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Cited by 97Neurogenesis and neuroplasticity mechanismsAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

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Oligodendrocyte progenitor cells in Alzheimer's disease: from physiology to pathology

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Zou, Peibin, Wu, Chongyun, Liu, Timon Cheng-Yi, Duan, Rui, Yang, Luodan·2023·Translational Neurodegeneration
DOI 10.1186/s40035-023-00385-7PMC PMC10644503
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Abstract

Oligodendrocyte progenitor cells (OPCs) play pivotal roles in myelin formation and phagocytosis, communicating with neighboring cells and contributing to the integrity of the blood–brain barrier (BBB). However, under the pathological circumstances of Alzheimer’s disease (AD), the brain’s microenvironment undergoes detrimental changes that significantly impact OPCs and their functions. Starting with OPC functions, we delve into the transformation of OPCs to myelin-producing oligodendrocytes, the intricate signaling interactions with other cells in the central nervous system (CNS), and the fascinating process of phagocytosis, which influences the function of OPCs and affects CNS homeostasis. Moreover, we discuss the essential role of OPCs in BBB formation and highlight the critical contribution of OPCs in forming CNS-protective barriers. In the context of AD, the deterioration of the local microenvironment in the brain is discussed, mainly focusing on neuroinflammation, oxidative stress, and the accumulation of toxic proteins. The detrimental changes disturb the delicate balance in the brain, impacting the regenerative capacity of OPCs and compromising myelin integrity. Under pathological conditions, OPCs experience significant alterations in migration and proliferation, leading to impaired differentiation and a reduced ability to produce mature oligodendrocytes. Moreover, myelin degeneration and formation become increasingly active in AD, contributing to progressive neurodegeneration. Finally, we summarize the current therapeutic approaches targeting OPCs in AD. Strategies to revitalize OPC senescence, modulate signaling pathways to enhance OPC differentiation, and explore other potential therapeutic avenues are promising in alleviating the impact of AD on OPCs and CNS function. In conclusion, this review highlights the indispensable role of OPCs in CNS function and their involvement in the pathogenesis of AD. The intricate interplay between OPCs and the AD brain microenvironment underscores the complexity of neurodegenerative diseases. Insights from studying OPCs under pathological conditions provide a foundation for innovative therapeutic strategies targeting OPCs and fostering neurodegeneration. Future research will advance our understanding and management of neurodegenerative diseases, ultimately offering hope for effective treatments and improved quality of life for those affected by AD and related disorders.

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Fig. 1 The process of oligodendrocyte progenitor cell (OPC) myelination varies during different stages. a During development, OPCs generated from neural stem cells rapidly form myelin sheaths, and a fraction of OPCs will be reserved in the stem cell pool. b In adulthood, upon demyelination, OPCs residing in the stem cell pool are swiftly recruited to the site of injury along the vasculature, where they proliferate and differentiate to initiate remyelination
Fig. 1 The process of oligodendrocyte progenitor cell (OPC) myelination varies during different stages. a During development, OPCs generated from neural stem cells rapidly form myelin sheaths, and a fraction of OPCs will be reserved in the stem cell pool. b In adulthood, upon demyelination, OPCs residing in the stem cell pool are swiftly recruited to the site of injury along the vasculature, where they proliferate and differentiate to initiate remyelinationCC BY · PubMed Central
Fig. 2 AD pathology and alterations in OPC-related events under pathological circumstances of AD. Under AD pathological conditions, alterations in mitochondrial structure and function result in an overproduction of reactive oxygen species (ROS), leading to oxidative damage of subcellular structures and fragmentation of mitochondria. The oxidative damage and mitochondrial fragmentation further induce inflammatory responses, involving changes in microglial and astrocyte phenotypes. Pro-inflammatory DAM type microglia and DAA type astrocytes release pro-inflammatory cytokines, exacerbating mitochondrial dysfunction and oxidative stress, culminating in a vicious cycle termed “mitochondrial dysfunction-oxidative stress-inflammation response.” Consequently, these changes exacerbate the AD pathology. Within unfavorable cerebral microenvironment, OPC myelination-related events are adversely affected to varying degrees
Fig. 2 AD pathology and alterations in OPC-related events under pathological circumstances of AD. Under AD pathological conditions, alterations in mitochondrial structure and function result in an overproduction of reactive oxygen species (ROS), leading to oxidative damage of subcellular structures and fragmentation of mitochondria. The oxidative damage and mitochondrial fragmentation further induce inflammatory responses, involving changes in microglial and astrocyte phenotypes. Pro-inflammatory DAM type microglia and DAA type astrocytes release pro-inflammatory cytokines, exacerbating mitochondrial dysfunction and oxidative stress, culminating in a vicious cycle termed “mitochondrial dysfunction-oxidative stress-inflammation response.” Consequently, these changes exacerbate the AD pathology. Within unfavorable cerebral microenvironment, OPC myelination-related events are adversely affected to varying degreesCC BY · PubMed Central
Fig. 3 Myelin dysfunction drives Aβ deposition. Myelin dysfunction and demyelination injury are also upstream risk factors contributing to formation of Aβ plaques in AD. Mechanistically, myelin dysfunction may exacerbate the accumulation of the Aβ-producing machinery within axonal swellings and cause the increased cleavage of cortical amyloid precursor protein. In addition, the microglia originally responsible for Aβ clearance are increasingly drawn to demyelination sites, reducing Aβ clearance
Fig. 3 Myelin dysfunction drives Aβ deposition. Myelin dysfunction and demyelination injury are also upstream risk factors contributing to formation of Aβ plaques in AD. Mechanistically, myelin dysfunction may exacerbate the accumulation of the Aβ-producing machinery within axonal swellings and cause the increased cleavage of cortical amyloid precursor protein. In addition, the microglia originally responsible for Aβ clearance are increasingly drawn to demyelination sites, reducing Aβ clearanceCC BY · PubMed Central
Fig. 4 Strategies targeting OPC differentiation-associated signaling pathways in AD. Strategies targeting OPC differentiation-associated signaling pathways include the mammalian target of rapamycin (mTOR) signaling agonist and retinoid X receptor (RXR) signaling agonist. a Streamline illustration. b Detailed molecular pathway diagrams: The mTOR inhibitor promotes OPC differentiation by downregulating p-mTOR and promoting autophagy-related genes. Elevated autophagy enhances OPC differentiation and myelination. RXR activation promotes Aβ clearance, inhibits Aβ generation, and modulates neuronal function. In addition, the interaction between RXR, ABCA1, and ApoE plays a crucial role in modulating cholesterol transport genes. The enhanced cholesterol transport gene expressions promote OPC differentiation
Fig. 4 Strategies targeting OPC differentiation-associated signaling pathways in AD. Strategies targeting OPC differentiation-associated signaling pathways include the mammalian target of rapamycin (mTOR) signaling agonist and retinoid X receptor (RXR) signaling agonist. a Streamline illustration. b Detailed molecular pathway diagrams: The mTOR inhibitor promotes OPC differentiation by downregulating p-mTOR and promoting autophagy-related genes. Elevated autophagy enhances OPC differentiation and myelination. RXR activation promotes Aβ clearance, inhibits Aβ generation, and modulates neuronal function. In addition, the interaction between RXR, ABCA1, and ApoE plays a crucial role in modulating cholesterol transport genes. The enhanced cholesterol transport gene expressions promote OPC differentiationCC BY · PubMed Central

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Metadata

Authors
Zou, P., Wu, C., Liu, T. C.-Y., Duan, R., & Yang, L.
Affiliations
  • Louisiana State University (US)
  • South China Normal University (CN)
Corresponding author
Yang, Luodan
ORCID
Venue
Translational Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2023-11-14
Volume
12
Issue
1
Pages
52-52
ISSN
2047-9158 (ISSN-L)
DOI
10.1186/s40035-023-00385-7
PMC
PMC10644503
OpenAlex
W4388667039
Cited by
97
References
274
Citations by year
2026: 34 · 2025: 49 · 2024: 14
FWCI
3.72
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Neurodegeneration (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (31971096, 32100918)
  • China Postdoctoral Science Foundation (2021M690060, 2022T150227)
  • Sigma Xi Grants in Aid of Research (GIAR) program (G03152021115804390)
  • Guangzhou Scientific Research Grant (SL2022B04J00013, SL2024A04J00578)
  • SCNU Young Faculty Development Program (22KJ04)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
oligodendrocyte precursor cells, Alzheimer's disease, myelination, phagocytosis, blood-brain barrier, neuroinflammation, oxidative stress, amyloid-beta, tau protein, OPC differentiation, myelin degeneration, neurodegeneration, cellular senescence
MeSH terms
Oligodendrocyte Precursor Cells, Alzheimer Disease, Cell Differentiation, Humans, Oligodendroglia, Quality of Life

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