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Cited by 2Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsBarrier Structure and Function Studies

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ApoE expression across the CNS: Who, What, Where, When, and How (much)?

Open access
Nolt, Georgia L., Lucido, Chloe C., Smith, Lily M., Johnson, Lance A.·2026·Molecular Neurodegeneration Advances
DOI 10.1186/s44477-026-00028-xPMC PMC13216210
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Abstract

Apolipoprotein E ( APOE ) is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD) and encodes a major lipid transporter in the central nervous system (CNS). Although apoE has been studied extensively, fundamental questions remain regarding its expression across the CNS. For example, which CNS cell types express APOE ? Where is APOE expression enriched across brain regions? When is APOE dynamically regulated – across development, aging, injury, and neurodegeneration? How much apoE is produced at the mRNA and protein level – particularly across the common E2, E3, and E4 isoforms? Here, we synthesize transcriptomic, spatial, biochemical, and genetic evidence to provide an organized framework for the “who, what, where, when, and how (much)” of CNS APOE /apoE. By assessing large-scale single-cell datasets along with in vivo and cell-type–specific genetic studies, we highlight that astrocytes are the predominant source of CNS apoE at baseline, while microglia, oligodendrocyte-lineage cells, vascular-associated populations, and border-interface macrophages exhibit context-dependent induction that is strongly influenced by aging, injury, and AD-related pathology. We also evaluate unresolved discrepancies, such as the extent of neuronal APOE expression and its contribution to total brain apoE, and describe how – across modalities – apoE abundance often follows an isoform-dependent hierarchy (typically E2 > E3 > E4 at the protein level) while transcript–protein discordance and model-specific effects underscore substantial post-transcriptional and contextual regulation. Finally, we discuss how clarifying spatiotemporal, cell-specific, and isoform-dependent apoE expression will enable better informed and more precise apoE-targeted therapeutic strategies.

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Crossref · 10.1186/s44477-026-00028-x

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Figures

Fig. 1 Cell-specific APOE expression in the CNS. Neuronal APOE/Apoe expression is low/absent across most neuronal subtypes but can be upregulated following injury or stress; select murine models suggest that neurons may contribute up to ~20% of total apoE. Oligodendrocytes exhibit low to moderate baseline APOE expression that is upregulated after injury or stress. Multiple vascular-associated cell types - including pericytes, endothelial, ependymal, smooth muscle, vascular leptomeningeal, and arachnoid barrier cells - express APOE to varying degrees, with pericytes constituting the primary vascular source. Astrocytes are the primary producers of apoE in the CNS, accounting for up to ~80% of total apoE at baseline, with region- and isoform-specific regulation and declining expression with aging and AD, Microglia display minimal, and in some cases undetectable, APOE expression under basal conditions; however, microglial APOE is robustly upregulated in response to injury, aging, and AD. Created with Biorender.com
Fig. 1 Cell-specific APOE expression in the CNS. Neuronal APOE/Apoe expression is low/absent across most neuronal subtypes but can be upregulated following injury or stress; select murine models suggest that neurons may contribute up to ~20% of total apoE. Oligodendrocytes exhibit low to moderate baseline APOE expression that is upregulated after injury or stress. Multiple vascular-associated cell types - including pericytes, endothelial, ependymal, smooth muscle, vascular leptomeningeal, and arachnoid barrier cells - express APOE to varying degrees, with pericytes constituting the primary vascular source. Astrocytes are the primary producers of apoE in the CNS, accounting for up to ~80% of total apoE at baseline, with region- and isoform-specific regulation and declining expression with aging and AD, Microglia display minimal, and in some cases undetectable, APOE expression under basal conditions; however, microglial APOE is robustly upregulated in response to injury, aging, and AD. Created with Biorender.comCC BY-NC-ND · PubMed Central
Fig. 2 Whole mouse brain transcriptomics. a, b, The 10X whole mouse brain (10X WMB) single cell RNA sequencing dataset integrates single-cell transcriptomics, single-nucleus multi-omics, and MERSCOPE spatial transcriptomics from wildtype (C57BL/6 J) mice aged postnatal day 50–71. a, Uniform manifold approximation and projection (UMAP) plots representing 4.04 million cells clustered into 34 classes (left) and colored by Apoe expression (right). High Apoe expressing classes include OPC-oligo (box 1), immune (box 2), and astro-epen / vascular (box 3). b, UMAP plots colored by subclass (left) and Apoe expression (right) reveal that border-associated macrophages (BAM) and astrocytes express the most Apoe in the mouse brain. ABC, Arachnoid barrier cell; Astro, astrocyte; CB, cerebellum; CGE, caudal ganglionic eminence; CNU, cerebral nuclei; CR, Cajal-Retzius cell; CT, CTX, cerebral cortex; DG, Dopa; Epen, ependymal; ET, extratelencephalic-projecting; GABA, GABAergic; Glut, glutamatergic; Gnrh1, gonadotropin releasing hormone 1; HB, hindbrain; Hya, anterior hypothalamus; HY, hypothalamus; OEC, olfactory ensheathing cell; Oligo, oligodendrocyte; OPC, oligodendrocyte precursor cell; IMN, immature neuron; IT, intratelencephalic-projecting; LGE, lateral ganglionic eminence; LH, lateral habenula; LSX, lateral septal complex; MB, midbrain; MGE, medial ganglionic eminence; MM, medial mammillary nucleus; MY, medulla; NP, near-projecting; OB, olfactory bulb; P, pons; Sero, serotonergic; SMC, smooth muscle cell; TH, thalamus; VLMC, vascular leptomeningeal cell
Fig. 2 Whole mouse brain transcriptomics. a, b, The 10X whole mouse brain (10X WMB) single cell RNA sequencing dataset integrates single-cell transcriptomics, single-nucleus multi-omics, and MERSCOPE spatial transcriptomics from wildtype (C57BL/6 J) mice aged postnatal day 50–71. a, Uniform manifold approximation and projection (UMAP) plots representing 4.04 million cells clustered into 34 classes (left) and colored by Apoe expression (right). High Apoe expressing classes include OPC-oligo (box 1), immune (box 2), and astro-epen / vascular (box 3). b, UMAP plots colored by subclass (left) and Apoe expression (right) reveal that border-associated macrophages (BAM) and astrocytes express the most Apoe in the mouse brain. ABC, Arachnoid barrier cell; Astro, astrocyte; CB, cerebellum; CGE, caudal ganglionic eminence; CNU, cerebral nuclei; CR, Cajal-Retzius cell; CT, CTX, cerebral cortex; DG, Dopa; Epen, ependymal; ET, extratelencephalic-projecting; GABA, GABAergic; Glut, glutamatergic; Gnrh1, gonadotropin releasing hormone 1; HB, hindbrain; Hya, anterior hypothalamus; HY, hypothalamus; OEC, olfactory ensheathing cell; Oligo, oligodendrocyte; OPC, oligodendrocyte precursor cell; IMN, immature neuron; IT, intratelencephalic-projecting; LGE, lateral ganglionic eminence; LH, lateral habenula; LSX, lateral septal complex; MB, midbrain; MGE, medial ganglionic eminence; MM, medial mammillary nucleus; MY, medulla; NP, near-projecting; OB, olfactory bulb; P, pons; Sero, serotonergic; SMC, smooth muscle cell; TH, thalamus; VLMC, vascular leptomeningeal cellCC BY-NC-ND · PubMed Central
Fig. 3 Whole human brain transcriptomics. a, b, The 10X whole adult human brain (10X WHB) single-nucleus RNA sequencing dataset is made up of 10Xv3 snRNA sequencing data from 3 male donors aged 18 to 68 years. a, UMAP plot represents 2.48 million neuronal cells colored by superclusters (left) and APOE expression (right). b, UMAP plot represents 888k non-neuronal cells colored by superclusters (left) and APOE expression (right). 6b, cortical layer 6b; AM, amygdaloid complex; CA1-3, regions CA1-3; CA4, region CA4; CB, cerebellar; CGE, caudal ganglionic eminence; CT, corticothalamic-projecting glutamatergic cortical neuron; DG, dentate gyrus; DL, deep layer of cortex; EMSN, eccentric medium spiny neuron; Ex, excitatory; HIPP, hippocampus; Inh, inhibitory; Int, interneuron; IT, intratelencephalic-projecting glutamatergic cortical neuron; L5-L6 Chan, LAMP5-LHX6 and chandelier cell; LRL, lower rhombic lip; MB, mamillary body; MGE, medial ganglionic eminence; MIDI, midbrain-derived inhibitory neuron; Misc, miscellaneous; MSN, medium spiny neuron; NP, near-projecting glutamatergic cortical neuron; TH, thalamus; UL, upper layers of cortex; URL, upper rhombic lip
Fig. 3 Whole human brain transcriptomics. a, b, The 10X whole adult human brain (10X WHB) single-nucleus RNA sequencing dataset is made up of 10Xv3 snRNA sequencing data from 3 male donors aged 18 to 68 years. a, UMAP plot represents 2.48 million neuronal cells colored by superclusters (left) and APOE expression (right). b, UMAP plot represents 888k non-neuronal cells colored by superclusters (left) and APOE expression (right). 6b, cortical layer 6b; AM, amygdaloid complex; CA1-3, regions CA1-3; CA4, region CA4; CB, cerebellar; CGE, caudal ganglionic eminence; CT, corticothalamic-projecting glutamatergic cortical neuron; DG, dentate gyrus; DL, deep layer of cortex; EMSN, eccentric medium spiny neuron; Ex, excitatory; HIPP, hippocampus; Inh, inhibitory; Int, interneuron; IT, intratelencephalic-projecting glutamatergic cortical neuron; L5-L6 Chan, LAMP5-LHX6 and chandelier cell; LRL, lower rhombic lip; MB, mamillary body; MGE, medial ganglionic eminence; MIDI, midbrain-derived inhibitory neuron; Misc, miscellaneous; MSN, medium spiny neuron; NP, near-projecting glutamatergic cortical neuron; TH, thalamus; UL, upper layers of cortex; URL, upper rhombic lipCC BY-NC-ND · PubMed Central
Fig. 4 Whole mouse brain MERSCOPE spatial transcriptomics. Whole mouse brain MERSCOPE spatial transcriptomics performed on 59 sections throughout the male mouse (postnatal day 56) reveals anatomically resolved Apoe expression. Representative images labeled by bregma distance are shown (left) with the dashed box denoting the enlarged brain section (right)
Fig. 4 Whole mouse brain MERSCOPE spatial transcriptomics. Whole mouse brain MERSCOPE spatial transcriptomics performed on 59 sections throughout the male mouse (postnatal day 56) reveals anatomically resolved Apoe expression. Representative images labeled by bregma distance are shown (left) with the dashed box denoting the enlarged brain section (right)CC BY-NC-ND · PubMed Central
Fig. 5 Reference table of CNS apoE studies. Reference numbers corresponding to our reference list. Species graphics indicate the species the study was carried out in (mouse, monkey, human, in vitro). Experimental design indicates the disease/injury model and/or apoE isoform present. “Who?” indicates the cell type, if any, in which apoE expression was measured. “What?” indicates if apoE protein (square) or mRNA (circle) was measured: E = ELISA, IHC = immunohistochemistry, P = proteomics, WB = western blot; PCR = reverse-transcription PCR, SC = single-cell RNA seq, ISH = in situ hybridization. “Where?” denotes in what brain region (mouse or human) apoE was measured. “When?” indicates at what time point the measurement was carried out. “How much? Isoform-specific differences?” describes apoE/APOE expression and any isoform-specific differences observed in the study. AD = Alzheimer’s disease, WT = wild-type, TR = targeted replacement, KO – knock out, LPS = lipopolysaccharide, KA = kainic acid, CB = cerebellum, HIP = hippocampus, CTX = cortex, THAL = thalamus, CC = corpus callosum, DG = dentate gyrus, micro = microglia, astro = astrocyte, olig = oligodendrocyte, IN = GABAergic interneuron, CP = choroid plexus cells, VLMC = vascular leptomeningeal cells, sol. [ApoE] = soluble apoE, insol. [ApoE] = insoluble apoE, intra[ApoE] = intracellular apoE
Fig. 5 Reference table of CNS apoE studies. Reference numbers corresponding to our reference list. Species graphics indicate the species the study was carried out in (mouse, monkey, human, in vitro). Experimental design indicates the disease/injury model and/or apoE isoform present. “Who?” indicates the cell type, if any, in which apoE expression was measured. “What?” indicates if apoE protein (square) or mRNA (circle) was measured: E = ELISA, IHC = immunohistochemistry, P = proteomics, WB = western blot; PCR = reverse-transcription PCR, SC = single-cell RNA seq, ISH = in situ hybridization. “Where?” denotes in what brain region (mouse or human) apoE was measured. “When?” indicates at what time point the measurement was carried out. “How much? Isoform-specific differences?” describes apoE/APOE expression and any isoform-specific differences observed in the study. AD = Alzheimer’s disease, WT = wild-type, TR = targeted replacement, KO – knock out, LPS = lipopolysaccharide, KA = kainic acid, CB = cerebellum, HIP = hippocampus, CTX = cortex, THAL = thalamus, CC = corpus callosum, DG = dentate gyrus, micro = microglia, astro = astrocyte, olig = oligodendrocyte, IN = GABAergic interneuron, CP = choroid plexus cells, VLMC = vascular leptomeningeal cells, sol. [ApoE] = soluble apoE, insol. [ApoE] = insoluble apoE, intra[ApoE] = intracellular apoECC BY-NC-ND · PubMed Central

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  1. Iadecola C, et al. Cell autonomous role of border associated macrophages in ApoE4 neurovascular dysfunction and susceptibility to white matter injury. Res Sq. 2023. · DOI

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Metadata

Authors
Nolt, G. L., Lucido, C. C., Smith, L. M., & Johnson, L. A.
Affiliations
University of Kentucky (US)
Corresponding author
Johnson, Lance A.
ORCID
Venue
Molecular Neurodegeneration Advances
Publisher
Springer Science and Business Media LLC
Published
2026-04-17
Volume
2
Issue
1
Pages
24-24
ISSN
3059-4944 (ISSN-L)
DOI
10.1186/s44477-026-00028-x
PMC
PMC13216210
OpenAlex
W7154709482
Cited by
2
References
193
Citations by year
2026: 2
FWCI
2.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration Advances (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
Funders
  • National Institutes of Health (R01AG081421)
  • National Institute of General Medical Sciences (COBRE P20 GM148326)
  • Alzheimer's Association (ABA-22-972169)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords
apolipoprotein E, APOE isoforms, Alzheimer's disease, central nervous system, astrocytes, microglia, oligodendrocyte lineage, spatiotemporal gene expression, post-transcriptional regulation, aging, neuroinflammation

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