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Cited by 164Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsBarrier Structure and Function Studies

Expression and secretion of apoE isoforms in astrocytes and microglia during inflammation

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Lanfranco, Maria Fe, Sepulveda, Jordy, Kopetsky, Gregory, Rebeck, G. William·2021·Glia
DOI 10.1002/glia.23974PMC PMC8717762
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Abstract

Neuroinflammation is a common feature in neurodegenerative diseases, modulated by the Alzheimer's disease risk factor, apolipoprotein E ( APOE ). In the brain, apoE protein is synthesized by astrocytes and microglia. We examined primary cultures of astrocytes and microglia from human APOE (E2 , E3 , and E4) targeted‐replacement mice. Astrocytes secreted two species of apoE, whereas cellular apoE consisted of only one. Both forms of secreted astrocytic apoE were bound during glycoprotein isolation, and enzymatic removal of glycans produced a convergence of the two forms of apoE to a single form; thus, the two species of astrocyte‐secreted apoE are differentially glycosylated. Microglia released only a single species of apoE, while cellular apoE consisted of two forms; the secreted apoE and one of the two forms of cellular apoE were glycosylated. We treated the primary glia with either endogenous (TNFα) or exogenous (LPS) pro‐inflammatory stimuli. While LPS had no effect on astrocytic apoE, APOE2 , and APOE3 microglia increased release of apoE; APOE4 microglia showed no effect. APOE4 microglia showed higher baseline secretion of TNFα compared to APOE2 and APOE3 microglia. TNFα treatment reduced the secretion and cellular expression of apoE only in APOE4 astrocytes. The patterns of apoE species produced by astrocytes and microglia were not affected by inflammation. No changes in APOE mRNA were observed in astrocytes after both treatments. Together, our data demonstrate that astrocytes and microglia differentially express and secrete glycosylated forms of apoE and that APOE4 astrocytes and microglia are deficient in immunomodulation compared to APOE2 and APOE3 .

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  • Microglia-derived APOE has distinct post-translational modifications compared with APOE produced by astrocytes, and this is isoform-dependent.

    “this microglia-derived APOE has distinct post-translational modifications when compared with APOE produced by astrocytes and this, too, is isoform-dependent156.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [156]

    The Results section (‘ApoE species differ between astrocytes and microglia’; page unavailable) reports different patterns of glycosylated apoE in the two cell types. It also finds an APOE-genotype difference in intracellular microglial apoE, but no genotype difference in the distribution of secreted astrocytic apoE. Thus, isoform dependence is supported for a specific intracellular form, not for the cell-type difference generally. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Astrocytes secrete approx. 50-60% of the APOE they produce, while neurons retain most APOE intracellularly and only secrete approx. 10%.

    “Astrocytes secrete approx. 50–60% of the APOE they produce, while neurons retain most APOE intracellularly and only secrete approx. 10% [5,6]”

    From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [5]

    The Results section (‘ApoE species differ between astrocytes and microglia’; page unavailable) reports that astrocytes secreted 50–60% of the apoE they produced. The paper studies astrocytes and microglia, not neuronal secretion; its Discussion mentions apoE expression in injured neurons but gives no evidence that neurons retain most apoE or secrete approximately 10%. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • APOE4 has been implicated in multiple pathophysiological functions including pro-inflammatory state in microglia and astrocytes, endolysosomal dysfunction, impaired autophagy, inducing and promoting spreading of tau pathology, neurodegeneration, maintaining integrity of pericytes and blood brain barrier, and impaired myelination in oligodendrocytes.

    “Indeed, APOE4 has been implicated in the pro-inflammatory state in microglia (Brown et al, 2002; Colton et al, 2005; Lanfranco et al, 2021; Lin et al, 2018; Serrano-Pozo et al, 2021; Vitek et al, 2009) and astrocytes (Arnaud et al, 2022); endolysosomal dysfunction (Ji et al, 2002; Nuriel et al, 2017; Pohlkamp et al, 2021; Prasad and Rao, 2018; Xian et al, 2018); impaired autophagy (Parcon et al, 2”

    From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Lanfranco et al, 2021

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Cited by

Sorted by citations

Authors
Lanfranco, M. F., Sepulveda, J., Kopetsky, G., & Rebeck, G. W.
Affiliations
Georgetown University Medical Center (US)
Corresponding author
Rebeck, G. William
ORCID
Venue
Glia
Publisher
Wiley
Published
2021-02-08
Volume
69
Issue
6
Pages
1478-1493
ISSN
  • 0894-1491 (ISSN-L)
  • 1098-1136
DOI
10.1002/glia.23974
PMC
PMC8717762
OpenAlex
W3128514412
Cited by
164
References
13
Citations by year
2026: 31 · 2025: 40 · 2024: 32 · 2023: 27 · 2022: 27 · 2021: 7
FWCI
9.28
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Glia (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health (R01 AG067258, R01 NS100714)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords
apolipoprotein E, APOE isoforms, astrocytes, microglia, neuroinflammation, glycosylation, apoE secretion, APOE ε4, APOE2, APOE3, TNF-α, lipopolysaccharide, immunomodulation, Alzheimer's disease, targeted replacement mice
MeSH terms
Neuroinflammatory Diseases, Animals, Apolipoproteins E, Astrocytes, Inflammation, Lipopolysaccharides, Mice, Transgenic, Tumor Necrosis Factor-alpha, Microglia, Protein Isoforms, Mice, Apolipoprotein E3, Apolipoprotein E4, Apolipoprotein E2

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