Absence of Apolipoprotein E is associated with exacerbation of prion pathology and promotes microglial neurodegenerative phenotype
Open accessAbstract
Prion diseases or prionoses are a group of rapidly progressing and invariably fatal neurodegenerative diseases. The pathogenesis of prionoses is associated with self-replication and connectomal spread of PrP Sc, a disease specific conformer of the prion protein. Microglia undergo activation early in the course of prion pathogenesis and exert opposing roles in PrP Sc mediated neurodegeneration. While clearance of PrP Sc and apoptotic neurons have disease-limiting effect, microglia-driven neuroinflammation bears deleterious consequences to neuronal networks. Apolipoprotein (apo) E is a lipid transporting protein with pleiotropic functions, which include controlling of the phagocytic and inflammatory characteristics of activated microglia in neurodegenerative diseases. Despite the significance of microglia in prion pathogenesis, the role of apoE in prionoses has not been established. We showed here that infection of wild type mice with 22L mouse adapted scrapie strain is associated with significant increase in the total brain apoE protein and mRNA levels and also with a conspicuous cell-type shift in the apoE expression. There is reduced expression of apoE in activated astrocytes and marked upregulation of apoE expression by activated microglia. We also showed apoE ablation exaggerates PrP Sc mediated neurodegeneration. Apoe−/− mice have shorter disease incubation period, increased load of spongiform lesion, pronounced neuronal loss, and exaggerated astro and microgliosis. Astrocytes of Apoe−/− mice display salient upregulation of transcriptomic markers defining A1 neurotoxic astrocytes while microglia show upregulation of transcriptomic markers characteristic for microglial neurodegenerative phenotype. There is impaired clearance of PrP Sc and dying neurons by microglia in Apoe−/− mice along with increased level of proinflammatory cytokines. Our work indicates that apoE absence renders clearance of PrP Sc and dying neurons by microglia inefficient, while the excess of neuronal debris promotes microglial neurodegenerative phenotype aggravating the vicious cycle of neuronal death and neuroinflammation.
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Both ApoE and TREM2 are upregulated in prion disease and affect the expression of pro-inflammatory proteins during the disease course in murine models, but their depletion did not change survival times.
“Both proteins are upregulated in prion disease and affect the expression of pro-inflammatory proteins during the disease course in murine models. However, their depletion did not change survival times [102,103,104].”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [104]
The microglia signature in prion diseases differs from that seen in other neurodegenerative diseases.
“The microglia signature in prion diseases also differs from that seen in other neurodegenerative diseases [104].”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [104]
Deletion of ApoE might influence the course of prion disease including exacerbation of prion pathology, a dysregulated microglial phenotype, and impaired clearance of PrPSc and dying neurons by microglia.
“However, the deletion of ApoE might influence the course of prion disease including the exacerbation of prion pathology, a dysregulated microglial phenotype, and impaired clearance of PrPSc and dying neurons by microglia [104].”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [104]
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Chen, X. R., Initiative, A. D. N., Shao, Y., & Sadowski, M. J. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210434 · Cited by 21 · see citing works
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Differential molecular chaperone response associated with various mouse adapted scrapie strains
Asuni, A. A., Pankiewicz, J. E., & Sadowski, M. J. (2013) · Neuroscience Letters · doi:10.1016/j.neulet.2013.01.027 · Cited by 10 · see citing works
Self-citationInfections of the Nervous System
Sadowski, M. C., Verma, A. K., & Wısnıewskı, T. (2008) · Elsevier eBooks · doi:10.1016/b978-0-7506-7525-3.50091-1 · Cited by 6 · see citing works
Self-citation
Flagged first, then by citations
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Cited by
Sorted by citations
Tian, Y., Zhao, M., Chen, Y., Yang, M., & Wang, Y. (2022) · Biomolecules · doi:10.3390/biom12060748 · Cited by 69 · see citing works
ApoE4-Mediated Blood Brain Barrier Damage in Alzheimer's Disease: Progress and Prospects
Zhou, X., Shi, Q., Zhang, X., Gu, L., Li, J., Ju, Y., Hu, M., Zhao, X., & Li, Q. (2022) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2023.110670 · Cited by 37 · see citing works
Multi-functional role of apolipoprotein E in neurodegenerative diseases
Islam, S., Noorani, A., Sun, Y., Michikawa, M., & Zou, K. (2025) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2025.1535280 · Cited by 30 · see citing works
Circadian Regulation of Apolipoproteins in the Brain: Implications in Lipid Metabolism and Disease
Lee, C., Murrell, C. E., Chu, A., & Pan, X. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242417415 · Cited by 20 · see citing works
Loss of Homeostatic Microglia Signature in Prion Diseases
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“However, the deletion of ApoE might influence the course of prion disease including the exacerbation of prion pathology, a dysregulated microglial phenotype, and impaired clearance of PrPSc and dying neurons by microglia [104].”
BackgroundInfluentialAshford, B., Simpson, J. E., Dawson, C., Boche, D., Cooper‐Knock, J., Heath, P. R., Fillingham, D. J., Appleby‐Mallinder, C., Wei, W., Dunning, M., et al. (2025) · Brain Pathology · doi:10.1111/bpa.70019 · Cited by 13 · see citing works
Diaz, J. R., Martá-Ariza, M., Khodadadi‐Jamayran, A., Heguy, A., Tsirigos, A., Pankiewicz, J. E., Sullivan, P. M., & Sadowski, M. J. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.845291 · Cited by 10 · see citing works
Self-citationCholesterol and its reciprocal association with prion infection
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Αnti-prion effects of anthocyanins
Christoudia, N., Bekas, N., Kanata, Ε., Chatziefsthathiou, A., Pettas, S., Karagianni, K., Correia, S., Schmitz, M., Zerr, I., Tsamesidis, I., et al. (2024) · Redox Biology · doi:10.1016/j.redox.2024.103133 · Cited by 5 · see citing works
The Role of Glial Cells in Neurobiology and Prion Neuropathology
Hay, A. J. D., Popichak, K. A., Moreno, J. A., & Zabel, M. D. (2024) · Cells · doi:10.3390/cells13100832 · Cited by 5 · see citing works
Zeng, S., Wang, Y., Liu, X., Feng, H., Cao, F., Chu, B., Wu, C., Fan, W., Hu, K., Lei, F., et al. (2026) · Science Advances · doi:10.1126/sciadv.aeb3991 · Cited by 4 · see citing works
Ashford, B., Simpson, J. E., Dawson, C., Boche, D., Cooper‐Knock, J., Heath, P. R., Fillingham, D. J., Appleby‐Mallinder, C., Wei, W., Dunning, M., et al. (2025) · medRxiv · doi:10.1101/2025.02.07.25321850
Glymphatic impairment in Moyamoya disease
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APOE genotype differentially modulates prion pathology in a mouse model
Lizińczyk, A. M., Pankiewicz, J. E., Cullina, W. L., Franco, L. A., Sullivan, P. M., & Sadowski, M. J. (2026) · Acta Neuropathologica Communications · doi:10.1186/s40478-025-02207-5
Self-citationFreire, M. H. O., Linden, R., & Cordeiro, Y. (2026) · Biochemical Society Transactions · doi:10.1042/bst20253081
- Authors
- Pankiewicz, J. E., Lizińczyk, A. M., Franco, L. A., Diaz, J. R., Martá-Ariza, M., & Sadowski, M. J.
- Affiliations
- NYU Langone Health (US)
- Corresponding author
- Sadowski, Martin J.
- Venue
- Acta Neuropathologica Communications
- Published
- 2021-09-26
- Volume
- 9
- Issue
- 1
- Pages
- 157-157
- ISSN
- 2051-5960 (ISSN-L)
- PMC
- PMC8474943
- OpenAlex
- W3202705426
- Cited by
- 15
- References
- 86
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 2 · 2023: 1 · 2022: 5
- FWCI
- 0.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Acta Neuropathologica Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- national institute on aging (R01 AG031221, R01 AG053990, R01 AG067478)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- apolipoprotein E, prion disease, scrapie, PrPSc, microglia, astrocytes, neuroinflammation, inflammatory cytokines, ApoE-deficient mice, neuronal loss
- MeSH terms
- Animals, Apolipoproteins E, Female, Male, Mice, Inbred C57BL, Nerve Degeneration, Phenotype, Prion Diseases, Microglia, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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