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Cited by 92Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNeurogenesis and neuroplasticity mechanisms

Single-cell RNA-sequencing identifies disease-associated oligodendrocytes in male APP NL-G-F and 5XFAD mice

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Park, Hanseul, Cho, Byounggook, Kim, Hongwon, Saito, Takashi, Saido, Takaomi C., Won, Kyoung-Jae, Kim, Jongpil·2023·Nature Communications
DOI 10.1038/s41467-023-36519-8PMC PMC9925742
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Abstract

Alzheimer’s disease (AD) is associated with progressive neuronal degeneration as amyloid-beta (Aβ) and tau proteins accumulate in the brain. Glial cells were recently reported to play an important role in the development of AD. However, little is known about the role of oligodendrocytes in AD pathogenesis. Here, we describe a disease-associated subpopulation of oligodendrocytes that is present during progression of AD-like pathology in the male App NL-G-F and male 5xFAD AD mouse brains and in postmortem AD human brains using single-cell RNA sequencing analysis. Aberrant Erk1/2 signaling was found to be associated with the activation of disease-associated oligodendrocytes (DAOs) in male App NL-G-F mouse brains. Notably, inhibition of Erk1/2 signaling in DAOs rescued impaired axonal myelination and ameliorated Aβ-associated pathologies and cognitive decline in the male App NL-G-F AD mouse model.

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  • Transcriptomic studies have shown changes in microglia, astrocytes, and oligodendrocytes in mouse models of Alzheimer's disease.

    “and in mouse models of AD [7,8]”

    From Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease (2024) · cites this paper as [8]

    The Results (no page available) report single-cell transcriptomic changes in oligodendrocytes from AD mouse models and analyze disease-associated microglia. The Introduction describes disease-associated astrocytes from another study, but the passages do not establish transcriptomic changes in astrocytes in mouse models. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Single-cell and single-nucleus RNA sequencing studies have identified multiple disease-associated glial subtypes with distinct transcriptional states and selectively vulnerable neuronal populations in amyloidosis or tauopathy models.

    “These studies have identified multiple disease‐associated glial subtypes with distinct transcriptional states and selectively vulnerable neuronal populations in amyloidosis models 16 , 17 , 18 or tauopathy models. 19 , 20 , 21”

    From Unique transcriptomic alterations in 5XFAD;PS19 mouse model identify glial lipid dysregulation and coordinated microglial–oligodendrocyte responses (2026) · cites this paper as [17]

    The Abstract (page unavailable) reports a disease-associated oligodendrocyte subpopulation identified by single-cell RNA sequencing in amyloidosis mouse models, and the Introduction describes other disease-associated glial subtypes. The paper does not identify selectively vulnerable neuronal populations; its contribution supports the glial part of the amyloidosis claim, not that neuronal part. The tauopathy portion is attached to other citations. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Like DAM, which appears in 5XFAD at 1 to 2 months of age, DAO is also enriched near Aβ plaques at 9 to 10 months of age.

    “Like DAM, which appears in 5XFAD at 1 to 2 months of age, DAO is also enriched near Aβ plaques at 9 to 10 months of age. 17 , 46”

    From Unique transcriptomic alterations in 5XFAD;PS19 mouse model identify glial lipid dysregulation and coordinated microglial–oligodendrocyte responses (2026) · cites this paper as [17]

    The Results section, “Molecular signature of disease-associated oligodendrocytes” (Fig. 3h–i; page unavailable), reports DAOs adjacent to Aβ plaques, but the pictured mice were 6-month-old AppNL-G-F mice, not 9–10 months old. Our copy does not establish that DAM appears in 5XFAD mice at 1–2 months of age. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • O_3 cluster was distinctly enriched for marker genes of disease-associated oligodendrocytes (DAO) compared to other oligodendrocyte clusters, with DAO signature most prominently expressed in 5XFAD;PS19.

    “Moreover, the O_3 cluster was distinctly enriched for marker genes of disease‐associated oligodendrocytes (DAO) 17 , 46 compared to other oligodendrocyte clusters, with the DAO signature most prominently expressed in the 5XFAD;PS19 model (Figure S4A,B in supporting information).”

    From Unique transcriptomic alterations in 5XFAD;PS19 mouse model identify glial lipid dysregulation and coordinated microglial–oligodendrocyte responses (2026) · cites this paper as [17]

  • Pro-inflammatory DAM and DAO localize to Aβ plaques.

    “The localization of pro‐inflammatory DAM and DAO to Aβ plaques 16 , 17 , 46 further reinforces the role of Aβ as the primary trigger for these immune responses.”

    From Unique transcriptomic alterations in 5XFAD;PS19 mouse model identify glial lipid dysregulation and coordinated microglial–oligodendrocyte responses (2026) · cites this paper as [17]

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References 56 · Cited by 92

Research works printed but not linked: 39

  1. [1]Finch CE Cohen DM Aging, metabolism, and Alzheimer disease: review and hypotheses Exp. Neurol. 1997 143 82 102 10.1006/exnr.1996.6339 9000448 · DOI
  2. [2]Rogers J Complement activation by beta-amyloid in Alzheimer disease Proc. Natl Acad. Sci. USA 1992 89 10016 10020 10.1073/pnas.89.21.10016 1438191 PMC50268 · DOI · Paper page
  3. [3]Hensley K A model for beta-amyloid aggregation and neurotoxicity based on the free radical generating capacity of the peptide: implications of “molecular shrapnel” for Alzheimer’s disease Proc. West Pharm. Soc. 1995 38 113 120 7480002
  4. [5]von Bernhardi R Glial cell dysregulation: a new perspective on Alzheimer disease Neurotox. Res. 2007 12 215 232 10.1007/BF03033906 18201950 · DOI
  5. [6]Dzamba, D., Harantova, L., Butenko, O. & Anderova, M. Glial cells—the key elements of Alzheimer’s disease. Curr. Alzheimer Res.13, 894–911 (2016). 26825092
  6. [9]Cameron B Landreth GE Inflammation, microglia, and Alzheimer’s disease Neurobiol. Dis. 2010 37 503 509 10.1016/j.nbd.2009.10.006 19833208 PMC2823849 · DOI
  7. [11]Habib N Disease-associated astrocytes in Alzheimer’s disease and aging Nat. Neurosci. 2020 23 701 706 10.1038/s41593-020-0624-8 32341542 PMC9262034 · DOI · Paper page
  8. [12]Nasrabady SE Rizvi B Goldman JE Brickman AM White matter changes in Alzheimer’s disease: a focus on myelin and oligodendrocytes Acta Neuropathol. Commun. 2018 6 22 10.1186/s40478-018-0515-3 29499767 PMC5834839 · DOI · Paper page
  9. [13]Bartzokis G Alzheimer’s disease as homeostatic responses to age-related myelin breakdown Neurobiol. Aging 2011 32 1341 1371 10.1016/j.neurobiolaging.2009.08.007 19775776 PMC3128664 · DOI · Paper page
  10. [14]Desai MK Triple-transgenic Alzheimer’s disease mice exhibit region-specific abnormalities in brain myelination patterns prior to appearance of amyloid and tau pathology Glia 2009 57 54 65 10.1002/glia.20734 18661556 PMC2584762 · DOI · Paper page
  11. [15]Pak K Chan SL Mattson MP Presenilin-1 mutation sensitizes oligodendrocytes to glutamate and amyloid toxicities, and exacerbates white matter damage and memory impairment in mice Neuromolecular Med. 2003 3 53 64 10.1385/NMM:3:1:53 12665676 · DOI
  12. [16]Behrendt G Dynamic changes in myelin aberrations and oligodendrocyte generation in chronic amyloidosis in mice and men Glia 2013 61 273 286 10.1002/glia.22432 23090919 · DOI · Paper page
  13. [17]Xu J Amyloid-beta peptides are cytotoxic to oligodendrocytes J. Neurosci. 2001 21 RC118 10.1523/JNEUROSCI.21-01-j0001.2001 11150354 PMC6762453 · DOI · Paper page
  14. [18]Desai MK Guercio BJ Narrow WC Bowers WJ An Alzheimer’s disease-relevant presenilin-1 mutation augments amyloid-beta-induced oligodendrocyte dysfunction Glia 2011 59 627 640 10.1002/glia.21131 21294162 PMC3045399 · DOI
  15. [19]Zhou Y Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease Nat. Med. 2020 26 131 142 10.1038/s41591-019-0695-9 31932797 PMC6980793 · DOI · Paper page
  16. [20]Kenigsbuch M A shared disease-associated oligodendrocyte signature among multiple CNS pathologies Nat. Neurosci. 2022 25 876 886 10.1038/s41593-022-01104-7 35760863 PMC9724210 · DOI · Paper page
  17. [25]Ximerakis M Single-cell transcriptomic profiling of the aging mouse brain Nat. Neurosci. 2019 22 1696 1708 10.1038/s41593-019-0491-3 31551601 · DOI · Paper page
  18. [28]Bryan KJ Expression of CD74 is increased in neurofibrillary tangles in Alzheimer’s disease Mol. Neurodegener. 2008 3 13 10.1186/1750-1326-3-13 18786268 PMC2565661 · DOI · Paper page
  19. [29]Lu T REST and stress resistance in ageing and Alzheimer’s disease Nature 2014 507 448 454 10.1038/nature13163 24670762 PMC4110979 · DOI
  20. [30]Potluri P A novel NDUFA1 mutation leads to a progressive mitochondrial complex I-specific neurodegenerative disease Mol. Genet Metab. 2009 96 189 195 10.1016/j.ymgme.2008.12.004 19185523 PMC2693342 · DOI
  21. [31]Zhu M Gong X Hu Y Ou W Wan Y Streptavidin-biotin-based directional double Nanobody sandwich ELISA for clinical rapid and sensitive detection of influenza H5N1 J. Transl. Med. 2014 12 352 10.1186/s12967-014-0352-5 25526777 PMC4274719 · DOI
  22. [34]Deng W Poretz RD Oligodendroglia in developmental neurotoxicity Neurotoxicology 2003 24 161 178 10.1016/S0161-813X(02)00196-1 12606289 · DOI
  23. [35]Lu PH Age-related slowing in cognitive processing speed is associated with myelin integrity in a very healthy elderly sample J. Clin. Exp. Neuropsychol. 2011 33 1059 1068 10.1080/13803395.2011.595397 22133139 PMC3269444 · DOI
  24. [36]Sims R Evidence that variation in the oligodendrocyte lineage transcription factor 2 (OLIG2) gene is associated with psychosis in Alzheimer’s disease Neurosci. Lett. 2009 461 54 59 10.1016/j.neulet.2009.05.051 19477230 · DOI
  25. [37]Sortwell CE Oligodendrocyte-type 2 astrocyte-derived trophic factors increase survival of developing dopamine neurons through the inhibition of apoptotic cell death J. Comp. Neurol. 2000 426 143 153 10.1002/1096-9861(20001009)426:1<143::AID-CNE10>3.0.CO;2-8 10980489 · DOI
  26. [39]Radde R Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology EMBO Rep. 2006 7 940 946 10.1038/sj.embor.7400784 16906128 PMC1559665 · DOI · Paper page
  27. [44]Yu KR Rapid and efficient direct conversion of human adult somatic cells into neural stem cells by HMGA2/let-7b Cell Rep. 2015 10 441 452 10.1016/j.celrep.2014.12.038 25600877 · DOI
  28. [45]Lee Y Two-step generation of oligodendrocyte progenitor cells from mouse fibroblasts for spinal cord injury Front Cell Neurosci. 2018 12 198 10.3389/fncel.2018.00198 30090058 PMC6070016 · DOI
  29. [46]Pang Y Neuron-oligodendrocyte myelination co-culture derived from embryonic rat spinal cord and cerebral cortex Brain Behav. 2012 2 53 67 10.1002/brb3.33 22574274 PMC3343299 · DOI
  30. [47]Diez-Revuelta N Neurons define non-myelinated axon segments by the regulation of galectin-4-containing axon membrane domains Sci. Rep. 2017 7 12246 10.1038/s41598-017-12295-6 28947766 PMC5612983 · DOI
  31. [48]Street K Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics BMC Genomics 2018 19 477 10.1186/s12864-018-4772-0 29914354 PMC6007078 · DOI · Paper page
  32. [49]Feld M Decrease of ERK/MAPK overactivation in prefrontal cortex reverses early memory deficit in a mouse model of Alzheimer’s disease J. Alzheimers Dis. 2014 40 69 82 10.3233/JAD-131076 24334722 · DOI
  33. [50]Park H In vivo neuronal gene editing via CRISPR-Cas9 amphiphilic nanocomplexes alleviates deficits in mouse models of Alzheimer’s disease Nat. Neurosci. 2019 22 524 528 10.1038/s41593-019-0352-0 30858603 · DOI
  34. [51]Koenning M Myelin gene regulatory factor is required for maintenance of myelin and mature oligodendrocyte identity in the adult CNS J. Neurosci. 2012 32 12528 12542 10.1523/JNEUROSCI.1069-12.2012 22956843 PMC3752083 · DOI
  35. [52]Wu D LINGO-1 antibody ameliorates myelin impairment and spatial memory deficits in the early stage of 5XFAD mice CNS Neurosci. Ther. 2018 24 381 393 10.1111/cns.12809 29427384 PMC6489849 · DOI · Paper page
  36. [53]Park H CRISPR/dCas9-Dnmt3a-mediated targeted DNA methylation of APP rescues brain pathology in a mouse model of Alzheimer’s disease Transl. Neurodegener. 2022 11 41 10.1186/s40035-022-00314-0 36109806 PMC9476342 · DOI
  37. [54]Park H Kim J Activation of melatonin receptor 1 by CRISPR-Cas9 activator ameliorates cognitive deficits in an Alzheimer’s disease mouse model J. Pineal Res. 2022 72 e12787 10.1111/jpi.12787 35133672 · DOI
  38. [55]Park H Hwang Y Kim J Transcriptional activation with Cas9 activator nanocomplexes rescues Alzheimer’s disease pathology Biomaterials 2021 279 121229 10.1016/j.biomaterials.2021.121229 34739981 · DOI
  39. [56]Kim H Dormant state of quiescent neural stem cells links Shank3 mutation to autism development Mol. Psychiatry 2022 27 2751 2765 10.1038/s41380-022-01563-1 35444258 · DOI

Authors
Park, H., Cho, B., Kim, H., Saito, T., Saido, T. C., Won, K.-J., & Kim, J.
Affiliations
  • Dongguk University (KR)
  • RIKEN Center for Brain Science (JP)
  • Cedars-Sinai Medical Center (US)
Corresponding author
  • Won, Kyoung-Jae
  • Kim, Jongpil
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-02-13
Volume
14
Issue
1
Pages
802-802
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-023-36519-8
PMC
PMC9925742
OpenAlex
W4320490883
Cited by
92
References
56
Citations by year
2026: 20 · 2025: 38 · 2024: 27 · 2023: 7
FWCI
17.94
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Mayo Clinic (P50 AG016574, R01 AG032990)
  • Arizona Department of Health Services (P50 AG016574, RF1AG057440, R01 AG032990)
  • Rush University
  • National Research Foundation
  • National Research Foundation of Korea (2022R1A6A1A03053343, 2021M3E5E5096464)
  • National Center for Geriatrics and Gerontology
  • Ministry of Science and ICT, South Korea (2021M3E5E5096464, 2021R1C1C1006551)
  • Arizona Biomedical Research Commission
  • National Institutes of Health (U24NS07-2026, U01AG006576, R01AG01-8023, R01AG03-6836, AG016574, R01AG025711, R01AG003949, R01AG017216)
  • Samsung
  • National Institute on Aging (R01AG017917, U01AG046170, R01AG018023, R01AG036836, U01AG046152, U01AG006786, P01AG003949, R01AG023571, R01AG015819, RF1AG057440, P30AG010161, U01AG061356, P50AG025711, R01AG032990, P30AG019610, P01AG017216, U01AG046139, U24AG061340, P30AG072975, P50AG016574)
  • National Institute of Neurological Disorders and Stroke (R01NS080820, U24NS072026)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
Alzheimer's disease, ERK signaling, 5xFAD mice, amyloid-beta, axonal myelination, cognitive decline, glial cells, male brain, single-cell RNA sequencing
MeSH terms
Alzheimer Disease, Animals, Disease Models, Animal, Humans, Male, Mice, Transgenic, Oligodendroglia, RNA, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Mice

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