In toxic demyelination oligodendroglial cell death occurs early and is FAS independent
Open accessAbstract
Oligodendroglial cell death is a frequent phenomenon of many neurological diseases, e.g. in demyelinating diseases such as multiple sclerosis (MS). The underlying mechanisms are largely unknown. Here, we demonstrate that in the toxic demyelination cuprizone model, oligodendroglial cell death and downregulation of myelin genes start days after initiation of the cuprizone diet and weeks before demyelination is obvious. In early - but not in later - stages, dying oligodendrocytes express activated caspase 3, suggesting a switch from classical apoptotic pathways to caspase 3-independent mechanisms during the course of the cuprizone diet. The expression level of FAS in the corpus callosum, a cell death receptor crucial for oligodendroglial cell death in experimental autoimmune encephalomyelitis (EAE), correlates with the expression of activated caspase 3 in oligodendrocytes. However, mice lacking FAS in oligodendrocytes are not protected against cuprizone-induced oligodendroglial cell death, showing that FAS is dispensable for oligodendroglial cell death in the cuprizone model.
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A switch from Caspase 3-dependent to Caspase 3-independent form of apoptosis is reported for later stages of cuprizone exposure.
“(1), a switch from Caspase 3-dependent to Caspase 3-independent form of apoptosis is reported for later stages of cuprizone exposure [33];”
From Strain differences in cuprizone induced demyelination (2017) · cites this paper as [33]
The Results report that activated caspase 3 was present in 97% of apoptotic cells on day 6 but absent from dying cells on day 21. The Discussion describes this as suggestive of a switch to caspase 3-independent cell death; it only speculates that apoptosis-like mechanisms contribute at later stages, rather than establishing a caspase 3-independent form of apoptosis. (LLM, conf=0.86)
Experimental — accuracy not yet measuredBy three weeks of cuprizone consumption, dying oligodendrocytes condense but are unfragmented and no longer co-label with CC-3.
“However, by three weeks of cuprizone consumption, dying oligodendrocytes condense, but are unfragmented, and no longer co-label with CC-3 [278].”
From Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination (2022) · cites this paper as [278]
The Results and Fig. 1 caption report that after 21 days of cuprizone feeding, dying oligodendrocytes had condensed nuclei and were negative for activated caspase 3 (CC-3). They say the nuclei were rarely fragmented, however, not that they were entirely unfragmented. (LLM, conf=0.86)
Experimental — accuracy not yet measuredOligodendrocyte apoptosis reaches its maximum between week 1 and week 3, with the number of apoptotic cells remaining constant thereafter.
“Oligodendrocyte apoptosis reaches its maximum between week 1 and week 3, with the number of apoptotic cells remaining constant thereafter [100, 161, 278].”
From Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination (2022) · cites this paper as [278]
The Discussion reports maximal numbers of apoptotic oligodendrocytes on days 10 and 21. The Results report similar numbers on days 6, 10, and 21, but the mice were studied only through day 21. The paper therefore does not establish that apoptotic-cell numbers remained constant after week 3 (page numbers unavailable in our copy). (LLM, conf=0.88)
Experimental — accuracy not yet measuredOther glial cells, such as GFAP+ astrocytes or IBA1+ microglia, do not show any signs of cell death during early cuprizone intoxication.
“In contrast, other glial cells, such as glial fibrillary acidic protein (GFAP)+ astrocytes or IBA1+ microglia, do not show any signs of cell death [22,45].”
From How to Use the Cuprizone Model to Study De- and Remyelination (2024) · cites this paper as [45]
The Results section reports no condensed or fragmented nuclei characteristic of apoptotic cell death in GFAP-positive astrocytes or MAC3-positive microglia/macrophages during early cuprizone treatment (page unavailable). It does not report testing IBA1-positive microglia, and absence of those apoptotic features is narrower than absence of any signs of cell death. (LLM, conf=0.83)
Experimental — accuracy not yet measuredAt early time points of cuprizone intoxication, no overt differences in major myelin proteins such as PLP or MBP can be observed.
“To estimate the extent of early myelin damage, the visualization of major myelin proteins, such as proteolipid protein (PLP) or myelin basic protein (MBP), is not considered to be an appropriate strategy because no overt differences can be observed at this early time point [22,45,53].”
From How to Use the Cuprizone Model to Study De- and Remyelination (2024) · cites this paper as [45]
The Results section, “Myelin gene expression during early cuprizone-induced demyelination,” reports comparable LFB-PAS and CNP staining on days 6 and 10 and no significant change in cortical MBP staining at those times. This supports the point about early visualization, but the paper does not report PLP staining, so the claim’s PLP example is not established by this source. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Numerous degenerating oligodendrocytes (condensed and/or fragmented nuclei of cells in a chain-like formation) can be seen in the corpus callosum as early as 2 days after initiation of cuprizone intoxication.
“Numerous degenerating oligodendrocytes (i.e., condensed and/or fragmented nuclei of cells in a chain-like formation) can be seen in the corpus callosum as early as 2 days after initiation of the cuprizone intoxication.”
From How to Use the Cuprizone Model to Study De- and Remyelination (2024) · cites this paper as [45]
The Results section (‘Oligodendroglial cell death occurs early in cuprizone-induced demyelination’; page not provided) reports apoptotic oligodendrocytes two days after cuprizone began and describes condensed or fragmented nuclei in the corpus callosum at later measured time points. It does not establish that the day-two cells were numerous or arranged in a chain-like formation. (LLM, conf=0.86)
Experimental — accuracy not yet measuredDuring cuprizone-induced demyelination, oligodendrocytes start to undergo apoptosis after 3-7 days of cuprizone exposure.
“During cuprizone-induced demyelination, oligodendrocytes start to undergo apoptosis after 3–7 days of cuprizone exposure (Mason et al., 2000a; Komoly, 2005; Hesse et al., 2010).”
From Glial response during cuprizone-induced de- and remyelination in the CNS: lessons learned (2014) · cites this paper as Hesse et al., 2010
The Results section reports apoptotic oligodendrocytes on day 6, within the claimed 3–7-day window. But it also reports apoptotic oligodendrocytes 2 days after the diet began, so the paper does not support 3–7 days as the time apoptosis starts. (LLM, conf=0.87)
Experimental — accuracy not yet measuredInitially oligodendrocytes die due to caspase-3-dependent apoptosis, while later caspase-3-independent apoptosis predominates.
“Thus, it seems that initially oligodendrocytes are dying due to caspase-3-dependent apoptosis, while later caspase-3-independent apoptosis predominates.”
From Glial response during cuprizone-induced de- and remyelination in the CNS: lessons learned (2014) · cites this paper as Hesse et al., 2010
The Results report activated caspase 3 in 97 ± 5% of apoptotic cells on day 6, falling to none of the dying cells on day 21. The Discussion interprets this as a possible switch to caspase-3-independent cell death in the cuprizone model, but treats the involvement of apoptotic-like mechanisms at later stages as speculation rather than establishing that caspase-3-independent apoptosis predominates. (LLM, conf=0.84)
Experimental — accuracy not yet measuredBy the end of the first week of cuprizone consumption, dying oligodendrocyte nuclei are almost all condensed, fragmented, and co-label with CC-3.
“Hesse and colleagues measured cell death based on nuclear morphology and found that by the end of the first week of cuprizone consumption, dying oligodendrocyte nuclei are almost all condensed, fragmented, and co-label with CC-3 [278].”
From Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination (2022) · cites this paper as [278]
Oligodendrocytes undergo apoptosis during cuprizone toxicity.
“Oligodendrocytes undergo apoptosis during cuprizone toxicity.”
From Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination (2022) · cites this paper as [278]
Oligodendrocyte degeneration is an early and specific event in the cuprizone model.
“Oligodendrocyte degeneration is an early and specific event in the cuprizone model.”
From How to Use the Cuprizone Model to Study De- and Remyelination (2024) · cites this paper as [45]
Oligodendrocyte degeneration is paralleled by a pronounced reduction in cells staining positive for mature oligodendrocyte marker proteins such as APC/CC1, GSTπ, or Nogo-A.
“Oligodendrocyte degeneration is paralleled by a pronounced reduction in cells staining positive for mature oligodendrocyte marker proteins, such as Adenomatous-polyposis-coli protein (APC), which is recognized by the CC1 antibody, Glutathione S-Transferase π (GSTπ), or Nogo-A [22,45,49].”
From How to Use the Cuprizone Model to Study De- and Remyelination (2024) · cites this paper as [45]
FAS is not essential for the induction of apoptosis in the cuprizone model.
“However, oligodendrocyte death was not prevented in mice lacking FAS in oligodendrocytes revealing that FAS is also not essential for the induction of apoptosis in the cuprizone model (Hesse et al., 2010).”
From Glial response during cuprizone-induced de- and remyelination in the CNS: lessons learned (2014) · cites this paper as Hesse et al., 2010
After 3 weeks of cuprizone treatment, mature oligodendrocytes are almost completely depleted.
“After 3 weeks of cuprizone treatment mature oligodendrocytes are almost completely depleted (Hesse et al., 2010; Skripuletz et al., 2011b).”
From Glial response during cuprizone-induced de- and remyelination in the CNS: lessons learned (2014) · cites this paper as Hesse et al., 2010
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“Oligodendrocyte degeneration is paralleled by a pronounced reduction in cells staining positive for mature oligodendrocyte marker proteins, such as Adenomatous-polyposis-coli protein (APC), which is recognized by the CC1 antibody, Glutathione S-Transferase π (GST π ), or Nogo-A [22,45,49].”
Background
- Authors
- Hesse, A., Wagner, M., Held, J., Brück, W., Salinas-Riester, G., Hao, Z., Waisman, A., & Kuhlmann, T.
- Affiliations
- University Hospital Münster (DE)
- Universitätsmedizin Göttingen (DE)
- University Health Network (CA)
- Johannes Gutenberg University Mainz (DE)
- Corresponding author
- Kuhlmann, Tanja
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2010-02
- Volume
- 37
- Issue
- 2
- Pages
- 362-369
- ISSN
- 0969-9961 (ISSN-L)
- PMC
- PMC7127175
- OpenAlex
- W2057093333
- Cited by
- 98
- References
- 1
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 4 · 2023: 9 · 2022: 7 · 2021: 4 · 2020: 8 · 2019: 6 · 2018: 7 · 2017: 7 · 2016: 2 · 2015: 6 · 2014: 7 · 2013: 8 · 2012: 8
- FWCI
- 2.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- GRO (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- oligodendrocyte death, cuprizone, Fas, caspase-3, apoptosis, multiple sclerosis, experimental autoimmune encephalomyelitis, corpus callosum, demyelinating disease
- MeSH terms
- Animals, Corpus Callosum, Cuprizone, Cytotoxins, Demyelinating Diseases, Disease Models, Animal, Female, Gene Expression Regulation, Male, Mice, Inbred C57BL, Mice, Transgenic, Myelin Proteins, Nerve Fibers, Myelinated, Oligodendroglia, RNA, Messenger, Signal Transduction, Down-Regulation, Cell Death, fas Receptor, Mice, Caspase 3
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