Oligodendroglial glycolytic stress triggers inflammasome activation and neuropathology in Alzheimer’s disease

Zhang, Xinwen; Wang, Rihua; Hu, Di; Sun, Xiaoyan; Fujioka, Hisashi; Lundberg, Kathleen; Chan, Ernest R.; Wang, Quanqiu; Xu, Rong; Flanagan, Margaret E.; Pieper, Andrew A.; Qi, Xin

doi:10.1126/sciadv.abb8680

Cited by 200Inflammasome and immune disordersAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

Oligodendroglial glycolytic stress triggers inflammasome activation and neuropathology in Alzheimer’s disease

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Zhang, Xinwen, Wang, Rihua, Hu, Di, Sun, Xiaoyan, Fujioka, Hisashi, Lundberg, Kathleen, Chan, Ernest R., Wang, Quanqiu +4 more·2020·Science Advances

DOI 10.1126/sciadv.abb8680PMC PMC7717916

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Abstract

The Drp1-HK1-NLRP3 axis is a key mechanism of oligodendrocyte damage and white matter degeneration in AD.

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Nearly all studies of oligodendrocytes and myelin in amyloid mouse models of AD have focused on the effect of amyloid plaques and Aβ on oligodendrocytes and myelin, partially describing secondary demyelination or hypomyelination.
“Nearly all have focused on the effect of amyloid plaques and Aβ on oligodendrocytes and myelin, partially describing secondary demyelination or hypomyelination.”
From Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease (2023) · cites this paper as [21]
The Discussion (page unavailable) describes studies in amyloid mouse models linking Aβ accumulation to oligodendrocyte damage and myelin degeneration. It does not establish that nearly all such studies focused on these effects or characterized the myelin changes as secondary demyelination or hypomyelination. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Only a few studies have experimentally investigated oligodendrocytes and myelin in amyloid mouse models of AD.
“Only a few studies have experimentally investigated oligodendrocytes and myelin in amyloid mouse models of AD20,21,41–43.”
From Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease (2023) · cites this paper as [21]

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Mitochondrial Behavior in Axon Degeneration and Regeneration
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HK2: a potential regulator of osteoarthritis via glycolytic and non-glycolytic pathways
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Neurotoxic β-amyloid oligomers cause mitochondrial dysfunction—the trigger for PANoptosis in neurons
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Cholesterol Metabolism in Aging and Age-Related Disorders
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Pyroptosis in development, inflammation and disease
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Current Insights Into Oligodendrocyte Metabolism and Its Power to Sculpt the Myelin Landscape
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The role of mitochondria-associated membranes mediated ROS on NLRP3 inflammasome in cardiovascular diseases
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Increased pyroptosis activation in white matter microglia is associated with neuronal loss in ALS motor cortex
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Implications of glial metabolic dysregulation in the pathophysiology of neurodegenerative diseases
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Hesperetin ameliorates spinal cord injury by inhibiting NLRP3 inflammasome activation and pyroptosis through enhancing Nrf2 signaling
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Heterogeneity and Molecular Markers for CNS Glial Cells Revealed by Single-Cell Transcriptomics
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Mechanistic and therapeutic role of NLRP3 inflammasome in the pathogenesis of Alzheimer's disease
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Cell type-specific potential pathogenic genes and functional pathways in Alzheimer’s Disease
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Combination of DNA demethylation and chemotherapy to trigger cell pyroptosis for inhalation treatment of lung cancer
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Mitochondrial Quality Control Strategies: Potential Therapeutic Targets for Neurodegenerative Diseases?
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Myelin Repair: From Animal Models to Humans
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Reelin links Apolipoprotein E4, Tau, and Amyloid‐β in Alzheimer’s disease
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Drp1 and neuroinflammation: Deciphering the interplay between mitochondrial dynamics imbalance and inflammation in neurodegenerative diseases
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Glial Cells and Brain Diseases: Inflammasomes as Relevant Pathological Entities
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Maintenance of mitochondrial homeostasis for Alzheimer's disease: Strategies and challenges
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Role of the caspase-8/RIPK3 axis in Alzheimer’s disease pathogenesis and Aβ-induced NLRP3 inflammasome activation
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Inflammasome-Mediated Neuroinflammation: A Key Driver in Alzheimer’s Disease Pathogenesis
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Improved Immunotherapy for Gastric Cancer by Nanocomposites with Capability of Triggering Dual-Damage of Nuclear/Mitochondrial DNA and Cgas/Sting-Mediated Innate Immunity
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mtDNA Maintenance and Alterations in the Pathogenesis of Neurodegenerative Diseases
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Secondary White Matter Injury Mediated by Neuroinflammation after Intracerebral Hemorrhage and Promising Therapeutic Strategies of Targeting the NLRP3 Inflammasome
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Development and in vivo Evaluation of Hydroxy-α-Sanshool Intranasal Liposomes as a Potential Remedial Treatment for Alzheimer’s Disease
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The Potential of NLRP3 Inflammasome as a Therapeutic Target in Neurological Diseases
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Dynasore Alleviates LPS-Induced Acute Lung Injury by Inhibiting NLRP3 Inflammasome-Mediated Pyroptosis
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Mitochondria and Other Organelles in Neural Development and Their Potential as Therapeutic Targets in Neurodegenerative Diseases
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Research progress of NLRP3 inflammasome and its inhibitors with aging diseases
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The Significance of NLRP Inflammasome in Neuropsychiatric Disorders
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Inhibiting mitochondrial inflammation through Drp1/ HK1 / NLRP3 pathway: A mechanism of alpinetin attenuated aging‐associated cognitive impairment
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Bio–Nano Toolbox for Precision Alzheimer's Disease Gene Therapy
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White matter injury, cholesterol dysmetabolism, and APP/Abeta dysmetabolism interact to produce Alzheimer’s disease (AD) neuropathology: A hypothesis and review
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Microglial immunometabolism endophenotypes contribute to sex difference in Alzheimer's disease
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Anti-Neuroinflammatory Effects of Ginkgo biloba Extract EGb 761 in LPS-Activated BV2 Microglial Cells
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OTUD1 exacerbates sepsis-associated encephalopathy by promoting HK2 mitochondrial release to drive microglia pyroptosis
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Hydroxysafflor yellow A protects against colitis in mice by suppressing pyroptosis via inhibiting HK1/NLRP3/GSDMD and modulating gut microbiota
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Resveratrol protects against a high-fat diet-induced neuroinflammation by suppressing mitochondrial fission via targeting SIRT1/PGC-1α
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Development and in vivo Evaluation of Hydroxy-α-Sanshool Intranasal Liposomes as a Potential Remedial Treatment for Alzheimer’s Disease
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Role of mitochondrial stress and the NLRP3 inflammasome in lung diseases
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Latest assessment methods for mitochondrial homeostasis in cognitive diseases
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Inhibition of the interaction between microglial adenosine 2A receptor and NLRP3 inflammasome attenuates neuroinflammation posttraumatic brain injury
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Greater Diffusion Restriction in White Matter in Preclinical Alzheimer Disease
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The role of dynamin-related protein 1 in cerebral ischemia/hypoxia injury
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Berberine modulates microglial polarization by activating TYROBP in Alzheimer's disease
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Physical Exercise Counteracts Aging-Associated White Matter Demyelination Causing Cognitive Decline
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Inflammasome activation in peritumoral astrocytes is a key player in breast cancer brain metastasis development
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Gasdermin D activation in oligodendrocytes and microglia drives inflammatory demyelination in progressive multiple sclerosis
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Inhibition of NLRP3 inflammasome activation and pyroptosis with the ethyl acetate fraction of Bungeanum ameliorated cognitive dysfunction in aged mice
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Glycolytic dysregulation in Alzheimer’s disease: unveiling new avenues for understanding pathogenesis and improving therapy
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Demyelination-derived lysophosphatidylserine promotes microglial dysfunction and neuropathology in a mouse model of Alzheimer’s disease
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The metabolic engine of cognition: microglia–neuron interactions in health, ageing and disease
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Neurovascular glial unit: A target of phytotherapy for cognitive impairments
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Mechanism of effect and therapeutic potential of NLRP3 inflammasome in spinal cord injury
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A Conceptual Model-Based Approach to Improve the Representation and Management of Omics Data in Precision Medicine
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Reactive Oxygen Species as a Common Pathological Link Between Alcohol Use Disorder and Alzheimer’s Disease with Therapeutic Implications
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Pyroptosis in Alzheimer’s Disease: Mechanisms and Therapeutic Potential
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White Matter Damage in Alzheimer’s Disease: Contribution of Oligodendrocytes
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Recognizing Alzheimer's disease from perspective of oligodendrocytes: Phenomena or pathogenesis?
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The emerging role of exercise in Alzheimer’s disease: Focus on mitochondrial function
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CMPK2 facilitates pain sensitization by promoting the lactylation and deactivation of cGAS-STING pathway in neuropathic pain
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Emerging Role of Oligodendrocytes Malfunction in the Progression of Alzheimer's Disease
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Bridging the Gap: Investigating the Link between Inflammasomes and Postoperative Cognitive Dysfunction
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The impact of glycolysis on ischemic stroke: from molecular mechanisms to clinical applications
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Glutamine limits NLRP3 inflammasome activation and pyroptosis in macrophages by sustaining the IRG1 /itaconate axis
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Microvascular and cellular dysfunctions in Alzheimer’s disease: an integrative analysis perspective
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The significance of glycolysis index and its correlations with immune infiltrates in Alzheimer’s disease
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Organelle stress in NLRP3 inflammasome: a central mediator of neurodegenerative diseases
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miR-483-5p-Containing exosomes treatment ameliorated deep vein thrombosis‑induced inflammatory response
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Emerging evidence for compromised axonal bioenergetics and axoglial metabolic coupling as drivers of neurodegeneration
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Mitochondrial modulation treating postoperative cognitive dysfunction neuroprotection via DRP1 inhibition by Mdivi1
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NLRP3-Mediated Glutaminolysis Regulates Microglia in Alzheimer's DiseasePreprint
McManus, R. M., Komes, M. P., Griep, A., Santarelli, F., Schwartz, S., Perea, J. R., Khalil, M., Lauterbach, M. A. R., Heinemann, L., Schlüter, T., et al. (2022) · SSRN Electronic Journal · doi:10.2139/ssrn.4178538 · Cited by 5 · see citing works
NLRP3-mediated glutaminolysis controls microglial phagocytosis to promote Alzheimer’s disease progression
McManus, R. M., Komes, M. P., Griep, A., Santarelli, F., Schwartz, S., Perea, J. R., Schlachetzki, J. C. M., Bouvier, D. S., Khalil, M., Lauterbach, M., et al. (2025) · Immunity · doi:10.1016/j.immuni.2025.01.007 · Cited by 76 · see citing works
Microglial NLRP3 Inflammasomes in Alzheimer’s Disease Pathogenesis: From Interaction with Autophagy/Mitophagy to Therapeutics
Ayyubova, G., & Madhu, L. N. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-04758-z · Cited by 23 · see citing works
NLRP3 regulates microglial metabolic function in Alzheimer’s disease
McManus, R. M., Komes, M. P., Griep, A., Santarelli, F., Schwartz, S., Khalil, M., Lauterbach, M. A. R., Gómez-Cabrero, D., Tegner, J. N., Hiller, K., et al. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.065598 · Cited by 3 · see citing works
NLRP3 Inflammasome: A Starring Role in Amyloid-β- and Tau-Driven Pathological Events in Alzheimer’s Disease
Zeller, M. V., Dias, D., Sebastião, A. M., & Valente, C. A. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210268 · Cited by 173 · see citing works

Authors: Zhang, X., Wang, R., Hu, D., Sun, X., Fujioka, H., Lundberg, K., Chan, E. R., Wang, Q., Xu, R., Flanagan, M. E., Pieper, A. A., & Qi, X.
Affiliations: Case Western Reserve University (US)
Northwestern University (US)
University Hospitals of Cleveland (US)
Corresponding author: Qi, Xin
ORCID: Zhang, Xinwen
Hu, Di
Sun, Xiaoyan
Fujioka, Hisashi
Lundberg, Kathleen
Chan, Ernest R.
Xu, Rong
Flanagan, Margaret E.
Pieper, Andrew A.
Qi, Xin
Venue: Science Advances
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2020-12-04
Volume: 6
Issue: 49
ISSN: 2375-2548 (ISSN-L)
DOI: 10.1126/sciadv.abb8680
PMC: PMC7717916
OpenAlex: W3107280407
Cited by: 200
References: 61
Citations by year: 2026: 24 · 2025: 49 · 2024: 44 · 2023: 43 · 2022: 29 · 2021: 10
FWCI: 6.65
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by-nc
creativecommons.org/licenses/by-nc/4.0/ (vor)
Locations: Science Advances (publishedVersion, cc-by-nc)
PubMed Central (publishedVersion, cc-by-nc)
PubMed (publishedVersion)
Funders: Dr. Ralph and Marian Falk Medical Research Foundation Transformative Award
Pilot fund from Department of Physiology and Biophysics, Case Western Reserve University
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: Alzheimer's disease, oligodendrocytes, NLRP3 inflammasome, gasdermin D, Drp1, mitochondrial fission, hexokinase 1, demyelination, white matter degeneration, axonal degeneration, neuroinflammation, cognitive impairment
MeSH terms: NLR Family, Pyrin Domain-Containing 3 Protein, Alzheimer Disease, Animals, Glycolysis, Humans, Oligodendroglia, Mice, Inflammasomes

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Oligodendroglial glycolytic stress triggers inflammasome activation and neuropathology in Alzheimer’s disease

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