Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins

Pitas, Robert E.; Boyles, J K; Lee, Susan H.; Foss, Donna; Mahley, Robert W.

doi:10.1016/0005-2760(87)90295-5

Cited by 619 publications

(383 citation statements)

References 35 publications

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“…ApoE is present in the brain as a component of HDL‐like particles that are secreted by astrocytes and are taken up by neurons by various lipoprotein receptors 15, 16. Following receptor‐mediated endocytosis, the ApoE‐containing HDL‐like particles are hydrolyzed in the lysosome, and the remaining ApoE is either degraded intracellularly or re‐lipidated in the secretory pathway or at the cell surface 34.…”

Section: Resultsmentioning

confidence: 99%

“…See text for details.Fractions from the discontinuous gradient were blotted with anti‐ApoE (WUE‐4) antibody; the doublet is a characteristic feature on ApoE Western blots due to ApoE sialylation 16.An ApoE‐containing fraction (fraction 5 [+]), an ApoE‐negative fraction (fraction 3 [−]), and recombinant lipid‐free ApoE protein were applied to human fibroblasts. Note increase in phospholipid synthesis using an ApoE4‐containing lipoprotein fraction, but not with either an ApoE4‐negative fraction or with lipoprotein‐free recombinant ApoE3 or ApoE4 protein (mean ± SE; n = 3, with 3 replicates/experiment).…”

Section: Resultsmentioning

confidence: 99%

“…Fractions from the discontinuous gradient were blotted with anti‐ApoE (WUE‐4) antibody; the doublet is a characteristic feature on ApoE Western blots due to ApoE sialylation 16.…”

Section: Resultsmentioning

confidence: 99%

“…APOE encodes apolipoprotein E (ApoE), a component of the lipoproteins that transport cholesterol and lipids throughout the body. In the brain, cholesterol is synthesized mainly by astrocytes but not neurons, with astrocyte‐derived cholesterol delivered to neurons via high‐density lipoproteins (HDL) 15, 16. The ε4 variant of APOE , denoted here as ApoE4 (arginines at positions 112 and 158; allele frequency in Europeans of ~10–30% 17), confers an increased gene dose‐dependent risk for developing AD of ~fourfold with one copy and ~12‐fold with 2 copies compared to individuals carrying ApoE3, the most common isotype (Cys112/Arg158; allele frequency of ~70–90%), while the rarest variant, ApoE2 (Cys112/Cys158; allele frequency of ~3–12%), is protective against AD 18.…”

Section: Introductionmentioning

confidence: 99%

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ApoE4 upregulates the activity of mitochondria‐associated ER membranes

et al. 2015

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In addition to the appearance of senile plaques and neurofibrillary tangles, Alzheimer's disease (AD) is characterized by aberrant lipid metabolism and early mitochondrial dysfunction. We recently showed that there was increased functionality of mitochondria‐associated endoplasmic reticulum (ER) membranes (MAM), a subdomain of the ER involved in lipid and cholesterol homeostasis, in presenilin‐deficient cells and in fibroblasts from familial and sporadic AD patients. Individuals carrying the ε4 allele of apolipoprotein E (ApoE4) are at increased risk for developing AD compared to those carrying ApoE3. While the reason for this increased risk is unknown, we hypothesized that it might be associated with elevated MAM function. Using an astrocyte‐conditioned media (ACM) model, we now show that ER–mitochondrial communication and MAM function—as measured by the synthesis of phospholipids and of cholesteryl esters, respectively—are increased significantly in cells treated with ApoE4‐containing ACM as compared to those treated with ApoE3‐containing ACM. Notably, this effect was seen with lipoprotein‐enriched preparations, but not with lipid‐free ApoE protein. These data are consistent with a role of upregulated MAM function in the pathogenesis of AD and may help explain, in part, the contribution of ApoE4 as a risk factor in the disease.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…Fractions from the discontinuous gradient were blotted with anti‐ApoE (WUE‐4) antibody; the doublet is a characteristic feature on ApoE Western blots due to ApoE sialylation 16.…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ApoE4 upregulates the activity of mitochondria‐associated ER membranes

et al. 2015

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“…In the brain, apoE is expressed predominantly by astrocytes but also by microglia ( Fig. 2) (Pitas et al 1987;Grehan et al 2001). Under certain conditions, such as after excitotoxic injury, some neurons appear to be able to synthesize apoE (Xu et al 1999;Xu et al 2006).…”

Section: Neurobiology Of Apoementioning

confidence: 99%

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

Holtzman

Herz²,

2012

Cold Spring Harbor Perspectives in Medicine

684

602

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Apolipoprotein E in Cerebrospinal Fluid in 85-Year-Old Subjects

Skoog¹

1997

Arch Neurol

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Whether our finding of an association between low CSF levels of Apo E and dementia disorders (both degenerative, such as AD, and vascular, such as VAD) is related to the pathogenesis of these disorders or is a secondary consequence of the disease process remains to be established. Although statistical correlations do not give direct evidence of causal relations, the correlations between CSF level of Apo E and severity of dementia and cortical atrophy suggest that CSF level of Apo E follows the disease process.

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Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins

Cited by 619 publications

References 35 publications

ApoE4 upregulates the activity of mitochondria‐associated ER membranes

ApoE4 upregulates the activity of mitochondria‐associated ER membranes

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

Apolipoprotein E in Cerebrospinal Fluid in 85-Year-Old Subjects

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