with amyloid-β

Morikawa

Fryer

Sullivan

et al. 2005

Neurobiology of Disease

119

127

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“…ApoE in the CNS appears to be produced predominantly by astrocytes (Boyles et al, 1985;Pitas et al, 1987a) and microglia (Nakai et al, 1996;Stone et al, 1997), and apoE receptors are present on glia and neurons (Pitas et al, 1987a;Moestrup et al, 1992;Wolf et al, 1992;Poirier et al, 1993;Rebeck et al, 1993;Bu et a!., 1994). In vitro, astrocytes secrete apoE-containing lipoproteins (Pitas et al, 1987a), although the nature of this lipoprotein particle has not been determined.…”

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confidence: 99%

Nascent Astrocyte Particles Differ from Lipoproteins in CSF

LaDu

Gilligan

Lukens

et al. 1998

Journal of Neurochemistry

259

253

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Abstract:Little is known about lipid transport and metabolism in the brain. As a further step toward understanding the origin and function of CNS lipoproteins, we have characterized by size and density fractionation lipoprotein particles from human CSF and primary cultures of rat astrocytes. The fractions were analyzed for esterified and free cholesterol, triglyceride, phospholipid, albumin, and apolipoproteins (apo) E, Al, All, and J. As determined by lipid and apolipoprotein profiles, gel electrophoresis, and electron microscopy, nascent astrocyte particles contain little core lipid, are primarily discoidal in shape, and contain apoE and apoJ. In contrast, CSF lipoproteins are the size and density of plasma high-density lipoprotein, contain the core lipid, esterified cholesterol, and are spherical. CSF lipoproteins were heterogeneous in apolipoprotein content with apoE, the most abundant apolipoprotein, localized to the largest particles, apoAl and apoAll localized to progressively smaller particles, and apoJ distributed relatively evenly across particle size. There was substantial loss of protein from both CSF and astrocyte particles after density centrifugation compared with gel-filtration chromatography. The differences between lipoproteins secreted by astrocytes and present in CSF suggest that in addition to delivery of their constituents to cells, lipoprotein particles secreted within the brain by astrocytes may have the potential to participate in cholesterol clearance, developing a core of esterified cholesterol before reaching the CSF. Study of the functional properties of both astrocyte-secreted and CSF lipoproteins isolated by techniques that preserve native particle structure may also provide insight into the function of apoE in the pathophysiology of specific neurological diseases such as Alzheimer's disease. Key Words: Apolipoprotein E-Apolipoprotein J -Apolipoprotein Al -Alzheimer's disease-Cholesterol. J. Neurochem. 70, 2070Neurochem. 70, -2081Neurochem. 70, (1998.The intercellular transport of lipids through the aqueous circulatory system requires the packaging of these hydrophobic molecules into water-soluble carriers known as lipoproteins (high-density lipoprotein HDL; low-density lipoprotein LDL; and very-low-density lipoprotein, VLDL). Lipoproteins are macromolecular complexes composed of a phospholipid (PL) and free cholesterol (FC) shell surrounding a triglyceride (TG) and cholesteryl ester (CE) core (see Fig. 6A). Lipoproteins also contain apolipoproteins (apo), proteins that stabilize the surface of lipoproteins as they have both hydrophobic and hydrophilic domains. Apolipoproteins can also serve as cofactors for enzymatic reactions (Fielding et al., 1972) and ligands for cell surface receptors (Brown and Goldstein, 1986). In addition, alterations in apolipoproteins are associated with pathological conditions (Mahley, 1988). Whereas the regulation of lipoprotein metabolism and its effects on systemic lipid regulation have been studied extensively, much less is known about lipid tran...

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“…It is synthesized first and foremost in the liver, followed by the brain, 1,2 where its expression is upregulated after insults 2 and by estrogens. 3,4 It is currently accepted that the ⑀4 allele is a risk factor in Alzheimer's disease (AD) and that it determines an earlier development of the disease in a dosedependent manner. 5,6 Nevertheless, the presence of an ⑀4 allele is neither sufficient nor necessary for the development of AD and its role in the neuropathology of this disorder and in other neuropsychiatric illnesses, including schizophrenia, remains unclear.…”

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confidence: 99%

“…3,4 However, the specific role of apoE in the brain and the functional differences between the three common variants (E2, E3 and E4) are still unknown. To explore this issue further, Raber et al 23 analysed apoE transgenic mice that expressed similar levels of human apoE3 or E4 in the brain.…”

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confidence: 99%

Schizophrenic women with the APOE ε4 allele have a worse prognosis than those without it

et al. 2001

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The ⑀4 allele of APOE is generally accepted to be a risk factor in Alzheimer's disease and it has been related to other neuropsychiatric disorders, including schizophrenia. The results of several case-control studies have been inconclusive. To shed more light on this issue we carried out an association study that compared the APOE common variant in a group of 365 schizophrenia patients and 584 controls. We found no differences in the genotype distributions and allele frequencies of patients and controls. In the group of patients, we also analysed the possible influence of the ⑀4 allele in the clinical variables. The most important findings are that the age at onset (AAO) of ⑀4+ schizophrenic women, those that have one or two ⑀4 alleles, is 4 years earlier than that of ⑀4− women and their risk of suffering a negative syndrome subtype is four times greater. This was not found in schizophrenic men. Our results show that the APOE variant is not a risk factor for developing schizophrenia but that it may modulate its phenotypic expression in a sex-dependent manner. Molecular Psychiatry (2001) 6, 307-310.

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Astrocytes and Microglia Respond to Estrogen with Increased apoE mRNAin Vivoandin Vitro

Cited by 234 publications

References 23 publications

Production and characterization of astrocyte-derived human apolipoprotein E isoforms from immortalized astrocytes and their interactions with amyloid-β

Production and characterization of astrocyte-derived human apolipoprotein E isoforms from immortalized astrocytes and their interactions with amyloid-β

Nascent Astrocyte Particles Differ from Lipoproteins in CSF

Schizophrenic women with the APOE ε4 allele have a worse prognosis than those without it

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