Human APOE4 increases microglia reactivity at Aβ plaques in a mouse model of Aβ deposition

Rodriguez, Gustavo A; Tai, Leon M; LaDu, Mary Jo; Rebeck, G William

doi:10.1186/1742-2094-11-111

Cited by 193Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNeurological Disease Mechanisms and Treatments

Human APOE4 increases microglia reactivity at Aβ plaques in a mouse model of Aβ deposition

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Rodriguez, Gustavo A, Tai, Leon M, LaDu, Mary Jo, Rebeck, G William·2014·Journal of Neuroinflammation

DOI 10.1186/1742-2094-11-111PMC PMC4077554

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Abstract

BACKGROUND: Having the apolipoprotein E4 (APOE-ϵ4) allele is the strongest genetic risk factor for the development of Alzheimer's disease (AD). Accumulation of amyloid beta (Aβ) in the brain is influenced by APOE genotype. Transgenic mice co-expressing five familial AD mutations (5xFAD) in the presence of human APOE alleles (ϵ2, ϵ3 or ϵ4) exhibit APOE genotype-specific differences in early Aβ accumulation, suggesting an interaction between APOE and AD pathology. Whether APOE genotype affects Aβ-plaque-associated neuroinflammation remains unclear. In the current study, we address the role of APOE genotype on Aβ-associated microglial reactivity in the EFAD transgenic mouse model. METHODS: We analyzed Aβ-induced glial activation in the brains of 6-month-old EFAD transgenic mice (E2FAD, E3FAD and E4FAD). Region-specific morphological profiles of Aβ plaques in EFAD brain sections were compared using immunofluorescence staining. We then determined the degree of glial activation in sites of Aβ deposition while comparing levels of the inflammatory cytokine Interleukin-1β (IL-1β) by ELISA. Finally, we quantified parameters of Aβ-associated microglial reactivity using double-stained EFAD brain sections. RESULTS: Characterization of Aβ plaques revealed there were larger and more intensely stained plaques in E4FAD mice relative to E2FAD and E3FAD mice. E4FAD mice also had a greater percentage of compact plaques in the subiculum than E3FAD mice. Reactive microglia and dystrophic astrocytes were prominent in EFAD brains, and primarily localized to two sites of significant Aβ deposition: the subiculum and deep layers of the cortex. Cortical levels of IL-1β were nearly twofold greater in E4FAD mice relative to E3FAD mice. To control for differences in levels of Aβ in the different EFAD mice, we analyzed the microglia within domains of specific Aβ deposits. Morphometric analyses revealed increased measures of microglial reactivity in E4FAD mice, including greater dystrophy, increased fluorescence intensity and a higher density of reactive cells surrounding cortical plaques, than in E3FAD mice. CONCLUSIONS: In addition to altering morphological profiles of Aβ deposition, APOE genotype influences Aβ-induced glial activation in the adult EFAD cortex. These data support a role for APOE in modulating Aβ-induced neuroinflammatory responses in AD progression, and support the use of EFAD mice as a suitable model for mechanistic studies of Aβ-associated neuroinflammation.

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APOE4 has been associated with altered plaque morphology, greater fibrillar amyloid deposition, and enhanced plaque-associated microglial reactivity.
“APOE4 has been associated with altered plaque morphology, greater fi brillar amyloid deposition, and enhanced plaque-associated microglialreactivity”
From APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease (2026) · cites this paper as [51]
The Results report altered plaque morphology in E4FAD mice and increased plaque-associated microglial reactivity in deep cortical layers; they found no genotype effect on microglial reactivity in the subiculum. The Discussion says this study used a pan-specific Aβ antibody, whereas a previous study used a stain for amyloid fibrils. This paper does not establish greater fibrillar amyloid deposition specifically. (LLM, conf=0.88)
Experimental — accuracy not yet measured
ApoE4-expressing 5xFAD mice display higher levels of glial activation and IL-1β as well as larger and more intensely stained Aβ plaques than apoE3-expressing 5xFAD mice.
“apoE4-expressing 5xFAD mice display higher levels of glial activation and the proinflammatory cytokine interleukin-1β (IL-1β) as well as larger and more intensely stained Aβ plaques than apoE3-expressing 5xFAD mice”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Rodriguez et al 2014
Other studies have reported that APOE2 expression is associated with similar or even higher plaque load than APOE3.
“Nevertheless other studies have also reported that APOE2 expression is associated with similar or even higher plaque load than APOE3 (Rodriguez et al, 2014; Youmans et al, 2012; Bales et al, 2009; Dodart et al, 2005).”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Rodriguez et al, 2014
The Results section on plaque morphology (page unavailable) reports a higher percentage of diffuse plaques in E2FAD than E3FAD mice, but percentages of plaque types do not establish total plaque load. Searches for E2FAD–E3FAD plaque burden and total Aβ load found no comparison showing that APOE2 has similar or higher plaque load than APOE3. (LLM, conf=0.76)
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Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies
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APOE mediated neuroinflammation and neurodegeneration in Alzheimer’s disease
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The increasing impact of cerebral amyloid angiopathy: essential new insights for clinical practice
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Apolipoprotein E and Alzheimer’s disease: Findings, hypotheses, and potential mechanisms
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APOE4 is associated with cognitive and pathological heterogeneity in patients with Alzheimer’s disease: a systematic review
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Updates on mouse models of Alzheimer’s disease
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Dl-3-n-Butylphthalide Inhibits NLRP3 Inflammasome and Mitigates Alzheimer's-Like Pathology via Nrf2-TXNIP-TrX Axis
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Melatonin and brain inflammaging
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Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention
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Therapeutic approaches targeting Apolipoprotein E function in Alzheimer’s disease
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<scp>APOE</scp>‐modulated Aβ‐induced neuroinflammation in Alzheimer's disease: current landscape, novel data, and future perspective
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Genetics ignite focus on microglial inflammation in Alzheimer’s disease
Malik, M., Parikh, I., Vasquez, J. B., Smith, C., Tai, L., Bu, G., LaDu, M. J., Fardo, D. W., Rebeck, G. W., & Estus, S. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0048-1 · Cited by 161 · see citing works
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The role of APOE on lipid homeostasis and inflammation in normal brains
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The Important Interface Between Apolipoprotein E and Neuroinflammation in Alzheimer’s Disease
Kloske, C. M., & Wilcock, D. M. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00754 · Cited by 152 · see citing works
APOE in the normal brain
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Invited Review: APOE at the interface of inflammation, neurodegeneration and pathological protein spread in Alzheimer's disease
Tzioras, M., Davies, C., Newman, A., Jackson, R., & Spires‐Jones, T. (2019) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12529 · Cited by 147 · see citing works
PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model
Katsouri, L., Lim, Y. M., Blondrath, K., Eleftheriadou, I., Lombardero, L., Birch, A. M., Mirzaei, N., Irvine, E. E., Mazarakis, N. D., & Sastre, M. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1606171113 · Cited by 146 · see citing works
Glial Contribution to Excitatory and Inhibitory Synapse Loss in Neurodegeneration
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Potential Bidirectional Relationship Between Periodontitis and Alzheimer’s Disease
Liccardo, D., Marzano, F., Carraturo, F., Guida, M., Femminella, G. D., Bencivenga, L., Agrimi, J., Addonizio, A., Melino, I., Valletta, A., et al. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00683 · Cited by 137 · see citing works
APOE-by-sex interactions on brain structure and metabolism in healthy elderly controls
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Microglia-Mediated Neuroprotection, TREM2, and Alzheimer’s Disease: Evidence From Optical Imaging
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Transgenic Mouse Models of Alzheimer’s Disease: An Integrative Analysis
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APOE4 drives inflammation in human astrocytes via TAGLN3 repression and NF-κB activation
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25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner
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APOE genotype and sex affect microglial interactions with plaques in Alzheimer’s disease mice
Stephen, T. L., Cacciottolo, M., Balu, D., Morgan, T. E., LaDu, M. J., Finch, C. E., & Pike, C. J. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0729-z · Cited by 115 · see citing works
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Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer’s disease via MFG-E8
Tzioras, M., Daniels, M. J. D., Davies, C., Baxter, P. S., King, D., McKay, S., Varga, B. V., Popovic, K., Hernandez, M., Stevenson, A. J., et al. (2023) · Cell Reports Medicine · doi:10.1016/j.xcrm.2023.101175 · Cited by 109 · see citing works
Innate Immunity Fights Alzheimer's Disease
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Plaque-associated local toxicity increases over the clinical course of Alzheimer disease
Serrano-Pozo, A., Betensky, R. A., Frosch, M. P., & Hyman, B. T. (2016) · The American Journal of Pathology · doi:10.1016/j.ajpath.2015.10.010 · Cited by 100 · see citing works
APOE4 enhances age-dependent decline in cognitive function by down-regulating an NMDA receptor pathway in EFAD-Tg mice
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EFAD transgenic mice as a human APOE relevant preclinical model of Alzheimerŉs disease
Tai, L. M., Balu, D., Avila-Munoz, E., Abdullah, L., Thomas, R., Collins, N., Valencia-Olvera, A. C., & LaDu, M. J. (2017) · Journal of Lipid Research · doi:10.1194/jlr.r076315 · Cited by 93 · see citing works
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Apolipoprotein E in Alzheimer’s disease: molecular insights and therapeutic opportunities
Belaidi, A. A., Bush, A. I., & Ayton, S. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00843-y · Cited by 91 · see citing works
Obesity and sex interact in the regulation of Alzheimer's disease
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Aβ propagation and strains: Implications for the phenotypic diversity in Alzheimer's disease
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Obesity Accelerates Alzheimer-Related Pathology inAPOE4but notAPOE3Mice
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Opposing effects of apoE2 and apoE4 on microglial activation and lipid metabolism in response to demyelination
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APOE ε4 associates with microglial activation independently of Aβ plaques and tau tangles
Ferrari-Souza, J. P., Lussier, F. Z., Leffa, D. T., Therriault, J., Tissot, C., Bellaver, B., Ferreira, P. C. L., Malpetti, M., Wang, Y.-T., Povala, G., et al. (2023) · Science Advances · doi:10.1126/sciadv.ade1474 · Cited by 81 · see citing works
Associations between brain inflammatory profiles and human neuropathology are altered based on apolipoprotein E ε4 genotype
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Remembering your A, B, C's: Alzheimer's disease and ABCA1
Lewandowski, C. T., Laham, M. S., & Thatcher, G. R. J. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.01.011 · Cited by 76 · see citing works
Chemogenetic attenuation of neuronal activity in the entorhinal cortex reduces Aβ and tau pathology in the hippocampus
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Viscoelastic and ultrastructural characteristics of whole blood and plasma in Alzheimer-type dementia, and the possible role of bacterial lipopolysaccharides (LPS)
Bester, J., Soma, P., Kell, D. B., & Pretorius, E. (2015) · Oncotarget · doi:10.18632/oncotarget.6074 · Cited by 75 · see citing works
ApoE4 and Connectivity-Mediated Spreading of Tau Pathology at Lower Amyloid Levels
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Animal Models of Metabolic Disorders in the Study of Neurodegenerative Diseases: An Overview
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Rosuvastatin enhances anti-inflammatory and inhibits pro-inflammatory functions in cultured microglial cells
Kata, D., Földesi, I., Fehér, L. Z., Hackler, L., Puskás, L. G., & Gulya, K. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.11.053 · Cited by 63 · see citing works
Murine Gut Microbiome Association With APOE Alleles
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Cancer Chemotherapy Related Cognitive Impairment and the Impact of the Alzheimer’s Disease Risk Factor APOE
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ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease
Li, Y., Macyczko, J. R., Liu, C.-C., & Bu, G. (2022) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2022.03.011 · Cited by 61 · see citing works
APOE ε4 specific imbalance of arachidonic acid and docosahexaenoic acid in serum phospholipids identifies individuals with preclinical Mild Cognitive Impairment/Alzheimer’s Disease
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Caffeic acid phenethyl ester reversed cadmium-induced cell death in hippocampus and cortex and subsequent cognitive disorders in mice: Involvements of AMPK/SIRT1 pathway and amyloid-tau-neuroinflammation axis
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Different mechanisms of apolipoprotein E isoform‐dependent modulation of prostaglandin E 2 production and triggering receptor expressed on myeloid cells 2 ( TREM2 ) expression after innate immune activation of microglia
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Early- and Late-Onset Alzheimer’s Disease: Two Sides of the Same Coin?
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Effect of APOE alleles on the glial transcriptome in normal aging and Alzheimer’s disease
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Ketogenic interventions in mild cognitive impairment, Alzheimer's disease, and Parkinson's disease: A systematic review and critical appraisal
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From beta amyloid to altered proteostasis in Alzheimer’s disease
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The efficacy of statins in the treatment of Alzheimer’s disease: a meta-analysis of randomized controlled trial
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Cholesterol Dysmetabolism in Alzheimer’s Disease: A Starring Role for Astrocytes?
Staurenghi, E., Giannelli, S., Testa, G., Sottero, B., Leonarduzzi, G., & Gamba, P. (2021) · Antioxidants · doi:10.3390/antiox10121890 · Cited by 44 · see citing works
Neuroimmunometabolism: A New Pathological Nexus Underlying Neurodegenerative Disorders
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Calcium Ions Aggravate Alzheimer’s Disease Through the Aberrant Activation of Neuronal Networks, Leading to Synaptic and Cognitive Deficits
Guan, P.-P., Cao, L., Yang, Y., & Wang, P. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.757515 · Cited by 44 · see citing works
Acute phase markers in CSF reveal inflammatory changes in Alzheimer’s disease that intersect with pathology, APOE ε4, sex and age
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Functional connectivity among brain regions affected in Alzheimer's disease is associated with CSF TNF-α in APOE4 carriers
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APOE genetics influence murine gut microbiome
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Microglia‐specific <scp>ApoE</scp> knock‐out does not alter Alzheimer's disease plaque pathogenesis or gene expression
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Quantification of molecular interactions between ApoE, amyloid-beta (Aβ) and laminin: Relevance to accumulation of Aβ in Alzheimer's disease
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Synapses, Microglia, and Lipids in Alzheimer’s Disease
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The role of ApoE-mediated microglial lipid metabolism in brain aging and disease
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Association of Hyperreflective Foci Present in Early Forms of Age-Related Macular Degeneration With Known Age-Related Macular Degeneration Risk Polymorphisms
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Self-citation

Authors: Rodriguez, G. A., Tai, L. M., LaDu, M. J., & Rebeck, G. W.
Affiliations: Georgetown University Medical Center (US)
University of Illinois Chicago (US)
Corresponding author: Rebeck, G William
ORCID: Rodriguez, Gustavo A
Tai, Leon M
LaDu, Mary Jo
Rebeck, G William
Venue: Journal of Neuroinflammation
Publisher: Springer Science and Business Media LLC
Published: 2014-06-19
Volume: 11
Issue: 1
Pages: 111-111
ISSN: 1742-2094 (ISSN-L)
DOI: 10.1186/1742-2094-11-111
PMC: PMC4077554
OpenAlex: W2107281222
Cited by: 193
References: 67
Citations by year: 2026: 11 · 2025: 15 · 2024: 19 · 2023: 20 · 2022: 28 · 2021: 19 · 2020: 21 · 2019: 13 · 2018: 14 · 2017: 12 · 2016: 5 · 2015: 15 · 2014: 1
FWCI: 7.33
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
Locations: Journal of Neuroinflammation (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: National Institutes of Health (UL1TR000050)
University of Illinois at Urbana-Champaign (UL1TR000050)
University of Illinois at Chicago (UL1TR000050)
National Institute on Aging (P01AG030128, R01AG035379, R01 AG035379-S)
National Institute of Neurological Disorders and Stroke (T32 NS041218-S1, T32NS041218)
National Center for Advancing Translational Sciences
Office of the Vice Chancellor for Research, University of Illinois at Chicago
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords: APOE ε4, apolipoprotein E, Alzheimer's disease, amyloid plaques, microglial activation, neuroinflammation, 5xFAD mice, IL-1β, APOE genotype, plaque morphology, subiculum, glial activation, APOE ε3
MeSH terms: Alzheimer Disease, Animals, Cerebral Cortex, Disease Models, Animal, Gene Expression Regulation, Humans, Mice, Transgenic, Mutation, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Microglia, Microscopy, Confocal, Mice, Apolipoprotein E4, Interleukin-1beta, Presenilin-1, Plaque, Amyloid

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Human APOE4 increases microglia reactivity at Aβ plaques in a mouse model of Aβ deposition

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